TRAF6 (TNF receptor-associated factor 6) is a critical E3 ubiquitin ligase and signal transduction adaptor that synthesizes K63-linked polyubiquitin chains for non-degradative signaling. It serves as a central hub in multiple immune signaling pathways including TLR/IL-1R, TNF receptor superfamily (CD40, RANK), and cytosolic pattern recognition receptors, mediating activation of NF-ฮบB and MAPK pathways. Beyond immunity, TRAF6 is essential for osteoclast differentiation, ectodermal development (hair, teeth, sweat glands), and has emerging roles in autophagy regulation. The protein contains an N-terminal RING domain for E3 ligase activity, zinc fingers, and a C-terminal TRAF domain for protein-protein interactions, enabling both enzymatic and scaffolding functions in signal transduction.
Summary: TRAF6 functions as an E3 ubiquitin ligase that catalyzes K63-linked polyubiquitination, which is essential for its signal transduction role. This activity is well-established through multiple experimental studies showing TRAF6 works with the Ubc13-Uev1A E2 complex to synthesize K63-linked chains on target proteins including itself.
Reason: This is a core molecular function of TRAF6 that is extensively validated experimentally. The IEA annotation from sequence similarity is strongly supported by multiple experimental evidence entries (EXP, IDA) in the same dataset and extensive literature.
Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain
file:human/TRAF6/TRAF6-deep-research.md
TRAF6 functions as a ubiquitin-protein transferase (E3 ubiquitin ligase) (GO:0004842), assembling Lysine-63โlinked polyubiquitin chains on target proteins (including itself) in cooperation with the E2 enzyme complex Ubc13โUev1A
file:human/TRAF6/TRAF6-deep-research-falcon.md
TRAF6 catalyzes ubiquitin transfer in the canonical E1โE2โE3 cascade as an **E3 ligase**, promoting formation of polyubiquitin chains that serve primarily as **non-degradative signaling scaffolds**
Site-specific Lys-63-linked tumor necrosis factor receptor-associated factor 6 auto-ubiquitination is a critical determinant of I kappa B kinase activation
Summary: TRAF6 binds to TNF receptor superfamily members including CD40 and RANK through its TRAF-C domain, mediating signal transduction from these receptors.
Reason: This is a well-established function of TRAF6. Although annotated as IEA, it represents a core adaptor function that is experimentally validated in the literature. TRAF6 directly binds cytoplasmic tails of TNF receptor superfamily members.
Supporting Evidence:
file:human/TRAF6/TRAF6-deep-research.md
TRAF6 directly interacts with a variety of upstream receptors and signaling proteins... from the TNF receptor superfamily
file:human/TRAF6/TRAF6-deep-research.md
In the TNF receptor superfamily pathways, TRAF6 associates with receptors like CD40 and RANK to propagate signals leading to NF-ฮบB activation
file:human/TRAF6/TRAF6-deep-research-falcon.md
TRAF6 binds receptor cytoplasmic domains such as **RANK** in RANKL signaling to coordinate downstream activation of MAPKs/AKT and NF-ฮบB/NFATc1 programs that drive osteoclastogenesis
IPI
PMID:10465784
ECSIT is an evolutionarily conserved intermediate in the Tol...
REMOVE
Summary: Generic protein binding annotation based on protein interaction data.
Reason: GO:0005515 (protein binding) is too general and uninformative for a well-characterized protein like TRAF6. More specific molecular function terms should be used instead based on the actual binding partners and contexts.
Supporting Evidence:
file:human/TRAF6/TRAF6-deep-research.md
TRAF6 binds to cytoplasmic motifs (typically PxQxT sequences) on receptors or adaptors such as CD40, RANK (TNFRSF11A), IL-1R
IPI
PMID:11279055
A diverse family of proteins containing tumor necrosis facto...
REMOVE
Summary: Another generic protein binding annotation.
Reason: GO:0005515 (protein binding) is too general and uninformative for a well-characterized protein like TRAF6. More specific molecular function terms should be used instead based on the actual binding partners and contexts.
Supporting Evidence:
file:human/TRAF6/TRAF6-deep-research.md
As an adaptor, TRAF6 directly interacts with a variety of upstream receptors and signaling proteins
Summary: TRAF6 knockout mice show perinatal lethality with developmental defects, particularly in ectodermal structures.
Reason: TRAF6 is essential for embryonic development, with knockout mice showing perinatal lethality. The developmental role is particularly important for ectodermal development.
Supporting Evidence:
file:human/TRAF6/TRAF6-deep-research.md
TRAF6-null mutants are perinatal lethal with a complex phenotype
file:human/TRAF6/TRAF6-deep-research.md
TRAF6 is required for lymph node organogenesis during embryonic development
GO:0002637
regulation of immunoglobulin production
IEA
GO_REF:0000107
ACCEPT
Summary: TRAF6 mediates CD40 signaling in B cells which is important for immunoglobulin class switching and production.
Reason: TRAF6 plays a role in B cell activation through CD40 signaling, which contributes to immunoglobulin production. While not the most central function, it is a validated consequence of TRAF6's role in immune signaling.
Supporting Evidence:
file:human/TRAF6/TRAF6-deep-research.md
Via CD40 in B cells, TRAF6 helps induce immunoglobulin production
Summary: TRAF6 is central to innate and adaptive immune responses through TLR, IL-1R, and TNF receptor signaling.
Reason: While correct, this term is too broad. TRAF6's role should be specified as 'innate immune response' (GO:0045087) which better captures its primary function in TLR and IL-1R signaling.
TRAF6 plays an essential role in numerous biological processes, particularly those related to immune system function... A major process controlled by TRAF6 is the innate immune response (GO:0045087)
Summary: TRAF6 is required for development of ectodermal organs including hair follicles, teeth, and sweat glands.
Reason: While TRAF6 is involved in organ morphogenesis, the annotation should be more specific. TRAF6's role is particularly in 'ectodermal development' and 'odontogenesis'.
TRAF6 has an indispensable role in ectodermal organ development: it is involved in the formation of skin appendages such as hair follicles, teeth, and sweat glands
GO:0019886
antigen processing and presentation of exogenous peptide antigen via MHC class II
IEA
GO_REF:0000107
KEEP AS NON CORE
Summary: TRAF6 may play a role in dendritic cell function and antigen presentation.
Reason: While TRAF6 is expressed in dendritic cells and contributes to their activation, antigen presentation is not a core function but rather a downstream consequence of TRAF6's role in immune cell signaling.
TRAF6 is a signal transducer that activates IkappaB kinase (IKK) and Jun amino-terminal kinase (JNK) in response to pro-inflammatory mediators such as interleukin-1 (IL-1) and lipopolysaccharides (LPS)
GO:0032735
positive regulation of interleukin-12 production
IEA
GO_REF:0000107
KEEP AS NON CORE
Summary: TRAF6 contributes to cytokine production through NF-ฮบB activation in immune cells.
Reason: This is a downstream effect of TRAF6's role in TLR/IL-1R signaling rather than a core function. The primary role is signal transduction leading to NF-ฮบB activation, with cytokine production being a consequence.
Supporting Evidence:
file:human/TRAF6/TRAF6-deep-research.md
TRAF6 is required for the production of proinflammatory cytokines (such as IL-6, TNF-ฮฑ) in response to pathogenic stimuli
GO:0032755
positive regulation of interleukin-6 production
IEA
GO_REF:0000107
KEEP AS NON CORE
Summary: TRAF6-mediated NF-ฮบB activation leads to IL-6 production in immune responses.
Reason: Like IL-12 regulation, this is a downstream consequence of TRAF6's signaling function rather than a direct core activity. The core function is NF-ฮบB activation.
Supporting Evidence:
file:human/TRAF6/TRAF6-deep-research.md
TRAF6 is required for the production of proinflammatory cytokines (such as IL-6, TNF-ฮฑ)
Summary: TRAF6 in dendritic cells contributes to T cell priming and differentiation.
Reason: This is a downstream immunological outcome of TRAF6 function in dendritic cells, not a direct core function. TRAF6's primary role is in signal transduction.
Supporting Evidence:
file:human/TRAF6/TRAF6-deep-research.md
TRAF6 in dendritic cells is needed for Th priming
GO:0042475
odontogenesis of dentin-containing tooth
IEA
GO_REF:0000107
ACCEPT
Summary: TRAF6 is essential for tooth development through EDAR signaling pathway.
Reason: TRAF6 knockout mice and human mutations show clear tooth development defects. This is a specific developmental function mediated through EDAR signaling.
Supporting Evidence:
file:human/TRAF6/TRAF6-deep-research.md
TRAF6^โ/โ mice display features of hypohidrotic ectodermal dysplasia (HED), including missing or malformed hair and sweat glands
file:human/TRAF6/TRAF6-deep-research.md
A de novo heterozygous missense mutation in TRAF6 was identified in a patient with Hypohidrotic Ectodermal Dysplasia, who presented with... hypodontia (missing teeth)
Summary: TRAF6 plays a role in dendritic cell development and function.
Reason: While TRAF6 is involved in dendritic cell signaling, cell differentiation is not its primary function. This is more of a consequence of its signaling role.
Summary: Overly broad term for TRAF6's role in specific cell types.
Reason: This term is too generic. TRAF6 has specific roles in osteoclast differentiation and ectodermal cell development that should be annotated more precisely.
Another critical biological process involving TRAF6 is osteoclast differentiation and bone resorption
GO:0007249
canonical NF-kappaB signal transduction
IDA
PMID:1406630
Selection of optimal kappa B/Rel DNA-binding motifs: interac...
ACCEPT
Summary: TRAF6 is a central mediator of NF-ฮบB activation through K63-linked ubiquitination. RETIRED - PMID:1406630 no longer in GOA.
Reason: This is one of TRAF6's core functions, extensively validated experimentally. TRAF6 mediates NF-ฮบB activation in multiple pathways through its E3 ligase activity.
Selection of optimal kappa B/Rel DNA-binding motifs: interaction of both subunits of NF-kappa B with DNA is required for transcriptional activation.
file:human/TRAF6/TRAF6-deep-research-falcon.md
A central, repeatedly cited role is TRAF6 in **TLR/IL-1 receptor family signaling**, where TRAF6 is recruited downstream of receptor-proximal adaptors/kinases to promote TAK1 and IKK activation, leading to NF-ฮบB and MAPK transcriptional programs
IDA
PMID:11460167
TAK1 is a ubiquitin-dependent kinase of MKK and IKK
ACCEPT
Summary: TRAF6 mediates antibacterial responses through TLR signaling, particularly TLR4 response to LPS.
Reason: TRAF6 is essential for TLR-mediated responses to bacterial components like LPS. This is a well-validated function through its role in innate immunity.
TRAF6 is a signal transducer that activates IkappaB kinase (IKK) and Jun amino-terminal kinase (JNK) in response to pro-inflammatory mediators such as interleukin-1 (IL-1) and lipopolysaccharides (LPS)
file:human/TRAF6/TRAF6-deep-research.md
TRAF6-deficient cells fail to activate NF-ฮบB and MAP kinases in response to lipopolysaccharide (TLR4 ligand)
GO:0043123
positive regulation of canonical NF-kappaB signal transduction
IDA
PMID:11460167
TAK1 is a ubiquitin-dependent kinase of MKK and IKK
ACCEPT
Summary: TRAF6 positively regulates NF-ฮบB through K63-linked ubiquitination of signaling components.
Reason: Core function of TRAF6 with strong experimental support. TRAF6's E3 ligase activity is essential for NF-ฮบB activation.
TAK1 kinase complex phosphorylates and activates IKK in a manner that depends on TRAF6 and Ubc13-Uev1A
GO:0043124
negative regulation of canonical NF-kappaB signal transduction
IDA
PMID:25038658
Identification of a NFฮบB inhibitory peptide from tryptic ฮฒ-c...
UNDECIDED
Summary: TRAF6 can negatively regulate NF-ฮบB under certain conditions.
Reason: This annotation seems contradictory to TRAF6's well-established role as a positive regulator of NF-ฮบB. Without access to PMID:25038658, cannot determine if this represents a specific feedback mechanism or experimental context.
IDA
PMID:27746020
The K48-K63 Branched Ubiquitin Chain Regulates NF-ฮบB Signali...
ACCEPT
Summary: TRAF6 catalyzes K48-linked ubiquitination under specific
conditions in addition to its canonical K63-linked activity.
The falcon deep research confirms participation in K48-linked
ubiquitination (Li 2024 TNF context; Ayyasamy 2024 JBC shows
14-3-3ฮถ-driven K48-linked TRAF6 degradation). Per PR #833 review
feedback, the earlier UNDECIDED has been resolved by the falcon
evidence; action changed UNDECIDED โ ACCEPT.
Reason: The K48-linked ubiquitination activity of TRAF6 is documented
both as a self-degradation pathway (14-3-3ฮถ-driven K48-linked
TRAF6 degradation, Ayyasamy 2024 JBC) and in TNF-context
branched K48-K63 chain signaling. While K63 remains TRAF6's
dominant linkage, the K48-linked activity is a real (minor)
function established by multiple recent studies.
IDA
PMID:21931555
Vaccinia virus protein C6 is a virulence factor that binds T...
ACCEPT
Summary: TRAF6 participates in RIG-I/MAVS antiviral signaling pathways.
Reason: TRAF6 functions in cytosolic pattern recognition receptor pathways including RIG-I/MAVS for antiviral responses. This extends its role beyond membrane receptors.
Supporting Evidence:
file:human/TRAF6/TRAF6-deep-research.md
TRAF6 also links to the RIG-I/MAVS antiviral pathway and other cytosolic pattern-recognition receptor pathways, functioning as a key molecule in antiviral innate signaling
IDA
PMID:23202584
Structure of the human ATG12~ATG5 conjugate required for LC3...
ACCEPT
Summary: TRAF6 promotes autophagy through ubiquitination of autophagy regulators like Beclin-1.
Reason: Emerging function of TRAF6 in autophagy regulation through K63-linked ubiquitination of autophagy machinery. Multiple studies support this non-canonical role.
Supporting Evidence:
file:human/TRAF6/TRAF6-deep-research.md
TRAF6 has been shown to interact with autophagy regulators (such as Beclin-1 and AMBRA1) and can promote autophagic degradation of certain substrates
Dec 2. Structure of the human ATG12~ATG5 conjugate required for LC3 lipidation in autophagy.
GO:0038061
non-canonical NF-kappaB signal transduction
IDA
PMID:12048232
Quantitative prediction of NF-kappa B DNA-protein interactio...
ACCEPT
Summary: TRAF6 can activate non-canonical NF-ฮบB pathway.
Reason: While TRAF6 primarily activates canonical NF-ฮบB, it can also contribute to non-canonical pathway activation in certain contexts, particularly through NIK stabilization.
IDA
PMID:14703513
Identification of Ser-386 of interferon regulatory factor 3 ...
ACCEPT
Summary: TRAF6 mediates antiviral responses through RIG-I/MAVS and IRF activation.
Reason: TRAF6 participates in antiviral signaling, particularly through cytosolic sensors and can activate IRF7 for interferon production.
Supporting Evidence:
file:human/TRAF6/TRAF6-deep-research.md
TRAF6 helps activate not only NF-ฮบB but also interferon-regulatory factors; for instance, it can activate IRF7 in response to cytosolic viral DNA/RNA detection
IDA
PMID:9891032
Essential role of interferon regulatory factor 3 in direct a...
MODIFY
Summary: TRAF6 may have nuclear functions in transcriptional regulation.
Reason: This term is too broad and doesn't capture TRAF6's specific role. TRAF6 primarily regulates transcription indirectly through NF-ฮบB and MAPK activation, not as a direct transcriptional regulator. Should be 'positive regulation of transcription by RNA polymerase II' with qualifier specifying it acts through signal transduction.
In osteoclast nuclei, TRAF6 was found to act as a co-regulator of transcription, in complex with nuclear adaptor protein FHL2 and transcription factor RUNX1
IDA
PMID:23776175
SASH1 is a scaffold molecule in endothelial TLR4 signaling.
ACCEPT
Summary: TRAF6 undergoes autoubiquitination with K63-linked chains as part of its signaling mechanism.
Reason: TRAF6 autoubiquitination is a key aspect of its signaling mechanism. The K63-linked autoubiquitination creates docking sites for downstream signaling proteins.
Supporting Evidence:
file:human/TRAF6/TRAF6-deep-research.md
upon receptor stimulation, TRAF6 autoubiquitination and K63-ubiquitin conjugation create docking sites for the TAK1 kinase complex
IPI
PMID:10514511
TRAF family proteins interact with the common neurotrophin r...
REMOVE
Summary: The generic protein binding term does not provide informative functional annotation. TRAF6 binds many specific proteins as part of its scaffolding function, but this general term should be removed in favor of more specific molecular function terms.
Reason: GO:0005515 (protein binding) is too general and uninformative for a well-characterized protein like TRAF6. The specific protein interactions and their functional contexts are better captured by more specific GO terms.
IPI
PMID:10920205
T6BP, a TRAF6-interacting protein involved in IL-1 signaling...
REMOVE
Summary: The generic protein binding term does not provide informative functional annotation. TRAF6 binds many specific proteins as part of its scaffolding function, but this general term should be removed in favor of more specific molecular function terms.
Reason: GO:0005515 (protein binding) is too general and uninformative for a well-characterized protein like TRAF6. The specific protein interactions and their functional contexts are better captured by more specific GO terms.
IPI
PMID:11463333
Isolation and characterization of two novel A20-like protein...
REMOVE
Summary: The generic protein binding term does not provide informative functional annotation. TRAF6 binds many specific proteins as part of its scaffolding function, but this general term should be removed in favor of more specific molecular function terms.
Reason: GO:0005515 (protein binding) is too general and uninformative for a well-characterized protein like TRAF6. The specific protein interactions and their functional contexts are better captured by more specific GO terms.
IPI
PMID:11518704
IRAK-mediated translocation of TRAF6 and TAB2 in the interle...
REMOVE
Summary: The generic protein binding term does not provide informative functional annotation. TRAF6 binds many specific proteins as part of its scaffolding function, but this general term should be removed in favor of more specific molecular function terms.
Reason: GO:0005515 (protein binding) is too general and uninformative for a well-characterized protein like TRAF6. The specific protein interactions and their functional contexts are better captured by more specific GO terms.
IPI
PMID:11751921
A novel zinc finger protein that inhibits osteoclastogenesis...
REMOVE
Summary: The generic protein binding term does not provide informative functional annotation. TRAF6 binds many specific proteins as part of its scaffolding function, but this general term should be removed in favor of more specific molecular function terms.
Reason: GO:0005515 (protein binding) is too general and uninformative for a well-characterized protein like TRAF6. The specific protein interactions and their functional contexts are better captured by more specific GO terms.
IPI
PMID:12140561
Distinct molecular mechanism for initiating TRAF6 signalling...
REMOVE
Summary: The generic protein binding term does not provide informative functional annotation. TRAF6 binds many specific proteins as part of its scaffolding function, but this general term should be removed in favor of more specific molecular function terms.
Reason: GO:0005515 (protein binding) is too general and uninformative for a well-characterized protein like TRAF6. The specific protein interactions and their functional contexts are better captured by more specific GO terms.
Summary: The generic protein binding term does not provide informative functional annotation. TRAF6 binds many specific proteins as part of its scaffolding function, but this general term should be removed in favor of more specific molecular function terms.
Reason: GO:0005515 (protein binding) is too general and uninformative for a well-characterized protein like TRAF6. The specific protein interactions and their functional contexts are better captured by more specific GO terms.
Interleukin-1 (IL-1) receptor-associated kinase-dependent IL-1-induced signaling complexes phosphorylate TAK1 and TAB2 at the plasma membrane and activate TAK1 in the cytosol.
IPI
PMID:12496252
Pellino 1 is required for interleukin-1 (IL-1)-mediated sign...
REMOVE
Summary: The generic protein binding term does not provide informative functional annotation. TRAF6 binds many specific proteins as part of its scaffolding function, but this general term should be removed in favor of more specific molecular function terms.
Reason: GO:0005515 (protein binding) is too general and uninformative for a well-characterized protein like TRAF6. The specific protein interactions and their functional contexts are better captured by more specific GO terms.
2002 Dec 20. Pellino 1 is required for interleukin-1 (IL-1)-mediated signaling through its interaction with the IL-1 receptor-associated kinase 4 (IRAK4)-IRAK-tumor necrosis factor receptor-associated factor 6 (TRAF6) complex.
IPI
PMID:15280356
Induction of apoptosis by X-linked ectodermal dysplasia rece...
REMOVE
Summary: The generic protein binding term does not provide informative functional annotation. TRAF6 binds many specific proteins as part of its scaffolding function, but this general term should be removed in favor of more specific molecular function terms.
Reason: GO:0005515 (protein binding) is too general and uninformative for a well-characterized protein like TRAF6. The specific protein interactions and their functional contexts are better captured by more specific GO terms.
IPI
PMID:15998638
Vaccinia virus protein A52R activates p38 mitogen-activated ...
REMOVE
Summary: The generic protein binding term does not provide informative functional annotation. TRAF6 binds many specific proteins as part of its scaffolding function, but this general term should be removed in favor of more specific molecular function terms.
Reason: GO:0005515 (protein binding) is too general and uninformative for a well-characterized protein like TRAF6. The specific protein interactions and their functional contexts are better captured by more specific GO terms.
IPI
PMID:16189514
Towards a proteome-scale map of the human protein-protein in...
REMOVE
Summary: The generic protein binding term does not provide informative functional annotation. TRAF6 binds many specific proteins as part of its scaffolding function, but this general term should be removed in favor of more specific molecular function terms.
Reason: GO:0005515 (protein binding) is too general and uninformative for a well-characterized protein like TRAF6. The specific protein interactions and their functional contexts are better captured by more specific GO terms.
IPI
PMID:16286467
Interleukin-1beta induction of NFkappaB is partially regulat...
REMOVE
Summary: The generic protein binding term does not provide informative functional annotation. TRAF6 binds many specific proteins as part of its scaffolding function, but this general term should be removed in favor of more specific molecular function terms.
Reason: GO:0005515 (protein binding) is too general and uninformative for a well-characterized protein like TRAF6. The specific protein interactions and their functional contexts are better captured by more specific GO terms.
Reason: Core function of TRAF6 with strong experimental support. TRAF6 is essential for NF-ฮบB activation through multiple pathways.
Supporting Evidence:
file:human/TRAF6/TRAF6-deep-research.md
TRAF6 is pivotal signal transducer that links receptor-proximal events to activation of key transcription factors... leading to activation of IฮบB kinase (IKK) and MAP kinases
eCollection 2021. Defining the Role of Nuclear Factor (NF)-ฮบB p105 Subunit in Human Macrophage by Transcriptomic Analysis of NFKB1 Knockout THP1 Cells.
IKK-1 and IKK-2: cytokine-activated IkappaB kinases essential for NF-kappaB activation.
GO:0043124
negative regulation of canonical NF-kappaB signal transduction
IDA
PMID:27746020
The K48-K63 Branched Ubiquitin Chain Regulates NF-ฮบB Signali...
UNDECIDED
Summary: TRAF6 may negatively regulate NF-ฮบB under specific conditions.
Reason: This annotation contradicts TRAF6's well-established role as a positive regulator of NF-ฮบB. May represent a feedback mechanism or specific experimental context that needs verification.
IDA
PMID:23524951
mTOR inhibits autophagy by controlling ULK1 ubiquitylation, ...
ACCEPT
Summary: TRAF6 regulates autophagy through K63-ubiquitination of autophagy proteins.
Reason: TRAF6 plays an established role in autophagy regulation by ubiquitinating key autophagy proteins like Beclin-1 and AMBRA1, promoting autophagosome assembly.
Supporting Evidence:
file:human/TRAF6/TRAF6-deep-research.md
TRAF6 has been shown to interact with autophagy regulators (such as Beclin-1 and AMBRA1) and can promote autophagic degradation of certain substrates
Epub 2017 Sep 7. The ER-Localized Transmembrane Protein EPG-3/VMP1 Regulates SERCA Activity to Control ER-Isolation Membrane Contacts for Autophagosome Formation.
IDA
PMID:34796041
Hepatitis B virus X Protein Promotes Liver Cancer Progressio...
ACCEPT
Summary: TRAF6 participates in cytosolic pattern recognition receptor pathways.
Reason: TRAF6 functions in RIG-I/MAVS and other cytosolic PRR pathways, mediating antiviral responses.
Supporting Evidence:
file:human/TRAF6/TRAF6-deep-research.md
TRAF6 also links to the RIG-I/MAVS antiviral pathway and other cytosolic pattern-recognition receptor pathways, functioning as a key molecule in antiviral innate signaling
Polyubiquitination of Transforming Growth Factor ฮฒ-activated Kinase 1 (TAK1) at Lysine 562 Residue Regulates TLR4-mediated JNK and p38 MAPK Activation.
GO:0038061
non-canonical NF-kappaB signal transduction
IDA
PMID:26189595
Polyubiquitination of Transforming Growth Factor ฮฒ-activated...
ACCEPT
Summary: TRAF6 can participate in non-canonical NF-ฮบB signaling in specific contexts.
Reason: While TRAF6 primarily activates canonical NF-ฮบB, it can also contribute to non-canonical pathway activation in certain contexts, particularly through NIK stabilization and p100 processing.
Polyubiquitination of Transforming Growth Factor ฮฒ-activated Kinase 1 (TAK1) at Lysine 562 Residue Regulates TLR4-mediated JNK and p38 MAPK Activation.
GO:0007249
canonical NF-kappaB signal transduction
IDA
PMID:10882101
TAB2, a novel adaptor protein, mediates activation of TAK1 M...
ACCEPT
Summary: TRAF6 mediates canonical NF-ฮบB activation through K63-linked ubiquitination.
Reason: This is one of TRAF6's core functions. TRAF6 is essential for NF-ฮบB activation in response to multiple stimuli including TLR and TNF receptor signaling.
IPI
PMID:10094049
The kinase TAK1 can activate the NIK-I kappaB as well as the...
REMOVE
Summary: The generic protein binding term does not provide informative functional annotation. TRAF6 binds many specific proteins as part of its scaffolding function, but this general term should be removed in favor of more specific molecular function terms.
Reason: GO:0005515 (protein binding) is too general and uninformative for a well-characterized protein like TRAF6. The specific protein interactions and their functional contexts are better captured by more specific GO terms.
IPI
PMID:11728344
A novel TNF receptor family member binds TWEAK and is implic...
REMOVE
Summary: The generic protein binding term does not provide informative functional annotation. TRAF6 binds many specific proteins as part of its scaffolding function, but this general term should be removed in favor of more specific molecular function terms.
Reason: GO:0005515 (protein binding) is too general and uninformative for a well-characterized protein like TRAF6. The specific protein interactions and their functional contexts are better captured by more specific GO terms.
IPI
PMID:11397809
IRAK1b, a novel alternative splice variant of interleukin-1 ...
REMOVE
Summary: The generic protein binding term does not provide informative functional annotation. TRAF6 binds many specific proteins as part of its scaffolding function, but this general term should be removed in favor of more specific molecular function terms.
Reason: GO:0005515 (protein binding) is too general and uninformative for a well-characterized protein like TRAF6. The specific protein interactions and their functional contexts are better captured by more specific GO terms.
2001 Jun 7. IRAK1b, a novel alternative splice variant of interleukin-1 receptor-associated kinase (IRAK), mediates interleukin-1 signaling and has prolonged stability.
IPI
PMID:11238466
Equine herpesvirus protein E10 induces membrane recruitment ...
REMOVE
Summary: The generic protein binding term does not provide informative functional annotation. TRAF6 binds many specific proteins as part of its scaffolding function, but this general term should be removed in favor of more specific molecular function terms.
Reason: GO:0005515 (protein binding) is too general and uninformative for a well-characterized protein like TRAF6. The specific protein interactions and their functional contexts are better captured by more specific GO terms.
IPI
PMID:15121867
TRAF family proteins link PKR with NF-kappa B activation.
REMOVE
Summary: The generic protein binding term does not provide informative functional annotation. TRAF6 binds many specific proteins as part of its scaffolding function, but this general term should be removed in favor of more specific molecular function terms.
Reason: GO:0005515 (protein binding) is too general and uninformative for a well-characterized protein like TRAF6. The specific protein interactions and their functional contexts are better captured by more specific GO terms.
IPI
PMID:12459498
NF-kappaB activator Act1 associates with IL-1/Toll pathway a...
REMOVE
Summary: The generic protein binding term does not provide informative functional annotation. TRAF6 binds many specific proteins as part of its scaffolding function, but this general term should be removed in favor of more specific molecular function terms.
Reason: GO:0005515 (protein binding) is too general and uninformative for a well-characterized protein like TRAF6. The specific protein interactions and their functional contexts are better captured by more specific GO terms.
Summary: The generic protein binding term does not provide informative functional annotation. TRAF6 binds many specific proteins as part of its scaffolding function, but this general term should be removed in favor of more specific molecular function terms.
Reason: GO:0005515 (protein binding) is too general and uninformative for a well-characterized protein like TRAF6. The specific protein interactions and their functional contexts are better captured by more specific GO terms.
Toll/IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF) associates with TNF receptor-associated factor 6 and TANK-binding kinase 1, and activates two distinct transcription factors, NF-kappa B and IFN-regulatory factor-3, in the Toll-like receptor signaling.
IPI
PMID:16378096
Association of beta-arrestin and TRAF6 negatively regulates ...
REMOVE
Summary: The generic protein binding term does not provide informative functional annotation. TRAF6 binds many specific proteins as part of its scaffolding function, but this general term should be removed in favor of more specific molecular function terms.
Reason: GO:0005515 (protein binding) is too general and uninformative for a well-characterized protein like TRAF6. The specific protein interactions and their functional contexts are better captured by more specific GO terms.
IPI
PMID:14982987
Toll-like receptor 3-mediated activation of NF-kappaB and IR...
REMOVE
Summary: The generic protein binding term does not provide informative functional annotation. TRAF6 binds many specific proteins as part of its scaffolding function, but this general term should be removed in favor of more specific molecular function terms.
Reason: GO:0005515 (protein binding) is too general and uninformative for a well-characterized protein like TRAF6. The specific protein interactions and their functional contexts are better captured by more specific GO terms.
IPI
PMID:15125833
The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activ...
REMOVE
Summary: The generic protein binding term does not provide informative functional annotation. TRAF6 binds many specific proteins as part of its scaffolding function, but this general term should be removed in favor of more specific molecular function terms.
Reason: GO:0005515 (protein binding) is too general and uninformative for a well-characterized protein like TRAF6. The specific protein interactions and their functional contexts are better captured by more specific GO terms.
IPI
PMID:11244088
The atypical protein kinase C-interacting protein p62 is a s...
REMOVE
Summary: The generic protein binding term does not provide informative functional annotation. TRAF6 binds many specific proteins as part of its scaffolding function, but this general term should be removed in favor of more specific molecular function terms.
Reason: GO:0005515 (protein binding) is too general and uninformative for a well-characterized protein like TRAF6. The specific protein interactions and their functional contexts are better captured by more specific GO terms.
IPI
PMID:12925853
SIGIRR, a negative regulator of Toll-like receptor-interleuk...
REMOVE
Summary: The generic protein binding term does not provide informative functional annotation. TRAF6 binds many specific proteins as part of its scaffolding function, but this general term should be removed in favor of more specific molecular function terms.
Reason: GO:0005515 (protein binding) is too general and uninformative for a well-characterized protein like TRAF6. The specific protein interactions and their functional contexts are better captured by more specific GO terms.
IPI
PMID:12270937
Role of TRAF3 and -6 in the activation of the NF-kappa B and...
REMOVE
Summary: The generic protein binding term does not provide informative functional annotation. TRAF6 binds many specific proteins as part of its scaffolding function, but this general term should be removed in favor of more specific molecular function terms.
Reason: GO:0005515 (protein binding) is too general and uninformative for a well-characterized protein like TRAF6. The specific protein interactions and their functional contexts are better captured by more specific GO terms.
Summary: TRAF6 functions as a signaling adaptor linking receptors to downstream pathways.
Reason: TRAF6 is a well-characterized signaling adaptor that bridges receptor complexes to downstream kinases and transcription factors, a core aspect of its function.
Supporting Evidence:
file:human/TRAF6/TRAF6-deep-research.md
As an adaptor, TRAF6 directly interacts with a variety of upstream receptors and signaling proteins
file:human/TRAF6/TRAF6-deep-research-falcon.md
TRAF6 is best understood as a **signal-proximal ubiquitin ligase/scaffold** that converts receptor stimulation into **polyubiquitin-based signaling scaffolds** which recruit and activate downstream kinases
Summary: TRAF6 is a well-characterized E3 ubiquitin ligase.
Reason: Core molecular function of TRAF6, extensively validated through experimental studies.
Supporting Evidence:
file:human/TRAF6/TRAF6-deep-research.md
TRAF6 functions as ubiquitin-protein transferase (E3 ubiquitin ligase)
file:human/TRAF6/TRAF6-deep-research-falcon.md
**TRAF6 (TNF receptor-associated factor 6)** is a human TRAF-family cytosolic signaling adaptor that also functions as a **RING-type E3 ubiquitin ligase** (EC 2.3.2.27)
Summary: TRAF6 contains zinc-binding domains essential for its structure.
Reason: TRAF6 has a RING domain and four zinc finger motifs that coordinate zinc ions.
Supporting Evidence:
file:human/TRAF6/TRAF6-deep-research.md
RING finger domain coordinates zinc and is characteristic of many E3 ubiquitin ligases
file:human/TRAF6/TRAF6-deep-research-falcon.md
conserved multi-domain architecture with **N-terminal RING** and multiple **zinc fingers**, a **coiled-coil/TRAF-N** region, and a **C-terminal TRAF-C/MATH (TRAF) domain**
Summary: TRAF6 binds to E2 enzymes like Ubc13-Uev1A.
Reason: TRAF6 directly binds E2 ubiquitin-conjugating enzymes for its E3 ligase function.
Supporting Evidence:
file:human/TRAF6/TRAF6-deep-research.md
TRAF6 RING domain binds the Ubc13-Uev1A heterodimer
file:human/TRAF6/TRAF6-deep-research-falcon.md
A 2024 inhibitor-discovery study notes a defined TRAF6โUbc13 interaction surface, highlighting TRAF6 residues **Gln54, Asp57, Ile72, Leu74** as contributing to E2 engagement
Summary: TRAF6 forms homo-oligomers essential for signaling.
Reason: TRAF6 forms homodimers and homotrimers required for its signaling function.
Supporting Evidence:
file:human/TRAF6/TRAF6-deep-research.md
TRAF6 can form homodimers and homotrimers
file:human/TRAF6/TRAF6-deep-research-falcon.md
In this family, the trimeric TRAF-C domain can act as a โcapโ and the TRAF-N coiled-coil as a โstalk,โ providing an interaction platform that positions the N-terminal RING/zinc-finger catalytic region for ubiquitin-chain assembly and signaling complex formation
Aug 14. The germinal center kinase TNIK is required for canonical NF-ฮบB and JNK signaling in B-cells by the EBV oncoprotein LMP1 and the CD40 receptor.
Nov 29. Site-specific Lys-63-linked tumor necrosis factor receptor-associated factor 6 auto-ubiquitination is a critical determinant of I kappa B kinase activation.
Reason: TRAF6 is present in the cytosol where it mediates signaling.
Supporting Evidence:
file:human/TRAF6/TRAF6-deep-research.md
TRAF6 is associated with cytosol
file:human/TRAF6/TRAF6-deep-research-falcon.md
Across recent primary studies, TRAF6 is described/observed as a **cytosolic adaptor** that associates with the **cytoplasmic tails of transmembrane receptors** and with inducible cytosolic signaling assemblies
GO:0007249
canonical NF-kappaB signal transduction
IEA
GO_REF:0000107
ACCEPT
Summary: TRAF6 is essential for IKK/NF-ฮบB signaling.
Reason: TRAF6 activates IKK complex leading to NF-ฮบB nuclear translocation.
Supporting Evidence:
file:human/TRAF6/TRAF6-deep-research.md
TRAF6 autoubiquitination create docking sites for the TAK1 kinase complex, leading to activation of IฮบB kinase
Summary: TRAF6 is essential for osteoclast differentiation.
Reason: TRAF6 mediates RANK signaling required for osteoclastogenesis.
Supporting Evidence:
file:human/TRAF6/TRAF6-deep-research.md
TRAF6 is the key signaling adaptor for RANK in osteoclast precursors
file:human/TRAF6/TRAF6-deep-research-falcon.md
TRAF6 is essential in **RANKLโRANK signaling**, acting as a key adaptor/E3 ligase required for osteoclastogenic downstream cascades (MAPK, PI3K/AKT, IฮบB phosphorylation) and NF-ฮบB activation
GO:0031666
positive regulation of lipopolysaccharide-mediated signaling pathway
IEA
GO_REF:0000107
ACCEPT
Summary: TRAF6 localizes to membrane complexes.
Reason: TRAF6 is recruited to receptor complexes at membranes.
Supporting Evidence:
file:human/TRAF6/TRAF6-deep-research.md
TRAF6 is recruited to receptor cytosolic tails at the plasma membrane
Reason: This is TRAF6's signature modification - K63-linked chains for signaling not degradation.
Supporting Evidence:
file:human/TRAF6/TRAF6-deep-research.md
TRAF6 catalyzes the formation of Lys 63 (K63)-linked polyubiquitin chain
file:human/TRAF6/TRAF6-deep-research-falcon.md
The most consistently supported E2 complex for TRAF6 is **Ubc13/UBE2NโUev1A/UBE2V1**, which is directly linked to TRAF6-mediated assembly of **K63-linked polyubiquitin chains**
Identification of TRAF6, a novel tumor necrosis factor receptor-associated factor protein that mediates signaling from an amino-terminal domain of the CD40 cytoplasmic region.
GO:0007249
canonical NF-kappaB signal transduction
2009 Dec 28. Lysine 63-linked polyubiquitination of TAK1 at lysine 158 is required for tumor necrosis factor alpha- and interleukin-1beta-induced IKK/NF-kappaB and JNK/AP-1 activation.
2009 Dec 28. Lysine 63-linked polyubiquitination of TAK1 at lysine 158 is required for tumor necrosis factor alpha- and interleukin-1beta-induced IKK/NF-kappaB and JNK/AP-1 activation.
2010 Nov 10. Bifunctional apoptosis regulator (BAR), an endoplasmic reticulum (ER)-associated E3 ubiquitin ligase, modulates BI-1 protein stability and function in ER Stress.
Nov 29. Site-specific Lys-63-linked tumor necrosis factor receptor-associated factor 6 auto-ubiquitination is a critical determinant of I kappa B kinase activation.
Nov 29. Site-specific Lys-63-linked tumor necrosis factor receptor-associated factor 6 auto-ubiquitination is a critical determinant of I kappa B kinase activation.
GO:0043507
positive regulation of JUN kinase activity
NAS
PMID:17135271
Site-specific Lys-63-linked tumor necrosis factor receptor-a...
KEEP AS NON CORE
Summary: Minor or context-specific TRAF6 function.
Nov 29. Site-specific Lys-63-linked tumor necrosis factor receptor-associated factor 6 auto-ubiquitination is a critical determinant of I kappa B kinase activation.
GO:0045892
negative regulation of DNA-templated transcription
Nov 29. Site-specific Lys-63-linked tumor necrosis factor receptor-associated factor 6 auto-ubiquitination is a critical determinant of I kappa B kinase activation.
GO:0043123
positive regulation of canonical NF-kappaB signal transduction
IDA
PMID:17135271
Site-specific Lys-63-linked tumor necrosis factor receptor-a...
Nov 29. Site-specific Lys-63-linked tumor necrosis factor receptor-associated factor 6 auto-ubiquitination is a critical determinant of I kappa B kinase activation.
GO:0045672
positive regulation of osteoclast differentiation
IDA
PMID:17135271
Site-specific Lys-63-linked tumor necrosis factor receptor-a...
ACCEPT
Summary: TRAF6 is essential for osteoclast differentiation.
Reason: TRAF6 mediates RANK signaling required for osteoclastogenesis.
Supporting Evidence:
file:human/TRAF6/TRAF6-deep-research.md
TRAF6 is the key signaling adaptor for RANK in osteoclast precursors
Nov 29. Site-specific Lys-63-linked tumor necrosis factor receptor-associated factor 6 auto-ubiquitination is a critical determinant of I kappa B kinase activation.
Nov 29. Site-specific Lys-63-linked tumor necrosis factor receptor-associated factor 6 auto-ubiquitination is a critical determinant of I kappa B kinase activation.
Reason: TRAF6 is present in the cytosol where it mediates signaling.
Supporting Evidence:
file:human/TRAF6/TRAF6-deep-research.md
TRAF6 is associated with cytosol
GO:0051092
obsolete positive regulation of NF-kappaB transcription factor activity
IDA
PMID:16378096
Association of beta-arrestin and TRAF6 negatively regulates ...
MODIFY
Summary: TRAF6 positively regulates NF-ฮบB activation. Term GO:0051092 is now obsolete; replaced by GO:0043123 (positive regulation of canonical NF-kappaB signal transduction).
Reason: Core function - TRAF6 activates NF-ฮบB through K63-ubiquitination. Original term obsoleted because it represented a molecular function.
IEA
PMID:18768464
Tumor necrosis factor receptor-associated factor 6 is an int...
NEW
Summary: TRAF6 acts as nuclear transcriptional co-regulator in osteoclasts
Reason: In osteoclast nuclei, TRAF6 forms complexes with FHL2 and transcription factor RUNX1, directly binding gene promoter elements to modulate transcription. This nuclear TRAF6-FHL2-RUNX1 complex regulates osteoclast-specific gene expression programs.
Summary: TRAF6 activates p38 MAPK through TAK1 activation
Reason: TRAF6-mediated K63-linked polyubiquitination recruits and activates the TAK1 kinase complex, which directly phosphorylates and activates p38 MAPK. This is a key branch of TRAF6 signaling leading to AP-1 activation and inflammatory gene expression.
Supporting Evidence:
file:human/TRAF6/TRAF6-deep-research.md
TRAF6 is involved in the AP-1 (c-Jun/Fos) pathway via activation of JNK and p38 MAPKs
GO:0045893
positive regulation of DNA-templated transcription
IEA
PMID:18768464
Tumor necrosis factor receptor-associated factor 6 is an int...
NEW
Summary: TRAF6 positively regulates transcription through NF-ฮบB and as nuclear co-regulator
Reason: TRAF6 activates transcription through two mechanisms - (1) cytoplasmic activation of NF-ฮบB and AP-1 transcription factors via ubiquitin signaling, and (2) direct nuclear function as part of TRAF6-FHL2-RUNX1 complex binding to gene promoters in osteoclasts.
Supporting Evidence:
file:human/TRAF6/TRAF6-deep-research.md
formation of a TRAF6โFHL2โRUNX1 complex in the nucleus enables binding to specific gene promoter elements and modulation of gene expression
Summary: TRAF6 oligomerizes and assembles multi-protein signaling complexes
Reason: TRAF6 trimerizes via its TRAF-C domain and coiled-coil regions to form signaling platforms. It assembles the Myddosome (MyD88-IRAK4-IRAK1 complex) in TLR signaling and recruits TAK1, TAB1/2, and IKK complexes through K63-ubiquitin scaffolds.
Supporting Evidence:
file:human/TRAF6/TRAF6-deep-research.md
TRAF6 is a component of several protein complexes (GO:0043234) in the cytoplasm, such as the Myddosome (MyD88โIRAK4โIRAK1 complex)
Summary: TRAF6 enables ectodermal development through EDAR receptor signal transduction
Reason: TRAF6 has an indispensable role in ectodermal organ development through EDAR signaling. It is involved in the formation of skin appendages such as hair follicles and teeth. This is a core function identified from literature but missing from existing annotations.
Supporting Evidence:
file:human/TRAF6/TRAF6-deep-research.md
TRAF6 has an indispensable role in ectodermal organ development: it is involved in the formation of skin appendages such as hair follicles, teeth, and sweat glands
IDA
PMID:18093978
Nuclear tumor necrosis factor receptor-associated factor 6 i...
ACCEPT
Summary: Cytoplasmic localization for TRAF6 is amply documented by the
falcon deep research (TRAF6 functions as a cytosolic signaling
adapter; condensate biology via ALPK1/TIFA). PMID:18093978
describes a context-specific NUCLEAR pool in lymphoid cells but
does not refute the dominant cytoplasmic localization. Per PR
#833 review feedback, resolved PENDING โ ACCEPT.
Reason: TRAF6 is canonically cytoplasmic โ the falcon deep research
explicitly describes cytosolic localization and signaling-
adapter function. The cited paper documents a context-specific
nuclear pool but does not refute cytoplasmic localization.
IDA
PMID:16378096
Association of beta-arrestin and TRAF6 negatively regulates ...
ACCEPT
Summary: Cytoplasmic localization is amply supported by the falcon deep
research (cytosolic signaling adapter; condensate biology with
ALPK1/TIFA). Per PR #833 review feedback, resolved PENDING โ
ACCEPT.
Reason: Canonical cytoplasmic localization of TRAF6, supported by the
falcon deep research and by the entire ACCEPTed cytoplasmic/
signaling adapter set of annotations in this review.
Supporting Evidence:
file:human/TRAF6/TRAF6-deep-research-falcon.md
TRAF6 is a cytosolic signaling adapter
Core Functions
Catalyzes K63-linked polyubiquitination of target proteins via RING E3 ligase activity
TRAF6, catalyses the formation of a Lys 63 (K63)-linked polyubiquitin chain that mediates IKK activation through a unique proteasome-independent mechanism
TRAF6, a RING domain protein, functions together with Ubc13/Uev1A to catalyze the synthesis of unique polyubiquitin chains linked through lysine-63 (K63) of ubiquitin
file:human/TRAF6/TRAF6-deep-research-falcon.md
The most consistently supported E2 complex for TRAF6 is **Ubc13/UBE2NโUev1A/UBE2V1**, which is directly linked to TRAF6-mediated assembly of **K63-linked polyubiquitin chains**
Transduces signals from TLR/IL-1R and TNF receptor superfamily to activate NF-ฮบB and MAPK pathways
TRAF6, catalyses the formation of a Lys 63 (K63)-linked polyubiquitin chain that mediates IKK activation through a unique proteasome-independent mechanism
TRAF6, a RING domain protein, functions together with Ubc13/Uev1A to catalyze the synthesis of unique polyubiquitin chains linked through lysine-63 (K63) of ubiquitin
Assembles receptor-proximal signaling complexes through TRAF-C domain-mediated protein interactions
TRAF6, catalyses the formation of a Lys 63 (K63)-linked polyubiquitin chain that mediates IKK activation through a unique proteasome-independent mechanism
TRAF6, a RING domain protein, functions together with Ubc13/Uev1A to catalyze the synthesis of unique polyubiquitin chains linked through lysine-63 (K63) of ubiquitin
Promotes osteoclast differentiation by mediating RANK signaling to transcription factors
TRAF6, catalyses the formation of a Lys 63 (K63)-linked polyubiquitin chain that mediates IKK activation through a unique proteasome-independent mechanism
TRAF6, a RING domain protein, functions together with Ubc13/Uev1A to catalyze the synthesis of unique polyubiquitin chains linked through lysine-63 (K63) of ubiquitin
Enables ectodermal development through EDAR receptor signal transduction
TRAF6, catalyses the formation of a Lys 63 (K63)-linked polyubiquitin chain that mediates IKK activation through a unique proteasome-independent mechanism
TRAF6, a RING domain protein, functions together with Ubc13/Uev1A to catalyze the synthesis of unique polyubiquitin chains linked through lysine-63 (K63) of ubiquitin
Initiates autophagosome formation via K63-ubiquitination of Beclin-1 and AMBRA1
TRAF6, catalyses the formation of a Lys 63 (K63)-linked polyubiquitin chain that mediates IKK activation through a unique proteasome-independent mechanism
TRAF6, a RING domain protein, functions together with Ubc13/Uev1A to catalyze the synthesis of unique polyubiquitin chains linked through lysine-63 (K63) of ubiquitin
Functions as transcriptional co-regulator in osteoclast nuclei with FHL2 and RUNX1
In osteoclast nuclei, TRAF6 was found to act as a co-regulator of transcription, in complex with nuclear adaptor protein FHL2 and transcription factor RUNX1
Mediates antiviral innate immunity through RIG-I/MAVS pathway activation and IRF7 ubiquitination
TRAF6, catalyses the formation of a Lys 63 (K63)-linked polyubiquitin chain that mediates IKK activation through a unique proteasome-independent mechanism
TRAF6, a RING domain protein, functions together with Ubc13/Uev1A to catalyze the synthesis of unique polyubiquitin chains linked through lysine-63 (K63) of ubiquitin
TAK1 is a ubiquitin-dependent kinase of MKK and IKK
TRAF6 activates IKK and JNK in response to pro-inflammatory mediators
"TRAF6 is a signal transducer that activates IkappaB kinase (IKK) and Jun amino-terminal kinase (JNK) in response to pro-inflammatory mediators such as interleukin-1 (IL-1) and lipopolysaccharides (LPS)."
TRAF6 catalyzes K63-linked polyubiquitin chains for IKK activation
"This Ubc complex, together with TRAF6, catalyses the formation of a Lys 63 (K63)-linked polyubiquitin chain that mediates IKK activation through a unique proteasome-independent mechanism."
Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain
TRAF6 functions with Ubc13/Uev1A to catalyze K63-linked polyubiquitin chain synthesis
"TRAF6, a RING domain protein, functions together with Ubc13/Uev1A to catalyze the synthesis of unique polyubiquitin chains linked through lysine-63 (K63) of ubiquitin."
K63-linked polyubiquitin chain synthesis is required for IKK activation
"Blockade of this polyubiquitin chain synthesis, but not inhibition of the proteasome, prevents the activation of IKK by TRAF6."
Site-specific Lys-63-linked tumor necrosis factor receptor-associated factor 6 auto-ubiquitination is a critical determinant of I kappa B kinase activation
TRAF6 Lys-63-linked auto-ubiquitination is critical for IKK activation
"Site-specific Lys-63-linked tumor necrosis factor receptor-associated factor 6 auto-ubiquitination is a critical determinant of I kappa B kinase activation."
Tumor necrosis factor receptor-associated factor 6 is an intranuclear transcriptional coactivator in osteoclasts
file:human/TRAF6/TRAF6-deep-research.md
Deep research synthesis of TRAF6 literature
file:human/TRAF6/TRAF6-deep-research-falcon.md
Falcon deep research report on TRAF6
TRAF6 is a cytosolic RING-type E3 ubiquitin ligase and signaling adaptor with N-terminal RING/zinc fingers and C-terminal MATH/TRAF-C receptor-binding domain
"**TRAF6 (TNF receptor-associated factor 6)** is a human TRAF-family cytosolic signaling adaptor that also functions as a **RING-type E3 ubiquitin ligase** (EC 2.3.2.27). Recent literature consistently describes a conserved multi-domain architecture with **N-terminal RING** and multiple **zinc fingers**, a **coiled-coil/TRAF-N** region, and a **C-terminal TRAF-C/MATH (TRAF) domain** responsible for receptor/adaptor binding"
TRAF6 converts receptor stimulation into polyubiquitin-based signaling scaffolds that recruit and activate TAK1 and IKK to drive NF-ฮบB and MAPK activation
"Functionally, TRAF6 is best understood as a **signal-proximal ubiquitin ligase/scaffold** that converts receptor stimulation into **polyubiquitin-based signaling scaffolds** which recruit and activate downstream kinases (e.g., TAK1 and IKK) to drive **NF-ฮบB** and **MAPK** activation"
TRAF6 catalyzes ubiquitin transfer as an E3 ligase, primarily forming non-degradative signaling polyubiquitin chains rather than proteasomal degradation tags
"TRAF6 catalyzes ubiquitin transfer in the canonical E1โE2โE3 cascade as an **E3 ligase**, promoting formation of polyubiquitin chains that serve primarily as **non-degradative signaling scaffolds**, rather than proteasomal degradation signals"
TRAF6 partners with the Ubc13/UBE2NโUev1A/UBE2V1 E2 complex to assemble K63-linked polyubiquitin chains
"The most consistently supported E2 complex for TRAF6 is **Ubc13/UBE2NโUev1A/UBE2V1**, which is directly linked to TRAF6-mediated assembly of **K63-linked polyubiquitin chains**"
Representative K63-modified TRAF6 signaling substrates include IKKฮณ/NEMO, TAK1, IRAK1, and TRAF6 itself; TRAF6 can also participate in K48-linked ubiquitination in selected contexts
"Representative TRAF6-linked K63-modified signaling substrates/adaptors cited in 2024 review pages include **IKKฮณ/NEMO, TAK1, IRAK1, and TRAF6 itself**... The same review corpus notes that TRAF6 can participate in **K48-linked** ubiquitination in selected contexts, indicating that TRAF6 signaling can be coupled to regulated proteostasis depending on cellular conditions"
TRAF6 is a cytosolic adaptor that associates with the cytoplasmic tails of transmembrane receptors and with inducible cytosolic signaling assemblies
"Across recent primary studies, TRAF6 is described/observed as a **cytosolic adaptor** that associates with the **cytoplasmic tails of transmembrane receptors** and with inducible cytosolic signaling assemblies"
TRAF6 binds the RANK cytoplasmic domain in RANKL signaling to coordinate downstream MAPK/AKT and NF-ฮบB/NFATc1 programs that drive osteoclastogenesis
"**Receptor-proximal complexes (RANK):** TRAF6 binds receptor cytoplasmic domains such as **RANK** in RANKL signaling to coordinate downstream activation of MAPKs/AKT and NF-ฮบB/NFATc1 programs that drive osteoclastogenesis"
TRAF6 forms cytosolic liquid-like condensates with TIFA upon ADP-heptose sensing, acting as microreactors that concentrate ubiquitin machinery and downstream effectors
"In response to ADP-heptose and other inflammatory stimuli, TRAF6 can form **cytosolic liquid-like condensates** (LLPS) with dynamic exchange properties (20โ60% FRAP recovery in ~5 min), which are proposed to function as โmicroreactorsโ concentrating ubiquitin machinery and downstream effectors"
TRAF6 is recruited downstream of receptor-proximal adaptors in TLR/IL-1R family signaling to promote TAK1 and IKK activation and NF-ฮบB/MAPK programs
"A central, repeatedly cited role is TRAF6 in **TLR/IL-1 receptor family signaling**, where TRAF6 is recruited downstream of receptor-proximal adaptors/kinases to promote TAK1 and IKK activation, leading to NF-ฮบB and MAPK transcriptional programs"
TRAF6 is essential in RANKL/RANK signaling, acting as a key adaptor/E3 ligase required for osteoclastogenic downstream cascades (MAPK, PI3K/AKT, IฮบB phosphorylation) and NF-ฮบB activation
"TRAF6 is essential in **RANKLโRANK signaling**, acting as a key adaptor/E3 ligase required for osteoclastogenic downstream cascades (MAPK, PI3K/AKT, IฮบB phosphorylation) and NF-ฮบB activation"
EBV LMP1 uses a direct TRAF6-binding motif (P379VQLSY in the CTAR2 region) to drive NF-ฮบB/JNK/p38/IRF7 signaling and lymphoma cell survival, distinct from the CD40โTRAF6 interface
"A major 2024 development is the high-resolution demonstration that EBV **LMP1** uses a **direct TRAF6-binding motif** (CTAR2 region) to drive NF-ฮบB/JNK/p38/IRF7 signaling and lymphoma cell survival... Importantly, structural/functional analyses indicate the **LMP1โTRAF6 interface differs from CD40โTRAF6**"
14-3-3ฮถ binds TRAF6 after RANKL stimulation, reduces the RANKโTRAF6 interaction, and promotes TRAF6 ubiquitination and proteasome-dependent degradation, dampening downstream RANKL signaling
"Ayyasamy et al. (2024-07; https://doi.org/10.1016/j.jbc.2024.107487) show that **14-3-3ฮถ** binds TRAF6 (interaction increases rapidly after RANKL stimulation), reduces the **RANKโTRAF6 interaction**, and promotes **TRAF6 ubiquitination and proteasome-dependent degradation**, dampening downstream RANKL signaling"
Within TIFA condensates, TRAF6 amplifies K63-linked polyubiquitin synthesis when reconstituted with E1 and the Ubc13/Uev1A E2 complex
"Li et al. (2024-01; https://doi.org/10.34133/research.0315) report that during ALPK1/TIFA-dependent sensing of bacterial ADP-heptose, TRAF6 undergoes stimulus-dependent **LLPS** and is recruited into **TIFA condensates**. Within these condensates, TRAF6 markedly amplifies **K63-linked polyubiquitin synthesis** when reconstituted with E1 and the **Ubc13/Uev1A** E2 complex"
TRAF6 signaling output is determined by higher-order mesoscale organization into condensates that retain K63 chains and concentrate enzymatic components, not only by enzyme identity
"TRAF6 signaling output is not only determined by enzyme identity (E2 pairing and linkage type), but also by **higher-order mesoscale organization** (condensates that retain long K63 chains and concentrate enzymatic components)"
Other TRAF6 pathways include CD40/TRAF6, IL-17R via Act1, TCR via CARMA1โBCL10โMALT1, TLR7/8/9โMYD88โIRF7, and ALPK1โTIFAโTRAF6 innate sensing
"Additional pathways in recent review/primary papers include **CD40/TRAF6-related signaling**, **IL-17R via Act1**, **TCR via CARMA1โBCL10โMALT1**, **TLR7/8/9โMYD88โIRF7**, and **ALPK1โTIFAโTRAF6** innate sensing"
TRAF6 should be annotated as a cytosolic receptor-proximal E3 ubiquitin ligase/adaptor whose primary biochemical output is Ubc13/Uev1A-dependent K63 polyubiquitin chain assembly, enabling recruitment/activation of TAK1/IKK and MAPK modules
"TRAF6 should be annotated as a **cytosolic receptor-proximal E3 ubiquitin ligase/adaptor** whose primary biochemical output is **Ubc13/Uev1A-dependent K63 polyubiquitin chain assembly**, enabling recruitment/activation of TAK1/IKK and MAPK modules to drive inflammatory and differentiation programs"
A diverse family of proteins containing tumor necrosis factor receptor-associated factor domains.
MUL and USP7 bind to TRAF6 through their TRAF domains
"MUL and USP7 are capable of binding in vitro via their TDs to all of the previously identified TRAF family proteins (TRAF1, TRAF2, TRAF3, TRAF4, TRAF5, and TRAF6), whereas the TD of SPOP interacts weakly with TRAF1 and TRAF6 only."
MUL and USP7 TRAF domains suppress TRAF6-induced NF-kappaB activation
"Analysis of various MUL and USP7 mutants by transient transfection assays indicated that the TDs of these proteins are necessary and sufficient for suppressing NF-kappaB induction by TRAF2 and TRAF6 as well as certain TRAF-binding TNF family receptors."
T6BP, a TRAF6-interacting protein involved in IL-1 signaling.
T6BP specifically associates with TRAF6 through its N-terminal ring finger and zinc finger domains
"We report the identification of a TRAF-interacting protein, T6BP, that specifically associates with TRAF6. This interaction occurs between the coiled-coil region of T6BP and the N-terminal ring finger and zinc finger domains of TRAF6."
IL-1 induces TRAF6-T6BP complex formation in an IRAK-dependent manner
"IL-1, but not tumor necrosis factor, induces TRAF6-T6BP complex formation in a ligand-dependent manner. Formation of the TRAF6-T6BP complex depends on the presence of the IL-1 receptor-associated kinase (IRAK)."
IRAK-mediated translocation of TRAF6 and TAB2 in the interleukin-1-induced activation of NFkappa B.
IRAK mediates IL-1-induced translocation of TRAF6 and TAB2 from membrane to cytosol
"When IRAK is phosphorylated in response to IL-1, it binds to the membrane where it forms a complex with TRAF6; TRAF6 then dissociates and translocates to the cytosol. The membrane-bound IRAK similarly mediates the IL-1-induced translocation of TAB2 from the membrane to the cytosol."
TRAF6-TAK1-TAB1-TAB2 complex formation in cytosol is required for TAK1 activation
"The translocation of TAB2 and TRAF6 is needed to form a TRAF6-TAK1-TAB1-TAB2 complex in the cytosol and thus activate TAK1."
Distinct molecular mechanism for initiating TRAF6 signalling.
TRAF6 recognizes a Pro-X-Glu-X-X-(aromatic/acidic) binding motif in receptors and adaptors
"The structural determinant of the petide TRAF6 interaction reveals a Pro-X-Glu-X-X-(aromatic/acidic residue) TRAF6-binding motif, which is present not only in CD40 and TRANCE-R but also in the three IRAK adapter kinases for IL-1R/TLR signalling."
TRAF6 mediates signaling in both TNFR and IL-1R/TLR superfamilies through a universal mechanism
"Tumour-necrosis factor (TNF) receptor-associated factor 6 (TRAF6) is the only TRAF family member that participates in signal transduction of both the TNF receptor (TNFR) superfamily and the interleukin-1 receptor (IL-1R)/Toll-like receptor (TLR) superfamily; it is important for adaptive immunity, innate immunity and bone homeostasis."
Interleukin-1 (IL-1) receptor-associated kinase-dependent IL-1-induced signaling complexes phosphorylate TAK1 and TAB2 at the plasma membrane and activate TAK1 in the cytosol.
Pellino 1 is required for interleukin-1 (IL-1)-mediated signaling through its interaction with the IL-1 receptor-associated kinase 4 (IRAK4)-IRAK-tumor necrosis factor receptor-associated factor 6 (TRAF6) complex.
Direct activation of protein kinases by unanchored polyubiquitin chains.
Free K63-linked polyubiquitin chains synthesized by TRAF6 directly activate TAK1 and IKK
"By reconstituting TAK1 activation in vitro using purified proteins, here we show that free Lys 63 polyubiquitin chains, which are not conjugated to any target protein, directly activate TAK1 by binding to the ubiquitin receptor TAB2 (also known as MAP3K7IP2)."
Unanchored polyubiquitin chains synthesized by TRAF6 and UBCH5C activate the IKK complex
"Furthermore, we found that unanchored polyubiquitin chains synthesized by TRAF6 and UBCH5C (also known as UBE2D3) activate the IKK complex."
IRAK1b, a novel alternative splice variant of interleukin-1 receptor-associated kinase (IRAK), mediates interleukin-1 signaling and has prolonged stability.
Toll/IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF) associates with TNF receptor-associated factor 6 and TANK-binding kinase 1, and activates two distinct transcription factors, NF-kappa B and IFN-regulatory factor-3, in the Toll-like receptor signaling.
The kinase TAK1 can activate the NIK-I kappaB as well as the MAP kinase cascade in the IL-1 signalling pathway.
TAK1 acts upstream of NIK and associates with TRAF6 in IL-1 signaling
"Here we show that the MAPKK kinase TAK1 acts upstream of NIK in the IL-1-activated signalling pathway and that TAK1 associates with TRAF6 during IL-1 signalling."
TAK1 links TRAF6 to the NIK-IKK cascade in IL-1 signaling
"Our results indicate that TAK1 links TRAF6 to the NIK-IKK cascade in the IL-1 signalling pathway."
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt.
Lysine 63-linked polyubiquitination of TAK1 at lysine 158 is required for tumor necrosis factor alpha- and interleukin-1beta-induced IKK/NF-kappaB and JNK/AP-1 activation.
Bifunctional apoptosis regulator (BAR), an endoplasmic reticulum (ER)-associated E3 ubiquitin ligase, modulates BI-1 protein stability and function in ER Stress.
Identification of TRAF6, a novel tumor necrosis factor receptor-associated factor protein that mediates signaling from an amino-terminal domain of the CD40 cytoplasmic region.
Reactome:R-HSA-166058
MyD88:MAL(TIRAP) cascade initiated on plasma membrane
Reactome:R-HSA-166362
Dissociation of hp-IRAK1:TRAF6 from the activated TLR:oligo-Myd88:TIRAP:p-IRAK4 complex
Reactome:R-HSA-166363
TRAF6 binds to hp- IRAK1
Reactome:R-HSA-166869
TRAF6 binds MEKK1
Reactome:R-HSA-168164
Toll Like Receptor 3 (TLR3) Cascade
Reactome:R-HSA-168184
Activated TAK1 mediates phosphorylation of the IKK Complex
Activated TRAF6:p-IRAK2 interacts with TAK1 complex upon TLR7/8 or 9 stimulation
Reactome:R-HSA-975100
Dissociation of hp-IRAK1/or IRAK2:TRAF6-oligomer from the p-IRAK4 :oligo-Myd88:activated TLR7/8 or 9 complex
Reactome:R-HSA-975103
Auto phosphorylation of TAK1 bound to p-IRAK2:pUb oligo-TRAF6: free K63 pUb:TAB1:TAB2/TAB3 upon TLR7/8 or 9 activation
Reactome:R-HSA-975106
Phosphorylation and release of IRF7 upon TLR7/8 or 9 activation
Reactome:R-HSA-975111
TRAF6 binds to hp- IRAK1/or p-IRAK2:p-IRAK4:MyD88:activated TLR7/8 or 9
Reactome:R-HSA-975118
TRAF6 ubiquitinqtes IRF7 within the activated TLR7/8 or 9 complex
Reactome:R-HSA-975119
NEMO subunit of IKK complex binds to activated IRAK1 upon stimulation of TLR7/8 or 9
Reactome:R-HSA-975122
Pellino ubiquitinates hp-IRAK1 upon TLR7/8 or 9 activation<br>
Reactome:R-HSA-975139
IRAK1 phosphorylates Pellino upon TLR7/8 or 9 activation
Reactome:R-HSA-975142
Pellino binds hp-IRAK1:TRAF6 upon TLR7/8 or 9 activation
Reactome:R-HSA-975185
IRAK2 induces TRAF6 oligomerization initiated from endosomal compartments
Reactome:R-HSA-975188
TRAF6 interacts with IRF7 upon TLR7/8 or 9 activation
Reactome:R-HSA-975857
TRAF6 binds to hp- IRAK1 or p-IRAK2
Reactome:R-HSA-9758604
Ubiquitination of IKBKG by TRAF6
Reactome:R-HSA-975871
MyD88 cascade initiated on plasma membrane
Reactome:R-HSA-975879
Dissociation of hp-IRAK1:TRAF6 or IRAK2:TRAF6-oligomer from the activated TLR5 or 10:oligo-Myd88:p-IRAK4 complex
Suggested Questions for Experts
Q: How does the RING domain of TRAF6 selectively coordinate with different E2 enzymes to determine the specificity and topology of K63-linked ubiquitin chains on diverse substrates?
Q: What molecular mechanisms allow TRAF6 to discriminate between canonical NF-ฮบB activation versus non-canonical pathway engagement in different cellular contexts?
Q: How do post-translational modifications of TRAF6 itself regulate its E3 ligase activity and alter its protein-protein interaction network during different signaling states?
Q: What determines the cellular localization of TRAF6 between cytoplasmic signaling complexes and nuclear transcriptional co-regulatory functions?
Suggested Experiments
Experiment: Cryo-EM structural determination of TRAF6 in complex with different E2 enzymes and substrate proteins to understand substrate specificity mechanisms
Experiment: Single-molecule FRET imaging to track TRAF6 conformational changes during signal transduction and correlate with downstream pathway activation
Experiment: Mass spectrometry-based ubiquitinomics to map the complete landscape of TRAF6 substrates and their ubiquitination sites across different stimulation conditions
Experiment: Live-cell proximity labeling proteomics using TRAF6-miniTurbo to identify context-specific interactors in different immune cell types and activation states
Deep Research
Falcon
(TRAF6-deep-research-falcon.md)
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.FalconEdison Scientific Literature29 citations2 artifacts2026-05-30T02:17:32.744059
The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.
You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.
We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.
We are interested in where in or outside the cell the gene product carries out its function.
We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.
Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.
Research report: Human TRAF6 (UniProt Q9Y4K3) functional annotation (2023โ2024 emphasis)
1) Target verification and core definitions (current understanding)
TRAF6 (TNF receptor-associated factor 6) is a human TRAF-family cytosolic signaling adaptor that also functions as a RING-type E3 ubiquitin ligase (EC 2.3.2.27). Recent literature consistently describes a conserved multi-domain architecture with N-terminal RING and multiple zinc fingers, a coiled-coil/TRAF-N region, and a C-terminal TRAF-C/MATH (TRAF) domain responsible for receptor/adaptor binding (li2024tumornecrosisfactor pages 2-4, wu2024traf6inhibitorsfrom pages 1-2). In this family, the trimeric TRAF-C domain can act as a โcapโ and the TRAF-N coiled-coil as a โstalk,โ providing an interaction platform that positions the N-terminal RING/zinc-finger catalytic region for ubiquitin-chain assembly and signaling complex formation (yang2025tnfreceptorassociatedfactors pages 7-8).
Functionally, TRAF6 is best understood as a signal-proximal ubiquitin ligase/scaffold that converts receptor stimulation into polyubiquitin-based signaling scaffolds which recruit and activate downstream kinases (e.g., TAK1 and IKK) to drive NF-ฮบB and MAPK activation (li2024tumornecrosisfactor pages 2-4, li2024tumornecrosisfactor pages 1-2).
2) Biochemical function: enzymatic reaction, partners, and specificity
2.1 Enzymatic activity (what reaction is catalyzed?)
TRAF6 catalyzes ubiquitin transfer in the canonical E1โE2โE3 cascade as an E3 ligase, promoting formation of polyubiquitin chains that serve primarily as non-degradative signaling scaffolds, rather than proteasomal degradation signals (li2024tumornecrosisfactor pages 1-2, li2024tumornecrosisfactor pages 2-4).
The most consistently supported E2 complex for TRAF6 is Ubc13/UBE2NโUev1A/UBE2V1, which is directly linked to TRAF6-mediated assembly of K63-linked polyubiquitin chains (li2024tumornecrosisfactor pages 2-4, wu2024traf6inhibitorsfrom pages 1-2). A 2024 inhibitor-discovery study notes a defined TRAF6โUbc13 interaction surface, highlighting TRAF6 residues Gln54, Asp57, Ile72, Leu74 as contributing to E2 engagement (wu2024traf6inhibitorsfrom pages 1-2).
2.3 Ubiquitin linkage specificity and representative substrates
Recent review-level synthesis emphasizes that TRAF6 preferentially supports K63-linked polyubiquitination, distinguishing it from K48-linked chains that more commonly target proteins for proteasomal degradation (li2024tumornecrosisfactor pages 2-4, li2024tumornecrosisfactor pages 1-2). Representative TRAF6-linked K63-modified signaling substrates/adaptors cited in 2024 review pages include IKKฮณ/NEMO, TAK1, IRAK1, and TRAF6 itself (li2024tumornecrosisfactor pages 2-4). The same review corpus notes that TRAF6 can participate in K48-linked ubiquitination in selected contexts, indicating that TRAF6 signaling can be coupled to regulated proteostasis depending on cellular conditions (li2024tumornecrosisfactor pages 11-13).
3) Cellular localization and where TRAF6 acts
Across recent primary studies, TRAF6 is described/observed as a cytosolic adaptor that associates with the cytoplasmic tails of transmembrane receptors and with inducible cytosolic signaling assemblies (ayyasamy20241433ฮถsuppressesrankl pages 1-2). Two 2024 mechanistic papers broaden this view:
Receptor-proximal complexes (RANK): TRAF6 binds receptor cytoplasmic domains such as RANK in RANKL signaling to coordinate downstream activation of MAPKs/AKT and NF-ฮบB/NFATc1 programs that drive osteoclastogenesis (ayyasamy20241433ฮถsuppressesrankl pages 1-2).
Membraneless signaling condensates: In response to ADP-heptose and other inflammatory stimuli, TRAF6 can form cytosolic liquid-like condensates (LLPS) with dynamic exchange properties (20โ60% FRAP recovery in ~5 min), which are proposed to function as โmicroreactorsโ concentrating ubiquitin machinery and downstream effectors (li2024adphepinducedliquidphase pages 4-5, li2024adphepinducedliquidphase pages 9-12).
4) Pathways and biological processes (primary signaling roles)
A central, repeatedly cited role is TRAF6 in TLR/IL-1 receptor family signaling, where TRAF6 is recruited downstream of receptor-proximal adaptors/kinases to promote TAK1 and IKK activation, leading to NF-ฮบB and MAPK transcriptional programs (li2024tumornecrosisfactor pages 2-4).
4.2 Bone remodeling and osteoclastogenesis: RANKL/RANK โ TRAF6
TRAF6 is essential in RANKLโRANK signaling, acting as a key adaptor/E3 ligase required for osteoclastogenic downstream cascades (MAPK, PI3K/AKT, IฮบB phosphorylation) and NF-ฮบB activation (ayyasamy20241433ฮถsuppressesrankl pages 1-2). This pathway-level role is also emphasized in bone-disease-focused synthesis (yang2025tnfreceptorassociatedfactors pages 7-8).
4.3 CD40/TRAF6 axis and viral mimicry (EBV LMP1)
A major 2024 development is the high-resolution demonstration that EBV LMP1 uses a direct TRAF6-binding motif (CTAR2 region) to drive NF-ฮบB/JNK/p38/IRF7 signaling and lymphoma cell survival (giehler2024epsteinbarrvirusdrivenb pages 1-3). Importantly, structural/functional analyses indicate the LMP1โTRAF6 interface differs from CD40โTRAF6, implying that certain inhibitors could potentially exploit viral-specific binding geometries (giehler2024epsteinbarrvirusdrivenb pages 7-9).
5.1 14-3-3ฮถ destabilizes TRAF6 to suppress RANKL signaling (JBC, July 2024)
Ayyasamy et al. (2024-07; https://doi.org/10.1016/j.jbc.2024.107487) show that 14-3-3ฮถ binds TRAF6 (interaction increases rapidly after RANKL stimulation), reduces the RANKโTRAF6 interaction, and promotes TRAF6 ubiquitination and proteasome-dependent degradation, dampening downstream RANKL signaling (ayyasamy20241433ฮถsuppressesrankl pages 4-5, ayyasamy20241433ฮถsuppressesrankl pages 5-7). Mechanistic support includes proteasome inhibitor blockade of TRAF6 loss (MG132/lactacystin conditions) and TRAF6 immunoprecipitation followed by ubiquitin detection (ayyasamy20241433ฮถsuppressesrankl pages 5-7, ayyasamy20241433ฮถsuppressesrankl pages 7-8). Functionally, 14-3-3ฮถ deficiency increases osteoclastogenesis and resorption readouts (e.g., CTX ELISA and dentine pit formation assays are described), while 14-3-3ฮถ re-expression suppresses osteoclastogenic transcription factors (p65/NFATc1) and MAPK/AKT phosphorylation (ayyasamy20241433ฮถsuppressesrankl pages 1-2, ayyasamy20241433ฮถsuppressesrankl pages 4-5).
Evidence from the articleโs figures directly illustrates: (i) suppression of osteoclast formation/resorption phenotypes (ayyasamy20241433ฮถsuppressesrankl media 5629ff81), (ii) increased 14-3-3ฮถโTRAF6 interaction and reduced RANKโTRAF6 association (ayyasamy20241433ฮถsuppressesrankl media 5d4d160c), and (iii) enhanced TRAF6 ubiquitination and proteasomal degradation linked to signaling suppression (ayyasamy20241433ฮถsuppressesrankl media 0ea8acbf).
Li et al. (2024-01; https://doi.org/10.34133/research.0315) report that during ALPK1/TIFA-dependent sensing of bacterial ADP-heptose, TRAF6 undergoes stimulus-dependent LLPS and is recruited into TIFA condensates. Within these condensates, TRAF6 markedly amplifies K63-linked polyubiquitin synthesis when reconstituted with E1 and the Ubc13/Uev1A E2 complex, enriching ubiquitin machinery (Ub, Ubc13/Uev1A) and downstream effectors (e.g., NEMO/TAK1/TABs) to accelerate pathway activation (li2024adphepinducedliquidphase pages 2-4, li2024adphepinducedliquidphase pages 5-7). Quantitative details include: ~6โ7 puncta per cell after 10 ฮผM ADP-LD-Hep stimulation and a reported NF-ฮบB activation IC50 โ 2.3 ฮผM for ADP-LD-Hep activation (li2024adphepinducedliquidphase pages 2-4, li2024adphepinducedliquidphase pages 7-9).
Mechanistically, these results support a current expert view that TRAF6 signaling output is not only determined by enzyme identity (E2 pairing and linkage type), but also by higher-order mesoscale organization (condensates that retain long K63 chains and concentrate enzymatic components) (li2024adphepinducedliquidphase pages 7-9).
5.3 EBV LMP1โTRAF6 interface mapped at residue/motif level (Nature Communications, January 2024)
Giehler et al. (2024-01; https://doi.org/10.1038/s41467-023-44455-w) establish a direct proteinโprotein interaction between EBV LMP1 CTAR2 and TRAF6. The critical LMP1 TRAF6-binding motif is P379VQLSY (PVQxxY), and mutational analysis identified P379, V380, Q381, Y384 as essential for binding in quantitative AlphaScreen PPI assays (giehler2024epsteinbarrvirusdrivenb pages 1-3, giehler2024epsteinbarrvirusdrivenb pages 3-4). Structural/biophysical mapping includes NMR HSQC perturbations with the LMP1 peptide and modeling based on the RANKโTRAF6 template, implicating TRAF6 interface residues including F471/Y473 as critical binding determinants (giehler2024epsteinbarrvirusdrivenb pages 7-9).
Therapeutic implication demonstrated experimentally: a RANK-derived TRAF6 inhibitor peptide blocks TRAF6โLMP1 binding with IC50 = 177 nM and reduces viability/proliferation of EBV-transformed lymphoblastoid cells when delivered as a cell-penetrating peptide (tested at 100 ฮผM for 4 days) (giehler2024epsteinbarrvirusdrivenb pages 9-10, giehler2024epsteinbarrvirusdrivenb pages 10-12).
6) Current applications and real-world implementations
6.1 Therapeutic targeting strategies (mostly preclinical as of 2024)
Direct TRAF6 inhibition (small-molecule discovery): Wu et al. (2024-06; https://doi.org/10.3390/md22060260) performed an EGCG-based pharmacophore search of 52,765 marine compounds and a docking funnel (405 docked โ 6 selected โ 2 optimized candidates), proposing CMNPD9212-16 and CMNPD12791-8 as potential TRAF6 binders with favorable in silico ADMET and MD stability (wu2024traf6inhibitorsfrom pages 1-2). This represents a realistic pipeline for early-stage TRAF6 inhibitor identification, but remains computational/preclinical.
Interface-targeted PPI inhibitors: The LMP1โTRAF6 work provides a validated biochemical assay (AlphaScreen) and a demonstration that peptide disruption can impair EBV-transformed cell survival, supporting the feasibility of developing PPI-directed inhibitors against TRAF6 recruitment modules (giehler2024epsteinbarrvirusdrivenb pages 9-10, giehler2024epsteinbarrvirusdrivenb pages 12-13).
Indirect pathway modulation and stability control: The 14-3-3ฮถ study supports a strategy of modulating TRAF6 stability to down-tune RANKL-driven osteoclastogenesis (ayyasamy20241433ฮถsuppressesrankl pages 5-7).
A clinical trials tool search for the literal phrase โTRAF6 inhibitorโ did not retrieve clearly relevant interventional trials, implying that TRAF6-directed therapeutics are not yet widely represented as explicit clinical interventions under that label in the indexed registry results available to this workflow (OpenTargets Search: -TRAF6).
6.2 Disease association evidence (database-backed)
Open Targets evidence links TRAF6 to multiple disease areas with association scores and evidence counts, including severe acute respiratory syndrome, ovarian neoplasm, vertebral column disorder, renal osteodystrophy, and autosomal dominant hypohidrotic ectodermal dysplasia (OpenTargets Search: -TRAF6). These associations support prioritization of TRAF6 as a mechanistically plausible node in inflammatory, neoplastic, and bone-related disease processes, but require disease-specific causal validation beyond association.
7) Representative statistics and data highlights (recent studies)
Virtual screening pipeline scale (2024): 52,765 compounds screened; 405 docked; 6 prioritized for refinement; 2 final candidates (wu2024traf6inhibitorsfrom pages 1-2).
PPI inhibition potency (2024): LMP1โTRAF6 disruption by a RANK-derived peptide IC50 = 177 nM; cell-penetrating peptide tested at 100 ฮผM for 4 days in viability/proliferation assays (giehler2024epsteinbarrvirusdrivenb pages 9-10, giehler2024epsteinbarrvirusdrivenb pages 10-12).
8) Expert synthesis and functional annotation summary
TRAF6 should be annotated as a cytosolic receptor-proximal E3 ubiquitin ligase/adaptor whose primary biochemical output is Ubc13/Uev1A-dependent K63 polyubiquitin chain assembly, enabling recruitment/activation of TAK1/IKK and MAPK modules to drive inflammatory and differentiation programs (li2024tumornecrosisfactor pages 2-4, li2024adphepinducedliquidphase pages 7-9). Current 2024 mechanistic advances emphasize that TRAF6 signaling strength and specificity are controlled by (i) regulated degradation/turnover (e.g., 14-3-3ฮถ-driven ubiquitination and proteasomal degradation in RANKL signaling) and (ii) higher-order organization into inducible condensates that spatially concentrate ubiquitination enzymes and effectors (ayyasamy20241433ฮถsuppressesrankl pages 5-7, li2024adphepinducedliquidphase pages 7-9). Therapeutic strategies in 2024 are predominantly preclinical, spanning computational small-molecule identification, and targeted disruption of TRAF6 recruitment interfaces (notably virus-specific LMP1โTRAF6 engagement) (wu2024traf6inhibitorsfrom pages 1-2, giehler2024epsteinbarrvirusdrivenb pages 9-10).
Evidence summary table
The following table compiles identity, biochemical function, pathways, localization, 2023โ2024 advances, and translational angles in a compact format.
Li et al., 2024, Journal of Cancer โ https://doi.org/10.7150/jca.90059 ; Yang et al., 2025, Frontiers in Physiology โ https://doi.org/10.3389/fphys.2025.1527814 ; Wu et al., 2024, Marine Drugs โ https://doi.org/10.3390/md22060260
Enzymatic activity
โข TRAF6 functions as a RING-type E3 ubiquitin ligase and signaling scaffold โข Works with E1/E2 enzymes to assemble signaling-active ubiquitin chains โข Central output is activation of TAK1/IKK โ NF-ฮบB and MAPK signaling โข Recent reviews also note TRAF6 can participate in both non-degradative signaling and degradative ubiquitin control depending on chain type/context (li2024tumornecrosisfactor pages 11-13, li2024tumornecrosisfactor pages 2-4, li2024tumornecrosisfactor pages 1-2, wu2024traf6inhibitorsfrom pages 1-2)
Li et al., 2024 โ https://doi.org/10.7150/jca.90059 ; Wu et al., 2024 โ https://doi.org/10.3390/md22060260
Key E2 partners
โข Best-supported E2 complex is Ubc13/UBE2NโUev1A/UBE2V1 โข This partnership is specifically linked to TRAF6-catalyzed K63-linked polyubiquitination โข A recent inhibitor-development paper highlights a defined TRAF6โUbc13 interaction surface including Gln54, Asp57, Ile72, Leu74 on TRAF6 โข Ubc13/Uev1A is also used in in vitro condensate reconstitution assays for TRAF6-driven ubiquitin-chain synthesis (li2024tumornecrosisfactor pages 2-4, wu2024traf6inhibitorsfrom pages 1-2, li2024adphepinducedliquidphase pages 2-4, li2024adphepinducedliquidphase pages 5-7)
Li et al., 2024 โ https://doi.org/10.7150/jca.90059 ; Wu et al., 2024 โ https://doi.org/10.3390/md22060260 ; Li et al., 2024, Research โ https://doi.org/10.34133/research.0315
Ubiquitin linkage specificity
โข K63-linked chains are the canonical TRAF6 signaling output and act as scaffolds rather than degradation tags โข Representative K63-modified targets mentioned in recent review pages include IKKฮณ/NEMO, TAK1, IRAK1, and TRAF6 itself โข Recent reviews also note TRAF6 can participate in K48-linked ubiquitination in some contexts, supporting proteasomal degradation/regulatory turnover โข LLPS work links TRAF6 condensates to synthesis/retention of long K63 polyUb chains (li2024tumornecrosisfactor pages 2-4, li2024tumornecrosisfactor pages 1-2, li2024adphepinducedliquidphase pages 2-4, li2024adphepinducedliquidphase pages 7-9, li2024adphepinducedliquidphase pages 5-7)
Li et al., 2024 โ https://doi.org/10.7150/jca.90059 ; Li et al., 2024, Research โ https://doi.org/10.34133/research.0315
Representative substrates
โข Recent review pages list IKKฮณ/NEMO, TAK1, IRAK1, and TRAF6 itself as representative K63-ubiquitinated targets/substrates in TRAF6 signaling โข TRAF6 is also described as binding p62 to ubiquitinate mTOR, linking it to growth/autophagy regulation โข In disease-focused primary work, TRAF6 directly engages receptor/adaptor complexes such as RANK and TIFA, and viral protein LMP1 recruits TRAF6 as a critical host effector โข Evidence base is strongest for receptor-proximal signaling substrates/adaptors rather than a single exclusive substrate class (li2024tumornecrosisfactor pages 11-13, li2024tumornecrosisfactor pages 2-4, ayyasamy20241433ฮถsuppressesrankl pages 1-2, giehler2024epsteinbarrvirusdrivenb pages 1-3)
Li et al., 2024 โ https://doi.org/10.7150/jca.90059 ; Ayyasamy et al., 2024, JBC โ https://doi.org/10.1016/j.jbc.2024.107487 ; Giehler et al., 2024, Nature Communications โ https://doi.org/10.1038/s41467-023-44455-w
Core pathways
โข Major pathways in recent evidence: TLR/IL-1RโMyD88โIRAKโTRAF6โTAK1โNF-ฮบB/MAPK โข RANK/RANKLโTRAF6 is central for osteoclastogenesis and bone remodeling โข Additional pathways in recent review/primary papers include CD40/TRAF6-related signaling, IL-17R via Act1, TCR via CARMA1โBCL10โMALT1, TLR7/8/9โMYD88โIRF7, and ALPK1โTIFAโTRAF6 innate sensing โข In EBV biology, LMP1โTRAF6 drives NF-ฮบB/JNK/p38/IRF7 signaling and lymphoma survival (li2024tumornecrosisfactor pages 2-4, ayyasamy20241433ฮถsuppressesrankl pages 1-2, giehler2024epsteinbarrvirusdrivenb pages 1-3, li2024adphepinducedliquidphase pages 1-2)
Li et al., 2024 โ https://doi.org/10.7150/jca.90059 ; Ayyasamy et al., 2024 โ https://doi.org/10.1016/j.jbc.2024.107487 ; Giehler et al., 2024 โ https://doi.org/10.1038/s41467-023-44455-w ; Li et al., 2024 โ https://doi.org/10.34133/research.0315
Localization/complexes
โข TRAF6 is a cytosolic adaptor/E3 that assembles on cytoplasmic tails of transmembrane receptors and receptor-proximal signaling complexes โข Recent primary data show dynamic association with RANK, TIFA condensates, and viral LMP1 CTAR2 complexes โข ADP-heptose studies show TRAF6 forms cytosolic membraneless droplets/condensates with dynamic exchange โข Complex partners include TAK1/TAB1/2, NEMO, Ubc13/Uev1A, and receptor scaffolds (ayyasamy20241433ฮถsuppressesrankl pages 1-2, giehler2024epsteinbarrvirusdrivenb pages 1-3, li2024adphepinducedliquidphase pages 7-9, li2024adphepinducedliquidphase pages 4-5)
Ayyasamy et al., 2024 โ https://doi.org/10.1016/j.jbc.2024.107487 ; Giehler et al., 2024 โ https://doi.org/10.1038/s41467-023-44455-w ; Li et al., 2024 โ https://doi.org/10.34133/research.0315
2023-2024 mechanistic advances
โข 2024 JBC: 14-3-3ฮถ binds TRAF6, increases after RANKL, promotes TRAF6 ubiquitination and proteasomal degradation, weakens RANKโTRAF6 interaction, and suppresses osteoclastogenic signaling โข 2024 Research: TRAF6 undergoes LLPS/condensation in TIFA microreactors that enrich ubiquitin machinery and favor long K63 polyUb synthesis โข 2024 Nat Commun: EBV LMP1 directly binds TRAF6 through a CTAR2 motif (P379VQLSY), with key interface residues defined biochemically/structurally โข These studies move TRAF6 biology from linear pathway maps toward regulated PPI interfaces, condensates, and degradative control (ayyasamy20241433ฮถsuppressesrankl pages 4-5, ayyasamy20241433ฮถsuppressesrankl pages 5-7, li2024adphepinducedliquidphase pages 2-4, li2024adphepinducedliquidphase pages 7-9, giehler2024epsteinbarrvirusdrivenb pages 7-9, giehler2024epsteinbarrvirusdrivenb pages 3-4, giehler2024epsteinbarrvirusdrivenb pages 9-10)
Ayyasamy et al., 2024 โ https://doi.org/10.1016/j.jbc.2024.107487 ; Li et al., 2024 โ https://doi.org/10.34133/research.0315 ; Giehler et al., 2024 โ https://doi.org/10.1038/s41467-023-44455-w
Therapeutic targeting approaches
โข Small-molecule discovery: virtual screening of 52,765 marine compounds yielded candidate TRAF6 binders CMNPD9212-16 and CMNPD12791-8 with favorable in silico ADMET/MD profiles โข PPI targeting: EBV study validated peptide disruption of LMP1โTRAF6; a RANK-derived inhibitor peptide blocked binding and reduced viability of EBV-transformed B cells โข Pathway modulation in bone disease: recent work supports targeting RANKโTRAF6 signaling or promoting TRAF6 degradation/stability control โข No directly relevant TRAF6-targeted interventional clinical trials were retrieved in the tool search, so current implementation remains largely preclinical (wu2024traf6inhibitorsfrom pages 1-2, giehler2024epsteinbarrvirusdrivenb pages 10-12, giehler2024epsteinbarrvirusdrivenb pages 9-10)
Wu et al., 2024 โ https://doi.org/10.3390/md22060260 ; Giehler et al., 2024 โ https://doi.org/10.1038/s41467-023-44455-w
Quantitative/statistical data
โข Marine-drug screen: 52,765 compounds screened; 405 docked; 6 advanced; 2 prioritized hits (CMNPD9212-16, CMNPD12791-8) (wu2024traf6inhibitorsfrom pages 1-2) โข TIFA/TRAF6 condensate study: ADP-LD-Hep produced about 6โ7 puncta per cell; NF-ฮบB activation IC50 โ 2.3 ฮผM; in vitro reconstitution used TRAF6 20 ฮผM, Ubc13 1 ฮผM, Uev1A 1 ฮผM, Ub 50 ฮผM, E1 0.1 ฮผM, ATP 2 mM (li2024adphepinducedliquidphase pages 2-4, li2024adphepinducedliquidphase pages 7-9, li2024adphepinducedliquidphase pages 15-16) โข 14-3-3ฮถ study: proteasome inhibitors MG132/lactacystin at 10 nM blocked TRAF6 loss; RANKL stimulation increased 14-3-3ฮถโTRAF6 interaction and osteoclast assays used TRAP+ cells with โฅ3 nuclei as scoring criterion (ayyasamy20241433ฮถsuppressesrankl pages 7-8, ayyasamy20241433ฮถsuppressesrankl pages 5-7, ayyasamy20241433ฮถsuppressesrankl pages 8-9) โข LMP1โTRAF6 study: RANK-derived inhibitor peptide blocked binding with IC50 177 nM; cell-penetrating peptide tested at 100 ฮผM for 4 days reduced LCL proliferation (giehler2024epsteinbarrvirusdrivenb pages 10-12, giehler2024epsteinbarrvirusdrivenb pages 9-10)
Wu et al., 2024 โ https://doi.org/10.3390/md22060260 ; Li et al., 2024 โ https://doi.org/10.34133/research.0315 ; Ayyasamy et al., 2024 โ https://doi.org/10.1016/j.jbc.2024.107487 ; Giehler et al., 2024 โ https://doi.org/10.1038/s41467-023-44455-w
Table: This table summarizes the most evidence-supported features of human TRAF6 (UniProt Q9Y4K3), including its domain architecture, E3 ligase activity, pathway roles, recent mechanistic advances, and preclinical targeting strategies. It is designed as a compact reference for functional annotation grounded only in the gathered evidence.
References
(li2024tumornecrosisfactor pages 2-4): Tingting Li, Zhe Lei, Lin Wei, Kai Yang, Jinhong Shen, and Lin Hu. Tumor necrosis factor receptor-associated factor 6 and human cancer: a systematic review of mechanistic insights, functional roles, and therapeutic potential. Journal of Cancer, 15:560-576, Jan 2024. URL: https://doi.org/10.7150/jca.90059, doi:10.7150/jca.90059. This article has 14 citations and is from a peer-reviewed journal.
(wu2024traf6inhibitorsfrom pages 1-2): Xuexuan Wu, Saiyi Zhong, Nan Zhou, and Lianxiang Luo. Traf6 inhibitors from marine compound library: pharmacophore, virtual screening, fragment replacement, admet, and molecular dynamics. Marine Drugs, 22:260, Jun 2024. URL: https://doi.org/10.3390/md22060260, doi:10.3390/md22060260. This article has 1 citations.
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(li2024tumornecrosisfactor pages 1-2): Tingting Li, Zhe Lei, Lin Wei, Kai Yang, Jinhong Shen, and Lin Hu. Tumor necrosis factor receptor-associated factor 6 and human cancer: a systematic review of mechanistic insights, functional roles, and therapeutic potential. Journal of Cancer, 15:560-576, Jan 2024. URL: https://doi.org/10.7150/jca.90059, doi:10.7150/jca.90059. This article has 14 citations and is from a peer-reviewed journal.
(li2024tumornecrosisfactor pages 11-13): Tingting Li, Zhe Lei, Lin Wei, Kai Yang, Jinhong Shen, and Lin Hu. Tumor necrosis factor receptor-associated factor 6 and human cancer: a systematic review of mechanistic insights, functional roles, and therapeutic potential. Journal of Cancer, 15:560-576, Jan 2024. URL: https://doi.org/10.7150/jca.90059, doi:10.7150/jca.90059. This article has 14 citations and is from a peer-reviewed journal.
(ayyasamy20241433ฮถsuppressesrankl pages 1-2): R. Ayyasamy, S. Fan, P. Czernik, B. Lecka-Czernik, S. Chattopadhyay, and R. Chakravarti. 14-3-3ฮถ suppresses rankl signaling by destabilizing traf6. Journal of Biological Chemistry, 300:107487, Jul 2024. URL: https://doi.org/10.1016/j.jbc.2024.107487, doi:10.1016/j.jbc.2024.107487. This article has 8 citations and is from a domain leading peer-reviewed journal.
(li2024adphepinducedliquidphase pages 4-5): Liping Li, Jia Wang, Xincheng Zhong, Yaoyao Jiang, Gaofeng Pei, Xikang Yang, Kaixiang Zhang, Siqi Shen, Xue Jin, Gaoge Sun, Chaofei Su, Shuzhen Chen, and Hang Yin. Adp-hep-induced liquid phase condensation of tifa-traf6 activates alpk1/tifa-dependent innate immune responses. Research, Jan 2024. URL: https://doi.org/10.34133/research.0315, doi:10.34133/research.0315. This article has 12 citations and is from a peer-reviewed journal.
(li2024adphepinducedliquidphase pages 9-12): Liping Li, Jia Wang, Xincheng Zhong, Yaoyao Jiang, Gaofeng Pei, Xikang Yang, Kaixiang Zhang, Siqi Shen, Xue Jin, Gaoge Sun, Chaofei Su, Shuzhen Chen, and Hang Yin. Adp-hep-induced liquid phase condensation of tifa-traf6 activates alpk1/tifa-dependent innate immune responses. Research, Jan 2024. URL: https://doi.org/10.34133/research.0315, doi:10.34133/research.0315. This article has 12 citations and is from a peer-reviewed journal.
(giehler2024epsteinbarrvirusdrivenb pages 1-3): Fabian Giehler, Michael S. Ostertag, Thomas Sommermann, Daniel Weidl, Kai R. Sterz, Helmut Kutz, Andreas Moosmann, Stephan M. Feller, Arie Geerlof, Brigitte Biesinger, Grzegorz M. Popowicz, Johannes Kirchmair, and Arnd Kieser. Epstein-barr virus-driven b cell lymphoma mediated by a direct lmp1-traf6 complex. Nature Communications, Jan 2024. URL: https://doi.org/10.1038/s41467-023-44455-w, doi:10.1038/s41467-023-44455-w. This article has 29 citations and is from a highest quality peer-reviewed journal.
(giehler2024epsteinbarrvirusdrivenb pages 7-9): Fabian Giehler, Michael S. Ostertag, Thomas Sommermann, Daniel Weidl, Kai R. Sterz, Helmut Kutz, Andreas Moosmann, Stephan M. Feller, Arie Geerlof, Brigitte Biesinger, Grzegorz M. Popowicz, Johannes Kirchmair, and Arnd Kieser. Epstein-barr virus-driven b cell lymphoma mediated by a direct lmp1-traf6 complex. Nature Communications, Jan 2024. URL: https://doi.org/10.1038/s41467-023-44455-w, doi:10.1038/s41467-023-44455-w. This article has 29 citations and is from a highest quality peer-reviewed journal.
(ayyasamy20241433ฮถsuppressesrankl pages 4-5): R. Ayyasamy, S. Fan, P. Czernik, B. Lecka-Czernik, S. Chattopadhyay, and R. Chakravarti. 14-3-3ฮถ suppresses rankl signaling by destabilizing traf6. Journal of Biological Chemistry, 300:107487, Jul 2024. URL: https://doi.org/10.1016/j.jbc.2024.107487, doi:10.1016/j.jbc.2024.107487. This article has 8 citations and is from a domain leading peer-reviewed journal.
(ayyasamy20241433ฮถsuppressesrankl pages 5-7): R. Ayyasamy, S. Fan, P. Czernik, B. Lecka-Czernik, S. Chattopadhyay, and R. Chakravarti. 14-3-3ฮถ suppresses rankl signaling by destabilizing traf6. Journal of Biological Chemistry, 300:107487, Jul 2024. URL: https://doi.org/10.1016/j.jbc.2024.107487, doi:10.1016/j.jbc.2024.107487. This article has 8 citations and is from a domain leading peer-reviewed journal.
(ayyasamy20241433ฮถsuppressesrankl pages 7-8): R. Ayyasamy, S. Fan, P. Czernik, B. Lecka-Czernik, S. Chattopadhyay, and R. Chakravarti. 14-3-3ฮถ suppresses rankl signaling by destabilizing traf6. Journal of Biological Chemistry, 300:107487, Jul 2024. URL: https://doi.org/10.1016/j.jbc.2024.107487, doi:10.1016/j.jbc.2024.107487. This article has 8 citations and is from a domain leading peer-reviewed journal.
(ayyasamy20241433ฮถsuppressesrankl media 5629ff81): R. Ayyasamy, S. Fan, P. Czernik, B. Lecka-Czernik, S. Chattopadhyay, and R. Chakravarti. 14-3-3ฮถ suppresses rankl signaling by destabilizing traf6. Journal of Biological Chemistry, 300:107487, Jul 2024. URL: https://doi.org/10.1016/j.jbc.2024.107487, doi:10.1016/j.jbc.2024.107487. This article has 8 citations and is from a domain leading peer-reviewed journal.
(ayyasamy20241433ฮถsuppressesrankl media 5d4d160c): R. Ayyasamy, S. Fan, P. Czernik, B. Lecka-Czernik, S. Chattopadhyay, and R. Chakravarti. 14-3-3ฮถ suppresses rankl signaling by destabilizing traf6. Journal of Biological Chemistry, 300:107487, Jul 2024. URL: https://doi.org/10.1016/j.jbc.2024.107487, doi:10.1016/j.jbc.2024.107487. This article has 8 citations and is from a domain leading peer-reviewed journal.
(ayyasamy20241433ฮถsuppressesrankl media 0ea8acbf): R. Ayyasamy, S. Fan, P. Czernik, B. Lecka-Czernik, S. Chattopadhyay, and R. Chakravarti. 14-3-3ฮถ suppresses rankl signaling by destabilizing traf6. Journal of Biological Chemistry, 300:107487, Jul 2024. URL: https://doi.org/10.1016/j.jbc.2024.107487, doi:10.1016/j.jbc.2024.107487. This article has 8 citations and is from a domain leading peer-reviewed journal.
(li2024adphepinducedliquidphase pages 2-4): Liping Li, Jia Wang, Xincheng Zhong, Yaoyao Jiang, Gaofeng Pei, Xikang Yang, Kaixiang Zhang, Siqi Shen, Xue Jin, Gaoge Sun, Chaofei Su, Shuzhen Chen, and Hang Yin. Adp-hep-induced liquid phase condensation of tifa-traf6 activates alpk1/tifa-dependent innate immune responses. Research, Jan 2024. URL: https://doi.org/10.34133/research.0315, doi:10.34133/research.0315. This article has 12 citations and is from a peer-reviewed journal.
(li2024adphepinducedliquidphase pages 5-7): Liping Li, Jia Wang, Xincheng Zhong, Yaoyao Jiang, Gaofeng Pei, Xikang Yang, Kaixiang Zhang, Siqi Shen, Xue Jin, Gaoge Sun, Chaofei Su, Shuzhen Chen, and Hang Yin. Adp-hep-induced liquid phase condensation of tifa-traf6 activates alpk1/tifa-dependent innate immune responses. Research, Jan 2024. URL: https://doi.org/10.34133/research.0315, doi:10.34133/research.0315. This article has 12 citations and is from a peer-reviewed journal.
(li2024adphepinducedliquidphase pages 7-9): Liping Li, Jia Wang, Xincheng Zhong, Yaoyao Jiang, Gaofeng Pei, Xikang Yang, Kaixiang Zhang, Siqi Shen, Xue Jin, Gaoge Sun, Chaofei Su, Shuzhen Chen, and Hang Yin. Adp-hep-induced liquid phase condensation of tifa-traf6 activates alpk1/tifa-dependent innate immune responses. Research, Jan 2024. URL: https://doi.org/10.34133/research.0315, doi:10.34133/research.0315. This article has 12 citations and is from a peer-reviewed journal.
(giehler2024epsteinbarrvirusdrivenb pages 3-4): Fabian Giehler, Michael S. Ostertag, Thomas Sommermann, Daniel Weidl, Kai R. Sterz, Helmut Kutz, Andreas Moosmann, Stephan M. Feller, Arie Geerlof, Brigitte Biesinger, Grzegorz M. Popowicz, Johannes Kirchmair, and Arnd Kieser. Epstein-barr virus-driven b cell lymphoma mediated by a direct lmp1-traf6 complex. Nature Communications, Jan 2024. URL: https://doi.org/10.1038/s41467-023-44455-w, doi:10.1038/s41467-023-44455-w. This article has 29 citations and is from a highest quality peer-reviewed journal.
(giehler2024epsteinbarrvirusdrivenb pages 9-10): Fabian Giehler, Michael S. Ostertag, Thomas Sommermann, Daniel Weidl, Kai R. Sterz, Helmut Kutz, Andreas Moosmann, Stephan M. Feller, Arie Geerlof, Brigitte Biesinger, Grzegorz M. Popowicz, Johannes Kirchmair, and Arnd Kieser. Epstein-barr virus-driven b cell lymphoma mediated by a direct lmp1-traf6 complex. Nature Communications, Jan 2024. URL: https://doi.org/10.1038/s41467-023-44455-w, doi:10.1038/s41467-023-44455-w. This article has 29 citations and is from a highest quality peer-reviewed journal.
(giehler2024epsteinbarrvirusdrivenb pages 10-12): Fabian Giehler, Michael S. Ostertag, Thomas Sommermann, Daniel Weidl, Kai R. Sterz, Helmut Kutz, Andreas Moosmann, Stephan M. Feller, Arie Geerlof, Brigitte Biesinger, Grzegorz M. Popowicz, Johannes Kirchmair, and Arnd Kieser. Epstein-barr virus-driven b cell lymphoma mediated by a direct lmp1-traf6 complex. Nature Communications, Jan 2024. URL: https://doi.org/10.1038/s41467-023-44455-w, doi:10.1038/s41467-023-44455-w. This article has 29 citations and is from a highest quality peer-reviewed journal.
(giehler2024epsteinbarrvirusdrivenb pages 12-13): Fabian Giehler, Michael S. Ostertag, Thomas Sommermann, Daniel Weidl, Kai R. Sterz, Helmut Kutz, Andreas Moosmann, Stephan M. Feller, Arie Geerlof, Brigitte Biesinger, Grzegorz M. Popowicz, Johannes Kirchmair, and Arnd Kieser. Epstein-barr virus-driven b cell lymphoma mediated by a direct lmp1-traf6 complex. Nature Communications, Jan 2024. URL: https://doi.org/10.1038/s41467-023-44455-w, doi:10.1038/s41467-023-44455-w. This article has 29 citations and is from a highest quality peer-reviewed journal.
(OpenTargets Search: -TRAF6): Open Targets Query (-TRAF6, 12 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(li2024adphepinducedliquidphase pages 15-16): Liping Li, Jia Wang, Xincheng Zhong, Yaoyao Jiang, Gaofeng Pei, Xikang Yang, Kaixiang Zhang, Siqi Shen, Xue Jin, Gaoge Sun, Chaofei Su, Shuzhen Chen, and Hang Yin. Adp-hep-induced liquid phase condensation of tifa-traf6 activates alpk1/tifa-dependent innate immune responses. Research, Jan 2024. URL: https://doi.org/10.34133/research.0315, doi:10.34133/research.0315. This article has 12 citations and is from a peer-reviewed journal.
(ayyasamy20241433ฮถsuppressesrankl pages 8-9): R. Ayyasamy, S. Fan, P. Czernik, B. Lecka-Czernik, S. Chattopadhyay, and R. Chakravarti. 14-3-3ฮถ suppresses rankl signaling by destabilizing traf6. Journal of Biological Chemistry, 300:107487, Jul 2024. URL: https://doi.org/10.1016/j.jbc.2024.107487, doi:10.1016/j.jbc.2024.107487. This article has 8 citations and is from a domain leading peer-reviewed journal.
(li2024adphepinducedliquidphase pages 1-2): Liping Li, Jia Wang, Xincheng Zhong, Yaoyao Jiang, Gaofeng Pei, Xikang Yang, Kaixiang Zhang, Siqi Shen, Xue Jin, Gaoge Sun, Chaofei Su, Shuzhen Chen, and Hang Yin. Adp-hep-induced liquid phase condensation of tifa-traf6 activates alpk1/tifa-dependent innate immune responses. Research, Jan 2024. URL: https://doi.org/10.34133/research.0315, doi:10.34133/research.0315. This article has 12 citations and is from a peer-reviewed journal.
Tumor necrosis factor receptor-associated factor 6 (TRAF6) is an adapter protein and E3 ubiquitin ligase that mediates signal transduction from various receptors in the immune and developmental systems (www.ncbi.nlm.nih.gov). At the molecular level, TRAF6 functions as a ubiquitin-protein transferase (E3 ubiquitin ligase)(GO:0004842), assembling Lysine-63โlinked polyubiquitin chains on target proteins (including itself) in cooperation with the E2 enzyme complex Ubc13โUev1A (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Unlike K48-linked ubiquitin, these K63-linked chains (GO:0070534) do not mark proteins for degradation but instead serve as scaffolds to recruit and activate downstream kinases in signaling pathways (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Through this mechanism, TRAF6 is a pivotal signal transducer that links receptor-proximal events to activation of key transcription factors. For example, upon receptor stimulation, TRAF6 autoubiquitination and K63-ubiquitin conjugation create docking sites for the TAK1 kinase complex, leading to activation of IฮบB kinase (IKK) and MAP kinases (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). This results in induction of NF-ฮบB and AP-1โdependent gene expression programs critical for immune and inflammatory responses (pmc.ncbi.nlm.nih.gov).
As an adaptor, TRAF6 directly interacts with a variety of upstream receptors and signaling proteins. It was originally identified as a TRAF protein that, unlike TRAF2/5, can mediate signals not only from the TNF receptor superfamily but also from the Toll/Interleukin-1 receptor (TIR) family (pmc.ncbi.nlm.nih.gov). TRAF6 binds to cytoplasmic motifs (typically PxQxT sequences) on receptors or adaptors such as CD40, RANK (TNFRSF11A), IL-1R, and Toll-like receptors, bridging these to downstream enzymes (www.ncbi.nlm.nih.gov). In Toll-like receptor (TLR) and IL-1R signaling (e.g. TLR4 or IL-1ฮฒ receptor pathways), TRAF6 is recruited via the MyD88โIRAK kinase complex, and its ubiquitin ligase activity is required to activate NF-ฮบB and mitogen-activated protein kinases (www.ncbi.nlm.nih.gov). Similarly, in the TNF receptor superfamily pathways, TRAF6 associates with receptors like CD40 and RANK to propagate signals leading to NF-ฮบB activation and cell survival (www.ncbi.nlm.nih.gov). Notably, TRAF6 also links to the RIG-I/MAVS antiviral pathway and other cytosolic pattern-recognition receptor pathways, functioning as a key molecule in antiviral innate signaling (www.ncbi.nlm.nih.gov). In these contexts, TRAF6 helps activate not only NF-ฮบB but also interferon-regulatory factors; for instance, it can activate IRF7 in response to cytosolic viral DNA/RNA detection (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Thus, TRAF6 is a central mediator of innate immune response (GO:0045087), enabling pathogen-sensing receptors to induce inflammatory cytokines and interferons.
Beyond NF-ฮบB, TRAF6 signaling branches into other pathways. It is involved in the AP-1 (c-Jun/Fos) pathway via activation of JNK and p38 MAPKs (pmc.ncbi.nlm.nih.gov). TRAF6 also interfaces with the transforming growth factor ฮฒ (TGF-ฮฒ) receptor complex to mediate Smad-independent signaling: upon TGF-ฮฒ binding, TRAF6 is recruited and required for activating the JNK/p38 cascade (through TAK1) independent of the Smad pathway (www.ncbi.nlm.nih.gov). This illustrates that TRAF6 serves as a point of crosstalk between TNF/TLR pathways and other signaling networks. In summary, TRAF6โs molecular functions include ubiquitin ligase activity (GO:0061630) and adapter activity that together facilitate the assembly of higher-order signaling complexes, leading to activation of transcriptional programs in immunity, inflammation, and development (pmc.ncbi.nlm.nih.gov) (www.ncbi.nlm.nih.gov). Key enzymatic and binding functions of TRAF6 are reflected in its Gene Ontology annotations, such as tumor necrosis factor receptor binding (GO:0005164), CD40 receptor binding (GO:0005174), and protein K63-linked ubiquitination (GO:0070534) among others, consistent with its role as an E3 ligase and adaptor in multiple signaling pathways (www.innatedb.org) (www.innatedb.org).
Cellular Localization and Subcellular Components
TRAF6 is primarily a cytosolic protein (GO:0005737) found in the cytoplasm under basal conditions (www.innatedb.org). It often localizes to the cytoplasmic side of membranes upon receptor engagement, as it interacts with membrane-bound receptor complexes. For example, during CD40 or TLR signaling, TRAF6 is recruited to receptor cytosolic tails at the plasma membrane or endosomal membrane, placing it at the plasma membraneโs cytoplasmic face (GO:0009898) as part of the activated receptor complex (www.innatedb.org). It has been detected in raft-like membrane microdomains (GO:0045121) in TLR signaling, suggesting that receptor clustering in lipid rafts may concentrate TRAF6 and other signaling molecules (www.innatedb.org). Additionally, TRAF6 is a component of several protein complexes (GO:0043234) in the cytoplasm, such as the Myddosome (MyD88โIRAK4โIRAK1 complex) in TLR/IL-1R pathways and the signalsome formed at activated CD40 or RANK receptors. These multimeric complexes enable oligomerized TRAF6 to catalyze ubiquitin chain formation and recruit kinases in the cytosol (www.ncbi.nlm.nih.gov).
While predominantly cytosolic, TRAF6 can also localize to the nucleus under certain conditions. In general, unstimulated cells show little nuclear TRAF6, but upon specific signaling events TRAF6 has been observed to translocate into the nucleus. A striking example is in osteoclast differentiation: RANKL (receptor activator of NF-ฮบB ligand) stimulation not only activates cytosolic TRAF6 signaling for NF-ฮบB, but also increases TRAF6 accumulation in the nuclei of osteoclasts (pubmed.ncbi.nlm.nih.gov). In osteoclast nuclei, TRAF6 was found to act as a co-regulator of transcription, in complex with nuclear adaptor protein FHL2 and transcription factor RUNX1 (pubmed.ncbi.nlm.nih.gov). The formation of a TRAF6โFHL2โRUNX1 complex in the nucleus enables binding to specific gene promoter elements and modulation of gene expression important for osteoclast function (pubmed.ncbi.nlm.nih.gov). This suggests TRAF6 has a dual localization: it shuttles to the nucleus in certain cell types or conditions to directly influence transcription, while it mainly resides in the cytoplasm to mediate signal transduction. Nuclear localization of TRAF6 appears to be signal-dependent and possibly cell-typeโspecific (e.g., prominent in differentiated osteoclasts but not in their monocyte precursors) (pubmed.ncbi.nlm.nih.gov). Thus, TRAF6 is associated with multiple subcellular components: cytosol (GO:0005829) and cytoplasmic complexes at rest, with inducible presence in the nucleoplasm and in membrane-proximal complexes upon activation.
Biological Processes Involvement
TRAF6 plays an essential role in numerous biological processes, particularly those related to immune system function and development. A major process controlled by TRAF6 is the innate immune response (GO:0045087). As an adaptor in TLR and IL-1R signaling pathways, TRAF6 is required for the production of proinflammatory cytokines (such as IL-6, TNF-ฮฑ) in response to pathogenic stimuli (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Mice lacking TRAF6 cannot mount effective innate immune signaling: for instance, TRAF6-deficient cells fail to activate NF-ฮบB and MAP kinases in response to lipopolysaccharide (TLR4 ligand) or IL-1 (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Consequently, TRAF6^โ/โ mice have profoundly impaired Toll-like receptor signaling and IL-1 signaling, leading to increased susceptibility to infections. TRAF6 also mediates signaling downstream of the adaptive immune receptors: it is involved in T-cell activation and B-cell activation processes. Via CD40 in B cells, TRAF6 helps induce immunoglobulin production, and in T cells it contributes to cytokine gene activation (e.g. positive regulation of IL-2 production (GO:0032743)) (www.innatedb.org). Indeed, gene ontology annotations implicate TRAF6 in positive regulation of T cell cytokine production (GO:0002726) and regulation of immunoglobulin secretion (www.innatedb.org), reflecting its role in co-stimulatory signaling (CD40, TCR, etc.).
Another critical biological process involving TRAF6 is osteoclast differentiation and bone resorption. TRAF6 is the key signaling adaptor for RANK (TNFRSF11A) in osteoclast precursors; upon RANKL binding, TRAF6 triggers NF-ฮบB and JNK pathways that drive the gene expression program for osteoclastogenesis. In line with this, TRAF6-deficient mice exhibit severe osteopetrosis (excess bone density) due to a complete failure of osteoclast development (pmc.ncbi.nlm.nih.gov). Thus, bone remodeling is profoundly dependent on TRAF6-mediated signaling. Likewise, TRAF6 is required for lymph node organogenesis during embryonic development (pmc.ncbi.nlm.nih.gov). Lymph nodes fail to form in TRAF6 knockout mice, indicating TRAF6 transduces signals (likely from lymphotoxin or other TNF-family instructions) necessary for secondary lymphoid organ development (pmc.ncbi.nlm.nih.gov). Additionally, TRAF6 has an indispensable role in ectodermal organ development: it is involved in the formation of skin appendages such as hair follicles, teeth, and sweat glands. TRAF6^โ/โ mice display features of hypohidrotic ectodermal dysplasia (HED), including missing or malformed hair and sweat glands (pmc.ncbi.nlm.nih.gov). This developmental phenotype arises from failure of EDAR (Ectodysplasin A receptor) signaling, a TNF-family receptor required for skin appendage formation, which uses TRAF6 in its downstream NF-ฮบB activation cascade. Indeed, the broad biological roles of TRAF6 โ from immune response to bone metabolism to skin and neural development โ were illuminated by phenotypes of TRAF6 knockout models (pmc.ncbi.nlm.nih.gov). These varied functions underscore TRAF6โs participation in processes such as inflammatory signaling, apoptosis regulation (it contributes to survival signals downstream of CD40, RANK, etc.), developmental morphogenesis, and more.
TRAF6 is also involved in pathways like tumor necrosis factor-mediated signaling (GO:0033209) and regulation of programmed cell death. For example, through its interaction with pro-apoptotic adapters (like TRADD) and E3 ubiquitin ligases (cIAPs), TRAF6 can influence apoptotic signaling from TNFR family members, though this is more prominently a function of TRAF2 โ nonetheless, TRAF6โs ubiquitination activity has been linked to downstream survival pathways (www.ncbi.nlm.nih.gov). Furthermore, emerging research implicates TRAF6 in autophagy and cell metabolism. TRAF6 has been shown to interact with autophagy regulators (such as Beclin-1 and AMBRA1) and can promote autophagic degradation of certain substrates. For instance, in colorectal cancer cells TRAF6 activity leads to autophagic degradation of ฮฒ-catenin, thereby suppressing metastasis (pmc.ncbi.nlm.nih.gov). In muscle, TRAF6 contributes to muscle atrophy processes via ubiquitination of muscle proteins during starvation-induced catabolism (www.ncbi.nlm.nih.gov). In summary, TRAF6 is a multifaceted regulator of biological processes: it is best known for activating NF-ฮบB (GO:0051092) and MAPK pathways in immunity, but it also intersects with pathways controlling development (bone and ectoderm), cell survival, differentiation, and homeostasis. This widespread involvement is reflected in numerous GO biological process terms associated with TRAF6, including signal transduction (GO:0007165), positive regulation of NF-ฮบB transcription factor activity (GO:0051092), toll-like receptor signaling pathway (GO:0002224), osteoclast differentiation (GO:0030316; inferred from phenotype), and innate immune response (GO:0045087) (www.innatedb.org) (pmc.ncbi.nlm.nih.gov).
Disease Associations and Phenotypes
Given its central role in immune and developmental pathways, dysregulation or mutation of TRAF6 can lead to various diseases and phenotypic abnormalities. Loss-of-function of TRAF6 has been most clearly studied in mice, where TRAF6-null mutants are perinatal lethal with a complex phenotype. Key features in TRAF6^โ/โ mice include osteopetrosis (due to absent osteoclasts) and severe immunodeficiency; these mice fail to transmit signals from IL-1, TLRs, and CD40, resulting in impaired innate and adaptive immune responses (pmc.ncbi.nlm.nih.gov). They also lack certain lymph nodes and exhibit hypohidrotic ectodermal dysplasia (HED)-like traits (sparse hair, defective sweat glands and teeth) (pmc.ncbi.nlm.nih.gov). This constellation of phenotypes (immunodeficiency, osteopetrosis, and ectodermal dysplasia) is reminiscent of human syndromes caused by impaired NF-ฮบB signaling (such as NEMO/IKKฮณ deficiency). In fact, human TRAF6 mutations have been reported to cause a similar condition. A de novo heterozygous missense mutation in TRAF6 was identified in a patient with Hypohidrotic Ectodermal Dysplasia, who presented with the characteristic features of hypotrichosis (sparse hair), anhidrosis (inability to sweat), and hypodontia (missing teeth) (pubmed.ncbi.nlm.nih.gov). Functional studies of this mutant TRAF6 protein showed that it lost the ability to bind the adaptor EDARADD (an adaptor for the Ectodysplasin receptor), thereby blocking NF-ฮบB signaling in the EDAR pathway and explaining the HED phenotype (pubmed.ncbi.nlm.nih.gov). This human case confirms the crucial role of TRAF6 in ectodermal appendage development, aligning with the mouse knockout phenotype. Interestingly, the patientโs mutation was heterozygous, suggesting a dominant-negative effect or haploinsufficiency (since complete absence of TRAF6 is likely embryonically lethal in humans, as it is in mice). Some level of immune dysfunction might accompany such a mutation, though the primary presentation was ectodermal dysplasia; further evaluation of immune function in these patients is warranted given TRAF6โs known role in host defense.
Beyond developmental disorders, TRAF6 has been implicated in autoimmune and inflammatory diseases. Genetic association studies have identified polymorphisms in the TRAF6 gene linked to susceptibility to conditions like rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and others. For example, a single-nucleotide polymorphism rs540386 in an intronic region of TRAF6 was reported as a risk factor for RA and SLE in certain populations (pubmed.ncbi.nlm.nih.gov). Although not a coding change, this variant may affect TRAF6 expression or splicing, thereby altering immune signaling thresholds. (Subsequent studies on this SNPโs role in diseases like systemic sclerosis and giant cell arteritis yielded negative results (pubmed.ncbi.nlm.nih.gov) (pubmed.ncbi.nlm.nih.gov), indicating that the influence of TRAF6 variants can be disease-specific or ethnicity-specific.) Nevertheless, the association with RA/SLE suggests that TRAF6-mediated NF-ฮบB activation in immune cells is a contributing factor in autoimmunity. Overactivation of TRAF6 can lead to excessive inflammation, so polymorphisms enhancing TRAF6 expression or function might predispose to autoimmune pathology. In support of this, mice with TRAF6 overexpression in certain cells show hyperactive NF-ฮบB and inflammatory phenotypes, whereas TRAF6 haploinsufficiency can ameliorate autoimmune disease models (as seen in some arthritis models where reducing TRAF6 dampens joint inflammation (pubmed.ncbi.nlm.nih.gov)).
TRAF6 has also been linked to cancer and other pathologies. Its constant activation of NF-ฮบB can contribute to oncogenesis by promoting survival, proliferation, and metastasis of cancer cells. Elevated TRAF6 expression or activity has been observed in multiple cancers, including leukemia, lymphoma, breast and prostate cancers, and others (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). In acute myeloid leukemia (AML), higher TRAF6 levels correlate with gene expression changes that favor tumor cell survival and metabolic adaptation (pmc.ncbi.nlm.nih.gov). Functional studies in cell lines have shown that knocking down TRAF6 can reduce NF-ฮบB signaling and slow tumor growth, suggesting TRAF6 might act as an oncogenic driver in certain contexts. Conversely, TRAF6 also has context-dependent tumor suppressor functions, as indicated by the finding that TRAF6 can limit colorectal cancer metastasis by promoting autophagic degradation of ฮฒ-catenin, an oncogenic protein (pmc.ncbi.nlm.nih.gov). Thus, TRAF6โs role in cancer appears complex: it may contribute to tumor-promoting inflammation in some cases while helping restrain oncogenic substrates in others. Finally, aberrations in TRAF6 signaling are implicated in other diseases such as sepsis-induced tissue injury (one study found a TRAF6 variant associated with acute lung injury in sepsis) (pmc.ncbi.nlm.nih.gov), and neurodegenerative diseases (via neuroinflammatory pathways, although this is an emerging area). In summary, TRAF6 is associated with a wide spectrum of diseases: primary immunodeficiencies/developmental disorders when its function is lost (e.g. HED with immunodeficiency), autoimmune diseases when its signaling is hyperactive or dysregulated, and cancers where it can modulate tumor survival and metastasis. These associations highlight TRAF6 as a potential therapeutic target in inflammatory and osteolytic diseases โ for instance, inhibitors of the TRAF6โUbc13 interaction are being explored to dampen overactive NF-ฮบB in autoimmunity and cancer.
Protein Domains and Structural Features
The human TRAF6 protein consists of 522 amino acids and contains several well-defined domains that underlie its function (www.ncbi.nlm.nih.gov). The N-terminus of TRAF6 (approximately residues 50โ80) harbors a RING finger domain (C3HC4-type), a cysteine/histidine-rich motif that coordinates zinc and is characteristic of many E3 ubiquitin ligases (www.ncbi.nlm.nih.gov). This RING domain (Really Interesting New Gene domain) is crucial for TRAF6โs ubiquitin ligase activity: it provides the binding interface for E2 ubiquitin-conjugating enzymes. In particular, the TRAF6 RING domain binds the Ubc13โUev1A heterodimer, positioning Ubc13 to catalyze Lys-63 polyubiquitin chain formation (pmc.ncbi.nlm.nih.gov). Mutations in the RING (such as a Cys โ Ala at a zinc-coordinating residue) abolish TRAF6โs ability to autoubiquitinate and activate downstream signaling (pmc.ncbi.nlm.nih.gov). Zinc coordination is essential to RING structure, and indeed TRAF6โs RING (and other domains) confer zinc ion binding (GO:0008270). Immediately following the RING, TRAF6 contains a series of four Zinc finger motifs in tandem (pmc.ncbi.nlm.nih.gov). These zinc fingers (C2H2 or similar motifs) span the mid portion of the protein (roughly residues ~80โ140 for ZF1, and additional fingers up to ~250). The exact function of all four zinc fingers is not fully defined, but they serve as a bridge between the RING and the coiled-coil region (pmc.ncbi.nlm.nih.gov). Notably, experimental mutagenesis has shown that the first zinc finger (ZF1) is especially important; ZF1, together with the RING, is required for TRAF6โs E3 ligase activity and signaling, whereas zinc fingers 2โ4 are dispensable for some signaling outputs (pmc.ncbi.nlm.nih.gov). These internal ZFs likely contribute to the structural integrity of TRAF6 or positioning of the RING for optimal E2 interaction (pmc.ncbi.nlm.nih.gov).
Following the zinc fingers, TRAF6 has a predicted coiled-coil region (also called the โTRAF-Nโ region in some literature) that mediates oligomerization (www.ncbi.nlm.nih.gov). This coiled-coil (around residues ~289โ350) enables TRAF6 molecules to self-associate. In solution, TRAF6 can form homodimers and homotrimers, and evidence suggests that the N-terminal region dimerizes, while the C-terminal region trimerizes (rloopbase.nju.edu.cn). Oligomerization is functionally important because TRAF proteins typically act as trimers when bound to receptor tails. The coiled-coil region contributes to this trimeric assembly by bringing multiple TRAF6 molecules together, which can enhance the avidity for multivalent receptor sites and promote ubiquitin chain synthesis (since two RING domains in proximity can work in tandem with the Ubc13 dimer). Indeed, protein homotrimerization is noted as a property of TRAF6 (GO:0070207, GO:0051865) and is required for efficient signaling complex formation (www.innatedb.org).
The C-terminus of TRAF6 (approximately residues 350โ522) is occupied by the TRAF domain, a conserved region also found in other TRAF family members. The TRAF domain is subdivided into two subdomains: a coiled-coil segment (TRAF-N, as mentioned) and a globular TRAF-C domain at the very end. The TRAF-C domain (~residues 400โ522 in TRAF6) is a highly conserved ฮฒ-sandwich fold that directly mediates proteinโprotein interactions (www.ncbi.nlm.nih.gov). This domain is responsible for recognizing and binding specific peptide motifs in the cytoplasmic tails of receptors or adaptor proteins. For example, TRAF6โs TRAF-C domain binds the peptide motif PxQx(T/S) (found in CD40, RANK, IL-1 receptor-associated kinase (IRAK), etc.), although the binding specificity of TRAF6 is somewhat broader than that of TRAF2/3 which prefer PxQxD motifs (pmc.ncbi.nlm.nih.gov). Through the TRAF-C domain, TRAF6 engages adapters like IRAK1/IRAK4 (in TLR/IL-1R signaling), TRADD (in TNFR signaling), and EDARADD (in EDA receptor signaling), as well as the cytosolic domains of CD40, TNFRSF19 (TROY), and p75^NTR (www.ncbi.nlm.nih.gov). The TRAF-C domain of TRAF6 typically forms a trimeric structure (as observed in crystal structures of other TRAFs), providing three equivalent binding surfaces per trimer for recruiting three receptor tail peptides โ this multivalent binding is key for cluster formation at receptors. In summary, the domain architecture of TRAF6 is: RING finger (E3 ligase activity) โ Zinc fingers 1โ4 (structural/regulatory) โ Coiled-coil (oligomerization) โ TRAF-C domain (protein binding) (www.ncbi.nlm.nih.gov). This structure enables TRAF6 to act as a hub: the N-terminal half performs ubiquitination, while the C-terminal half brings TRAF6 to the correct location by binding upstream partners. Each domain is crucial: the loss of the TRAF-C domain abolishes receptor interactions, whereas loss of the RING finger abrogates downstream signal propagation (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Consistent with these features, TRAF6 is annotated with multiple molecular function GO terms: e.g. tumor necrosis factor receptor binding (GO:0005164), protein complex binding (GO:0032403), identical protein binding (GO:0042802, reflecting oligomerization), ubiquitin protein ligase activity (GO:0061630), and zinc ion binding (GO:0008270) (www.innatedb.org) (www.innatedb.org).
Structurally, TRAF6 shares the typical fold of TRAF family proteins in its C-terminus, but its N-terminus (RING and ZFs) confers a unique function (ubiquitin ligation) not all TRAFs have (TRAF2 and 3 also have RINGs, but TRAF6โs role in ubiquitination is especially prominent). High-resolution structures of the TRAF6 RING domain have been solved by NMR, revealing a compact domain that interacts with Ubc13 on a specific surface (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). Crystal structures of related TRAF domains (e.g., TRAF2, TRAF5) show trimers; by homology, TRAF6 is expected to trimerize similarly via its TRAF-C domain. Indeed, a crystal structure of a TRAF6 TRAF-C peptide complex (by Ye et al., 2002) confirmed a trimeric TRAF6 bound to peptide from CD40 (pmc.ncbi.nlm.nih.gov). These structural insights have informed mutational analyses; for instance, mutations in the TRAF-C domain that disrupt trimerization or binding (like WTrp^ at certain conserved positions) impair TRAF6 function in assays (pubmed.ncbi.nlm.nih.gov). In summary, the protein domains of TRAF6 provide the scaffolding and catalytic features that allow it to assemble signaling complexes and modify proteins with ubiquitin, thereby executing its role in cell signaling.
Expression Patterns and Regulation
Expression patterns: The TRAF6 gene is widely expressed in human tissues, consistent with its involvement in fundamental cellular processes. According to RNA profiling data, TRAF6 mRNA is ubiquitously expressed, with notable levels in immune organs. For example, TRAF6 shows substantial expression in the bone marrow, lymph nodes, spleen, thymus, and also in non-immune tissues like thyroid, lung, and others (www.ncbi.nlm.nih.gov). NCBIโs expression atlas reports an RPKM of ~5.9 in bone marrow and moderate levels (~3.6 RPKM) in thyroid, with expression detected in at least 25 different tissues (www.ncbi.nlm.nih.gov). This broad expression pattern reflects the fact that many cell types (immune cells, osteoclasts, epithelial cells, etc.) utilize TRAF6 for signaling. Protein-level studies (e.g., by Western blot or immunohistochemistry) similarly show that TRAF6 is present in a variety of cell types. Immune cells (macrophages, dendritic cells, B and T lymphocytes) express robust levels of TRAF6, which can further increase upon activation. Developmentally, TRAF6 is expressed from early stages; mouse embryos show TRAF6 transcripts in mesenchymal tissues and epithelial appendages, aligning with its role in skeletal and skin development (pmc.ncbi.nlm.nih.gov). There is some evidence that TRAF6 expression may be higher in certain activated or differentiated states (for instance, mature osteoclasts express more TRAF6 protein than undifferentiated precursors, to meet the demand for RANK signaling (pubmed.ncbi.nlm.nih.gov)). In pathology, aberrant TRAF6 expression has been noted: some tumors or leukemic cells overexpress TRAF6, and conversely, certain immunodeficient conditions might have reduced TRAF6. Overall, the baseline expression of TRAF6 is constitutive in most tissues, implying it is a ready component of signaling cascades across cell types.
Regulation: TRAF6 activity is tightly regulated at multiple levels to prevent excessive or improper signaling. One key level of regulation is post-transcriptional, via microRNAs. miR-146a, a microRNA induced by NF-ฮบB during inflammatory responses, directly targets the mRNA of TRAF6 (and IRAK1) to negatively regulate the TLR/IL-1R signaling pathway. This was demonstrated in human cells where increased miR-146a levels (for instance after LPS or viral infection) led to reduced TRAF6 protein and consequently dampened NF-ฮบB activity (pmc.ncbi.nlm.nih.gov). miR-146a binds to the 3โ UTR of TRAF6 mRNA causing translational repression or mRNA degradation. This forms part of a feedback loop: TLR engagement causes NF-ฮบB to induce miR-146a, which then limits TRAF6/IRAK1, preventing overactivation of the inflammatory response (pmc.ncbi.nlm.nih.gov). Perturbation of this regulation (e.g., miR-146a deficiency in mice) results in hyper-inflammatory phenotypes due to unchecked TRAF6 signaling. In addition to miR-146a, other microRNAs (such as miR-146b, miR-150, miR-125b, etc.) have been reported to target TRAF6 in various contexts (viral infections, cancer cells, etc.), highlighting a common strategy of the cell to fine-tune TRAF6 levels.
Another level of regulation is post-translational modification of TRAF6 itself. TRAF6 activity requires its ubiquitination, but itโs also regulated by deubiquitinases (DUBs) and proteolysis. Several DUBs can remove ubiquitin chains from TRAF6, thereby turning off the signal. Notably, the enzyme A20 (TNFAIP3), a ubiquitin-editing enzyme induced by NF-ฮบB, can interact with TRAF6 and cleave K63 chains or add K48 chains to terminate signaling from TLRs. Similarly, the Zinc finger CCCH-type protein 12A (ZC3H12A, also known as MCPIP1) has been identified as a negative regulator of TRAF6. ZC3H12A was shown to function as a deubiquitinase for TRAF family proteins; in Zc3h12a knockout mice, TRAF6 remained aberrantly ubiquitinated and active after LPS stimulation, leading to prolonged NF-ฮบB activity (pmc.ncbi.nlm.nih.gov). Thus, ZC3H12A removes ubiquitin chains from TRAF6, limiting the duration of TLR signaling (pmc.ncbi.nlm.nih.gov). Another mechanism is via proteasomal degradation: while K63-linked chains on TRAF6 are signaling scaffolds, if TRAF6 becomes tagged with K48-linked ubiquitin (for example by the action of certain E3s like cIAP1 or via A20โs E3 activity), it can be targeted for proteasomal degradation. Indeed, there is evidence that in the absence of ongoing signaling, TRAF6 levels can be down-regulated by ubiquitin-proteasome pathways to prevent spontaneous activation. Some viral proteins also induce TRAF6 degradation as an immune evasion tactic.
Regulation of TRAF6 can also occur at the transcriptional level. Certain stimuli can induce TRAF6 gene transcription; for example, NF-ฮบB and AP-1 have binding sites in the TRAF6 promoter in some species, suggesting a possible positive feedback where strong immune stimuli upregulate TRAF6 mRNA. Conversely, negative regulation of transcription can occur in specific differentiation states; a noted example is in dendritic cells, where tolerogenic signals can decrease TRAF6 expression as part of inducing immune tolerance. Furthermore, cytokines like TGF-ฮฒ have been reported to down-modulate TRAF6 expression in some contexts, aligning with TGF-ฮฒโs anti-inflammatory role.
In summary, TRAF6 is expressed in almost all tissues (housekeeping level expression in most cells, higher in immune and skeletal systems) and is subject to elaborate regulation. MicroRNAs (e.g. miR-146a) and deubiquitinating enzymes (e.g. A20, ZC3H12A) provide crucial negative feedback to restrain TRAF6-mediated signaling (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). This ensures that signals like NF-ฮบB are activated transiently and appropriately. Dysregulation of these controls โ for instance, loss of miR-146a or A20 โ leads to hyperactivation of TRAF6 and has been linked to autoimmune inflammation and lymphoma, illustrating the importance of proper TRAF6 regulation in health.
Evolutionary Conservation
TRAF6 is a member of the TRAF family, which is conserved throughout metazoan evolution. Orthologs of human TRAF6 can be found in a wide range of species, indicating that its function in immune signaling arose early and has been maintained. All vertebrate groups examined (mammals, birds, reptiles, amphibians, fish) possess a TRAF6 gene that is highly similar in sequence and domain structure to human TRAF6 (pmc.ncbi.nlm.nih.gov). For instance, mouse Traf6 is ~87% identical in amino acid sequence to human TRAF6, and the two proteins are functionally interchangeable in many experimental systems (human TRAF6 can rescue Traf6^โ/โ mouse cells) (pmc.ncbi.nlm.nih.gov). Organisms as evolutionarily distant as chicken (Gallus gallus) and zebrafish have clear TRAF6 orthologs with the same domain architecture (RING, Zn fingers, TRAF domain) and known involvement in NF-ฮบB signaling during immune responses (pmc.ncbi.nlm.nih.gov).
Importantly, TRAF6 is also present in invertebrates, notably in insects. Drosophila melanogaster (fruit fly) encodes a TRAF6 ortholog (sometimes referred to as dTRAF6 or Traf6), which plays a critical role in the flyโs immune defense. Drosophila TRAF6 participates in the Toll pathway and the Imd pathway, the fly analogs of NF-ฮบB activation routes, serving as a positive regulator of these innate immune signaling cascades (flybase.org). It has been shown to mediate signaling downstream of the Drosophila Toll receptor (which fights fungal infections) and the Imd pathway (activated by gram-negative bacteria), mirroring the role of mammalian TRAF6 in TLR/IL-1R pathways. Additionally, Drosophila TRAF6 has been implicated in Notch signaling regulation and the TNF-like Eiger pathway (flybase.org), suggesting that even in flies TRAF6 connects multiple developmental and immune signals. The presence of TRAF6 in insects indicates that TRAF6 predates the divergence of vertebrates and invertebrates, and that the innate immune NF-ฮบB pathways in both lineages use this conserved adaptor. Simpler organisms like Caenorhabditis elegans (nematode) do not have a clear TRAF6 ortholog (worms lack many components of the TNF/Toll pathways), highlighting that TRAF6 is tied to the evolution of those specific signaling systems present in arthropods and vertebrates.
From an evolutionary perspective, TRAF6 appears to be more ancient than some other TRAFs that are restricted to vertebrates. Phylogenetic analyses (including studies in jawless fish like lamprey) suggest that TRAF6 and TRAF3 represent earlier-arising TRAF subfamilies, whereas TRAF2/5 might have arisen later by duplication (pmc.ncbi.nlm.nih.gov). Lampreys (which are jawless vertebrates) possess genes that cluster with TRAF3/6, supporting the idea that a common ancestor of these existed in early vertebrates (pmc.ncbi.nlm.nih.gov). In evolutionary terms, TRAF6 is unique among TRAFs because it combines the TRAF domain with a potent RING E3 ligase domain โ this combination endowed early immune systems with a direct means to invoke ubiquitin signaling. The functional conservation is exemplified by cross-species experiments: human TRAF6 can restore TLR signaling in TRAF6-deficient mouse cells, and conversely, overexpression of Drosophila TRAF6 in human cells can activate NF-ฮบB, indicating conserved mechanism of action. Even specific interactions are conserved; for example, the interaction between TRAF6 and the E2 enzyme Ubc13 is found in mammals, birds, and probably insects (in Drosophila, dTRAF6 works with Bendless, the fly Ubc13). The TRAF-C domain binding specificity (to PxQxT motifs) is also conserved โ the fly TRAF6 binds the Toll receptor adaptor dMyD88 which has a matching motif.
Overall, TRAF6โs presence in such diverse taxa underscores its importance: it is a conserved signaling node in the immune system of animals. The evolutionary conservation extends to the amino acid sequence (especially in the TRAF-C domain, which in human TRAF6 shares ~40-50% identity with insect TRAF6, and higher with other vertebrates), and to biological function (activation of NF-ฮบB and regulation of development). This deep conservation suggests strong selective pressure to maintain TRAF6โs role; mutations disrupting TRAF6 generally have severe fitness costs (as seen by lethal phenotypes). In the context of Gene Ontology, the evolutionary conservation of TRAF6 is captured by its InParanoid orthologs and Panther families, aligning TRAF6 across taxa in databases, and by the conserved GO annotations (e.g., innate immune response) assigned to TRAF6 orthologs in model organisms (flybase.org).
Key Experimental Evidence and Literature
The understanding of TRAF6โs function and importance comes from a body of research spanning over two decades. Some key experimental milestones and literature include:
Identification of TRAF6 (mid-1990s): TRAF6 was first described in 1995-1996 when several TRAF proteins were discovered. Unlike TRAF1-5, TRAF6 was noted to associate not only with TNF receptor family members but also with the IL-1/Toll pathway. Early biochemical studies (e.g., by Darnay et al. 1998, 1999) showed TRAF6 binding to CD40 and presence in signaling complexes upon IL-1 stimulation (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov). These studies established TRAF6 as a unique adapter bridging TNF and IL-1 receptor families.
TRAF6 knockout mouse studies (1999): Two independent groups (Lomaga et al., Genes & Development, 1999 (pmc.ncbi.nlm.nih.gov), and Naito et al., Genes to Cells, 1999 (pmc.ncbi.nlm.nih.gov)) generated TRAF6-deficient mice. They reported that TRAF6^โ/โ mice had osteopetrosis and severe combined immune defects, including defective IL-1, TLR, and CD40 signaling (pmc.ncbi.nlm.nih.gov). The Lomaga paperโs title, โTRAF6 deficiency results in osteopetrosis and defective IL-1, CD40, and LPS signaling,โ succinctly highlights these findings (pmc.ncbi.nlm.nih.gov). These landmark studies provided genetic proof of TRAF6โs essential role in both bone metabolism and immunity.
Hypohidrotic Ectodermal Dysplasia link (2001-2002): Subsequent work connected TRAF6 to ectodermal development. In 2001, Kobayashi et al. (EMBO J. 2001) observed that TRAF6^โ/โ mice lacked certain skin appendages, and in 2002 Naito et al. published PNAS findings that โTRAF6-deficient mice display hypohidrotic ectodermal dysplasiaโ (pmc.ncbi.nlm.nih.gov). This extended TRAF6โs importance to developmental biology. Much later (2012), a human case (as cited above by Fulton et al.) solidified this connection by identifying a TRAF6 mutation in a HED patient.
Discovery of K63 ubiquitination mechanism (2000): A breakthrough in understanding TRAF6 signaling was the discovery that TRAF6 activates NF-ฮบB through a novel ubiquitin-dependent mechanism. Deng et al., Cell 2000 and Wang et al., Nature 2001 demonstrated that TRAF6, together with Ubc13โUev1A, catalyzes K63-linked polyubiquitin chains on itself or associated proteins (pmc.ncbi.nlm.nih.gov). These non-degradative chains were shown to recruit and activate the TAK1 kinase complex, which then activates IKKฮฒ, leading to NF-ฮบB activation (pmc.ncbi.nlm.nih.gov). This was a paradigm-shifting discovery, revealing ubiquitination as a signaling event (not just a degradation signal). Those studies identified TAK1 (MAP3K7) and its partner TAB2 as key targets of TRAF6โs ubiquitin scaffold (www.ncbi.nlm.nih.gov). The Nature 2001 paper by Wang et al. and Cell 2000 paper by Deng et al. are heavily cited as foundational mechanistic work in NF-ฮบB signaling.
Structural studies (2002โ2008): Several structural biology studies provided insight into TRAF6. For example, Ye et al., Nature 2002 solved the crystal structure of the TRAF6โTRAF-C domain in complex with a peptide from CD40, illuminating how TRAF6 recognizes its binding motifs (pmc.ncbi.nlm.nih.gov). Mercier et al., Protein Sci. 2007 determined the NMR structure of the TRAF6 RING domain and mapped its interaction with Ubc13 (pmc.ncbi.nlm.nih.gov). These works clarified the interfaces for E2 enzyme binding and for receptor/adaptor binding, respectively. Furthermore, Lamothe et al., JBC 2008 performed mutational analysis of TRAF6โs zinc fingers and RING (pmc.ncbi.nlm.nih.gov) (pmc.ncbi.nlm.nih.gov), showing ZF1โs importance โ this indicated specific intra-molecular cooperation between domains for activity.
TRAF6 in T cell tolerance and autoimmunity (2003โ2008): A series of immunology studies (e.g., by King, Choi, Kobayashi et al.) explored TRAF6 in adaptive immunity. Notably, Kobayashi et al., Immunity 2003 showed TRAF6 in dendritic cells is needed for Th priming and that lack of TRAF6 can lead to defective T-cell activation (pmc.ncbi.nlm.nih.gov). Conversely, King et al., Nat. Med. 2006 found that TRAF6 in T cells regulates peripheral tolerance โ T cellโspecific TRAF6 deletion led to autoimmune inflammation (pmc.ncbi.nlm.nih.gov). These studies indicated TRAF6โs nuanced roles in immunity beyond just initial signaling: itโs involved in maintaining immune homeostasis.
Human disease associations (2010s): More recent clinical and genetic studies have implicated TRAF6 in human diseases. For instance, Bluml et al., Nat. Genet. 2010 identified TRAF6 polymorphisms associated with rheumatoid arthritis, and others linked it to lupus. The human HED case (PMID 22917955, 2013) gave direct evidence of a pathogenic TRAF6 mutation in humans. Additionally, research into cancer uncovered that TRAF6 is overexpressed in some tumors (e.g., Starczynowski et al., Cancer Cell 2011 linked TRAF6 overactivity to myelodysplastic syndrome/AML). These findings are expanding TRAF6โs relevance to oncology and genetic disease.
TRAF6 and autophagy/metabolism (2010s): Emerging experiments show TRAF6 in non-canonical roles. Ni et al., Nat. Cell Biol. 2013 reported TRAF6-mediated ubiquitination of Beclin-1 to activate autophagy in TLR signaling. Sun et al., MCB 2012 showed TRAF6 in muscle atrophy pathways (www.ncbi.nlm.nih.gov). Such studies highlight TRAF6โs involvement beyond classical inflammatory signaling, in processes like metabolic reprogramming in cancer (pmc.ncbi.nlm.nih.gov) and cell stress responses.
In sum, the literature on TRAF6 is extensive. Key evidence from knockout models, biochemical reconstitution, and structural analysis has firmly established TRAF6 as a critical adaptor and ubiquitin ligase in NF-ฮบB signaling. These findings have been captured in Gene Ontology annotations (with evidence codes from mutant phenotype experiments (IMP) to direct assays (IDA) for binding and activity, etc.) supporting numerous GO terms for TRAF6. Curators rely on these seminal studies โ for example, Lomaga 1999 for GO:0045087 (innate immune response, IMP evidence), Deng 2000 for GO:0004842 (ubiquitin ligase activity, IDA evidence), and Naito 2002 for GO:0009887 (organ development, IMP) โ to annotate TRAF6โs functions, processes, and locations. As research continues, TRAF6 remains a focus due to its central role in translating external signals into cellular responses, and it stands as a prime example of how a scaffold protein with enzymatic activity can orchestrate complex biological outcomes. (pmc.ncbi.nlm.nih.gov) (www.ncbi.nlm.nih.gov)
๐ Additional Documentation
Notes
(TRAF6-notes.md)
TRAF6 Gene Review Notes
2025-01-14 - Retired Annotation Fix
Issue: Validation failure due to 33 annotations not found in the current GOA file.
Root Cause: Multiple PMIDs that were referenced in the original annotations have been removed from the current GOA database. These include:
- PMID:1406630 (canonical NF-kappaB signal transduction)
- PMID:11460167 (defense response to bacterium, positive regulation of NF-kappaB)
- PMID:25038658 (negative regulation of NF-kappaB)
- PMID:27746020 (protein K48-linked ubiquitination)
- PMID:7479976 (toll-like receptor 4 signaling pathway)
- PMID:21931555 (cytoplasmic pattern recognition receptor signaling)
- PMID:20532808 (interleukin-33-mediated signaling pathway)
- PMID:31376257 (interleukin-17A-mediated signaling pathway)
- PMID:23202584 (autophagosome assembly)
Action Taken: Marked annotations with these missing PMIDs as retired: true to exclude them from GOA validation while preserving the annotation review work.
Validation Status: Reduced the number of missing annotations from 33 to approximately 27, though some complex annotations with multiple evidence types may still need individual attention.
Outstanding Issues:
- Some inconsistent review actions across evidence types for the same GO terms
- Evidence type mismatches with current GOA
- Additional retired annotations may need identification
Note: TRAF6 is a heavily studied immune signaling protein with extensive experimental literature, which explains the large number of annotations and the ongoing changes in the GOA database as curation standards evolve.
๐ View Raw YAML
id: Q9Y4K3
gene_symbol: TRAF6
taxon:
id: NCBITaxon:9606
label: Homo sapiens
description: TRAF6 (TNF receptor-associated factor 6) is a critical E3 ubiquitin ligase
and signal transduction adaptor that synthesizes K63-linked polyubiquitin chains
for non-degradative signaling. It serves as a central hub in multiple immune signaling
pathways including TLR/IL-1R, TNF receptor superfamily (CD40, RANK), and cytosolic
pattern recognition receptors, mediating activation of NF-ฮบB and MAPK pathways.
Beyond immunity, TRAF6 is essential for osteoclast differentiation, ectodermal development
(hair, teeth, sweat glands), and has emerging roles in autophagy regulation. The
protein contains an N-terminal RING domain for E3 ligase activity, zinc fingers,
and a C-terminal TRAF domain for protein-protein interactions, enabling both enzymatic
and scaffolding functions in signal transduction.
references:
- id: PMID:11460167
title: TAK1 is a ubiquitin-dependent kinase of MKK and IKK
findings:
- statement: TRAF6 activates IKK and JNK in response to pro-inflammatory mediators
supporting_text: TRAF6 is a signal transducer that activates IkappaB kinase (IKK)
and Jun amino-terminal kinase (JNK) in response to pro-inflammatory mediators
such as interleukin-1 (IL-1) and lipopolysaccharides (LPS).
reference_section_type: ABSTRACT
- statement: TRAF6 catalyzes K63-linked polyubiquitin chains for IKK activation
supporting_text: This Ubc complex, together with TRAF6, catalyses the formation
of a Lys 63 (K63)-linked polyubiquitin chain that mediates IKK activation through
a unique proteasome-independent mechanism.
reference_section_type: ABSTRACT
- id: PMID:11057907
title: Activation of the IkappaB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating
enzyme complex and a unique polyubiquitin chain
findings:
- statement: TRAF6 functions with Ubc13/Uev1A to catalyze K63-linked polyubiquitin
chain synthesis
supporting_text: TRAF6, a RING domain protein, functions together with Ubc13/Uev1A
to catalyze the synthesis of unique polyubiquitin chains linked through lysine-63
(K63) of ubiquitin.
reference_section_type: ABSTRACT
- statement: K63-linked polyubiquitin chain synthesis is required for IKK activation
supporting_text: Blockade of this polyubiquitin chain synthesis, but not inhibition
of the proteasome, prevents the activation of IKK by TRAF6.
reference_section_type: ABSTRACT
- id: PMID:9346484
title: 'IKK-1 and IKK-2: cytokine-activated IkappaB kinases essential for NF-kappaB
activation'
- id: PMID:17135271
title: Site-specific Lys-63-linked tumor necrosis factor receptor-associated factor
6 auto-ubiquitination is a critical determinant of I kappa B kinase activation
findings:
- statement: TRAF6 Lys-63-linked auto-ubiquitination is critical for IKK activation
supporting_text: Site-specific Lys-63-linked tumor necrosis factor receptor-associated
factor 6 auto-ubiquitination is a critical determinant of I kappa B kinase activation.
reference_section_type: TITLE
- id: PMID:18768464
title: Tumor necrosis factor receptor-associated factor 6 is an intranuclear transcriptional
coactivator in osteoclasts
- id: file:human/TRAF6/TRAF6-deep-research.md
title: Deep research synthesis of TRAF6 literature
- id: file:human/TRAF6/TRAF6-deep-research-falcon.md
title: Falcon deep research report on TRAF6
findings:
- statement: TRAF6 is a cytosolic RING-type E3 ubiquitin ligase and signaling adaptor
with N-terminal RING/zinc fingers and C-terminal MATH/TRAF-C receptor-binding
domain
supporting_text: '**TRAF6 (TNF receptor-associated factor 6)** is a human TRAF-family
cytosolic signaling adaptor that also functions as a **RING-type E3 ubiquitin
ligase** (EC 2.3.2.27). Recent literature consistently describes a conserved
multi-domain architecture with **N-terminal RING** and multiple **zinc fingers**,
a **coiled-coil/TRAF-N** region, and a **C-terminal TRAF-C/MATH (TRAF) domain**
responsible for receptor/adaptor binding'
reference_section_type: RESULTS
- statement: TRAF6 converts receptor stimulation into polyubiquitin-based signaling
scaffolds that recruit and activate TAK1 and IKK to drive NF-ฮบB and MAPK activation
supporting_text: 'Functionally, TRAF6 is best understood as a **signal-proximal
ubiquitin ligase/scaffold** that converts receptor stimulation into **polyubiquitin-based
signaling scaffolds** which recruit and activate downstream kinases (e.g., TAK1
and IKK) to drive **NF-ฮบB** and **MAPK** activation'
reference_section_type: RESULTS
- statement: TRAF6 catalyzes ubiquitin transfer as an E3 ligase, primarily forming
non-degradative signaling polyubiquitin chains rather than proteasomal degradation
tags
supporting_text: TRAF6 catalyzes ubiquitin transfer in the canonical E1โE2โE3
cascade as an **E3 ligase**, promoting formation of polyubiquitin chains that
serve primarily as **non-degradative signaling scaffolds**, rather than proteasomal
degradation signals
reference_section_type: RESULTS
- statement: TRAF6 partners with the Ubc13/UBE2NโUev1A/UBE2V1 E2 complex to assemble
K63-linked polyubiquitin chains
supporting_text: The most consistently supported E2 complex for TRAF6 is **Ubc13/UBE2NโUev1A/UBE2V1**,
which is directly linked to TRAF6-mediated assembly of **K63-linked polyubiquitin
chains**
reference_section_type: RESULTS
- statement: Representative K63-modified TRAF6 signaling substrates include IKKฮณ/NEMO,
TAK1, IRAK1, and TRAF6 itself; TRAF6 can also participate in K48-linked ubiquitination
in selected contexts
supporting_text: Representative TRAF6-linked K63-modified signaling substrates/adaptors
cited in 2024 review pages include **IKKฮณ/NEMO, TAK1, IRAK1, and TRAF6 itself**...
The same review corpus notes that TRAF6 can participate in **K48-linked** ubiquitination
in selected contexts, indicating that TRAF6 signaling can be coupled to regulated
proteostasis depending on cellular conditions
reference_section_type: RESULTS
- statement: TRAF6 is a cytosolic adaptor that associates with the cytoplasmic tails
of transmembrane receptors and with inducible cytosolic signaling assemblies
supporting_text: Across recent primary studies, TRAF6 is described/observed as
a **cytosolic adaptor** that associates with the **cytoplasmic tails of transmembrane
receptors** and with inducible cytosolic signaling assemblies
reference_section_type: RESULTS
- statement: TRAF6 binds the RANK cytoplasmic domain in RANKL signaling to coordinate
downstream MAPK/AKT and NF-ฮบB/NFATc1 programs that drive osteoclastogenesis
supporting_text: '**Receptor-proximal complexes (RANK):** TRAF6 binds receptor
cytoplasmic domains such as **RANK** in RANKL signaling to coordinate downstream
activation of MAPKs/AKT and NF-ฮบB/NFATc1 programs that drive osteoclastogenesis'
reference_section_type: RESULTS
- statement: TRAF6 forms cytosolic liquid-like condensates with TIFA upon ADP-heptose
sensing, acting as microreactors that concentrate ubiquitin machinery and downstream
effectors
supporting_text: 'In response to ADP-heptose and other inflammatory stimuli, TRAF6
can form **cytosolic liquid-like condensates** (LLPS) with dynamic exchange
properties (20โ60% FRAP recovery in ~5 min), which are proposed to function
as โmicroreactorsโ concentrating ubiquitin machinery and downstream effectors'
reference_section_type: RESULTS
- statement: TRAF6 is recruited downstream of receptor-proximal adaptors in TLR/IL-1R
family signaling to promote TAK1 and IKK activation and NF-ฮบB/MAPK programs
supporting_text: A central, repeatedly cited role is TRAF6 in **TLR/IL-1 receptor
family signaling**, where TRAF6 is recruited downstream of receptor-proximal
adaptors/kinases to promote TAK1 and IKK activation, leading to NF-ฮบB and MAPK
transcriptional programs
reference_section_type: RESULTS
- statement: TRAF6 is essential in RANKL/RANK signaling, acting as a key adaptor/E3
ligase required for osteoclastogenic downstream cascades (MAPK, PI3K/AKT, IฮบB
phosphorylation) and NF-ฮบB activation
supporting_text: TRAF6 is essential in **RANKLโRANK signaling**, acting as a key
adaptor/E3 ligase required for osteoclastogenic downstream cascades (MAPK, PI3K/AKT,
IฮบB phosphorylation) and NF-ฮบB activation
reference_section_type: RESULTS
- statement: EBV LMP1 uses a direct TRAF6-binding motif (P379VQLSY in the CTAR2
region) to drive NF-ฮบB/JNK/p38/IRF7 signaling and lymphoma cell survival, distinct
from the CD40โTRAF6 interface
supporting_text: A major 2024 development is the high-resolution demonstration
that EBV **LMP1** uses a **direct TRAF6-binding motif** (CTAR2 region) to drive
NF-ฮบB/JNK/p38/IRF7 signaling and lymphoma cell survival... Importantly, structural/functional
analyses indicate the **LMP1โTRAF6 interface differs from CD40โTRAF6**
reference_section_type: RESULTS
- statement: 14-3-3ฮถ binds TRAF6 after RANKL stimulation, reduces the RANKโTRAF6
interaction, and promotes TRAF6 ubiquitination and proteasome-dependent degradation,
dampening downstream RANKL signaling
supporting_text: Ayyasamy et al. (2024-07; https://doi.org/10.1016/j.jbc.2024.107487)
show that **14-3-3ฮถ** binds TRAF6 (interaction increases rapidly after RANKL
stimulation), reduces the **RANKโTRAF6 interaction**, and promotes **TRAF6 ubiquitination
and proteasome-dependent degradation**, dampening downstream RANKL signaling
reference_section_type: RESULTS
- statement: Within TIFA condensates, TRAF6 amplifies K63-linked polyubiquitin synthesis
when reconstituted with E1 and the Ubc13/Uev1A E2 complex
supporting_text: Li et al. (2024-01; https://doi.org/10.34133/research.0315)
report that during ALPK1/TIFA-dependent sensing of bacterial ADP-heptose, TRAF6
undergoes stimulus-dependent **LLPS** and is recruited into **TIFA condensates**.
Within these condensates, TRAF6 markedly amplifies **K63-linked polyubiquitin
synthesis** when reconstituted with E1 and the **Ubc13/Uev1A** E2 complex
reference_section_type: RESULTS
- statement: TRAF6 signaling output is determined by higher-order mesoscale organization
into condensates that retain K63 chains and concentrate enzymatic components,
not only by enzyme identity
supporting_text: TRAF6 signaling output is not only determined by enzyme identity
(E2 pairing and linkage type), but also by **higher-order mesoscale organization**
(condensates that retain long K63 chains and concentrate enzymatic components)
reference_section_type: RESULTS
- statement: Other TRAF6 pathways include CD40/TRAF6, IL-17R via Act1, TCR via CARMA1โBCL10โMALT1,
TLR7/8/9โMYD88โIRF7, and ALPK1โTIFAโTRAF6 innate sensing
supporting_text: Additional pathways in recent review/primary papers include **CD40/TRAF6-related
signaling**, **IL-17R via Act1**, **TCR via CARMA1โBCL10โMALT1**, **TLR7/8/9โMYD88โIRF7**,
and **ALPK1โTIFAโTRAF6** innate sensing
reference_section_type: RESULTS
- statement: TRAF6 should be annotated as a cytosolic receptor-proximal E3 ubiquitin
ligase/adaptor whose primary biochemical output is Ubc13/Uev1A-dependent K63
polyubiquitin chain assembly, enabling recruitment/activation of TAK1/IKK and
MAPK modules
supporting_text: TRAF6 should be annotated as a **cytosolic receptor-proximal
E3 ubiquitin ligase/adaptor** whose primary biochemical output is **Ubc13/Uev1A-dependent
K63 polyubiquitin chain assembly**, enabling recruitment/activation of TAK1/IKK
and MAPK modules to drive inflammatory and differentiation programs
reference_section_type: RESULTS
- id: GO_REF:0000002
title: Gene Ontology annotation through association of InterPro records with GO
terms
- id: GO_REF:0000107
title: Automatic transfer of experimentally verified manual GO annotation data to
orthologs using Ensembl Compara
- id: GO_REF:0000120
title: Automatic annotation of binding predictions from structures using InterPro
- id: PMID:15361868
title: Interferon-alpha induction through Toll-like receptors involves a direct
interaction of IRF7 with MyD88 and TRAF6.
findings:
- statement: IRF7 directly interacts with MyD88 and TRAF6 for interferon-alpha induction
supporting_text: Interferon-alpha induction through Toll-like receptors involves
a direct interaction of IRF7 with MyD88 and TRAF6.
reference_section_type: TITLE
- id: PMID:10465784
title: ECSIT is an evolutionarily conserved intermediate in the Toll/IL-1 signal
transduction pathway.
findings:
- statement: ECSIT bridges TRAF6 to MEKK-1 in Toll/IL-1 signaling pathways
supporting_text: We report the identification and characterization of a novel
intermediate in these signaling pathways that bridges TRAF6 to MEKK-1.
reference_section_type: ABSTRACT
- id: PMID:11279055
title: A diverse family of proteins containing tumor necrosis factor receptor-associated
factor domains.
findings:
- statement: MUL and USP7 bind to TRAF6 through their TRAF domains
supporting_text: MUL and USP7 are capable of binding in vitro via their TDs to
all of the previously identified TRAF family proteins (TRAF1, TRAF2, TRAF3,
TRAF4, TRAF5, and TRAF6), whereas the TD of SPOP interacts weakly with TRAF1
and TRAF6 only.
reference_section_type: ABSTRACT
- statement: MUL and USP7 TRAF domains suppress TRAF6-induced NF-kappaB activation
supporting_text: Analysis of various MUL and USP7 mutants by transient transfection
assays indicated that the TDs of these proteins are necessary and sufficient
for suppressing NF-kappaB induction by TRAF2 and TRAF6 as well as certain TRAF-binding
TNF family receptors.
reference_section_type: ABSTRACT
- id: PMID:1406630
title: 'Selection of optimal kappa B/Rel DNA-binding motifs: interaction of both
subunits of NF-kappa B with DNA is required for transcriptional activation.'
- id: PMID:25038658
title: Identification of a NFฮบB inhibitory peptide from tryptic ฮฒ-casein hydrolysate.
- id: PMID:27746020
title: The K48-K63 Branched Ubiquitin Chain Regulates NF-ฮบB Signaling.
- id: PMID:7479976
title: Signal-induced degradation of I kappa B alpha requires site-specific ubiquitination.
- id: PMID:21931555
title: Vaccinia virus protein C6 is a virulence factor that binds TBK-1 adaptor
proteins and inhibits activation of IRF3 and IRF7.
- id: PMID:20532808
title: Interleukin-33 stimulates formation of functional osteoclasts from human
CD14(+) monocytes.
- id: PMID:31376257
title: IL-17A upregulates P-glycoprotein expression in peripheral blood lymphocytes
of patients with rheumatoid arthritis through TAK1.
- id: PMID:23202584
title: Structure of the human ATG12~ATG5 conjugate required for LC3 lipidation in
autophagy.
- id: PMID:12048232
title: Quantitative prediction of NF-kappa B DNA-protein interactions.
- id: PMID:14703513
title: Identification of Ser-386 of interferon regulatory factor 3 as critical target
for inducible phosphorylation that determines activation.
- id: PMID:9891032
title: Essential role of interferon regulatory factor 3 in direct activation of
RANTES chemokine transcription.
- id: PMID:23776175
title: SASH1 is a scaffold molecule in endothelial TLR4 signaling.
- id: PMID:34721373
title: Defining the Role of Nuclear Factor (NF)-ฮบB p105 Subunit in Human Macrophage
by Transcriptomic Analysis of NFKB1 Knockout THP1 Cells.
- id: PMID:18079694
title: A critical role of RICK/RIP2 polyubiquitination in Nod-induced NF-kappaB
activation.
- id: PMID:10882101
title: TAB2, a novel adaptor protein, mediates activation of TAK1 MAPKKK by linking
TAK1 to TRAF6 in the IL-1 signal transduction pathway.
findings:
- statement: TAB2 mediates activation of TAK1 by linking it to TRAF6
supporting_text: TAB2, a novel adaptor protein, mediates activation of TAK1 MAPKKK
by linking TAK1 to TRAF6 in the IL-1 signal transduction pathway.
reference_section_type: TITLE
- statement: IL-1 induces TAB2 translocation to mediate TAK1-TRAF6 association
supporting_text: IL-1 stimulates translocation of TAB2 from the membrane to the
cytosol where it mediates the IL-1-dependent association of TAK1 with TRAF6.
reference_section_type: ABSTRACT
- id: PMID:29441066
title: TANK-Binding Kinase 1 (TBK1) Isoforms Negatively Regulate Type I Interferon
Induction by Inhibiting TBK1-IRF3 Interaction and IRF3 Phosphorylation.
- id: PMID:10514511
title: TRAF family proteins interact with the common neurotrophin receptor and modulate
apoptosis induction.
findings:
- statement: TRAF6 interaction with p75NTR provides cytoprotection against apoptosis
supporting_text: Coexpression of TRAF2 with p75(NTR) enhanced cell death, whereas
coexpression of TRAF6 was cytoprotective.
reference_section_type: ABSTRACT
- statement: TRAF6 enhances p75NTR-induced NF-kappaB activation
supporting_text: TRAF4 also inhibited the NF-kappaB response, whereas TRAF2 and
TRAF6 enhanced p75(NTR)-induced NF-kappaB activation.
reference_section_type: ABSTRACT
- id: PMID:10920205
title: T6BP, a TRAF6-interacting protein involved in IL-1 signaling.
findings:
- statement: T6BP specifically associates with TRAF6 through its N-terminal ring
finger and zinc finger domains
supporting_text: We report the identification of a TRAF-interacting protein, T6BP,
that specifically associates with TRAF6. This interaction occurs between the
coiled-coil region of T6BP and the N-terminal ring finger and zinc finger domains
of TRAF6.
reference_section_type: ABSTRACT
- statement: IL-1 induces TRAF6-T6BP complex formation in an IRAK-dependent manner
supporting_text: IL-1, but not tumor necrosis factor, induces TRAF6-T6BP complex
formation in a ligand-dependent manner. Formation of the TRAF6-T6BP complex
depends on the presence of the IL-1 receptor-associated kinase (IRAK).
reference_section_type: ABSTRACT
- id: PMID:11463333
title: Isolation and characterization of two novel A20-like proteins.
- id: PMID:11518704
title: IRAK-mediated translocation of TRAF6 and TAB2 in the interleukin-1-induced
activation of NFkappa B.
findings:
- statement: IRAK mediates IL-1-induced translocation of TRAF6 and TAB2 from membrane
to cytosol
supporting_text: When IRAK is phosphorylated in response to IL-1, it binds to
the membrane where it forms a complex with TRAF6; TRAF6 then dissociates and
translocates to the cytosol. The membrane-bound IRAK similarly mediates the
IL-1-induced translocation of TAB2 from the membrane to the cytosol.
reference_section_type: ABSTRACT
- statement: TRAF6-TAK1-TAB1-TAB2 complex formation in cytosol is required for TAK1
activation
supporting_text: The translocation of TAB2 and TRAF6 is needed to form a TRAF6-TAK1-TAB1-TAB2
complex in the cytosol and thus activate TAK1.
reference_section_type: ABSTRACT
- id: PMID:11751921
title: A novel zinc finger protein that inhibits osteoclastogenesis and the function
of tumor necrosis factor receptor-associated factor 6.
- id: PMID:12140561
title: Distinct molecular mechanism for initiating TRAF6 signalling.
findings:
- statement: TRAF6 recognizes a Pro-X-Glu-X-X-(aromatic/acidic) binding motif in
receptors and adaptors
supporting_text: The structural determinant of the petide TRAF6 interaction reveals
a Pro-X-Glu-X-X-(aromatic/acidic residue) TRAF6-binding motif, which is present
not only in CD40 and TRANCE-R but also in the three IRAK adapter kinases for
IL-1R/TLR signalling.
reference_section_type: ABSTRACT
- statement: TRAF6 mediates signaling in both TNFR and IL-1R/TLR superfamilies through
a universal mechanism
supporting_text: Tumour-necrosis factor (TNF) receptor-associated factor 6 (TRAF6)
is the only TRAF family member that participates in signal transduction of both
the TNF receptor (TNFR) superfamily and the interleukin-1 receptor (IL-1R)/Toll-like
receptor (TLR) superfamily; it is important for adaptive immunity, innate immunity
and bone homeostasis.
reference_section_type: ABSTRACT
- id: PMID:12242293
title: Interleukin-1 (IL-1) receptor-associated kinase-dependent IL-1-induced signaling
complexes phosphorylate TAK1 and TAB2 at the plasma membrane and activate TAK1
in the cytosol.
- id: PMID:12496252
title: Pellino 1 is required for interleukin-1 (IL-1)-mediated signaling through
its interaction with the IL-1 receptor-associated kinase 4 (IRAK4)-IRAK-tumor
necrosis factor receptor-associated factor 6 (TRAF6) complex.
- id: PMID:15280356
title: Induction of apoptosis by X-linked ectodermal dysplasia receptor via a caspase
8-dependent mechanism.
- id: PMID:15998638
title: Vaccinia virus protein A52R activates p38 mitogen-activated protein kinase
and potentiates lipopolysaccharide-induced interleukin-10.
- id: PMID:16189514
title: Towards a proteome-scale map of the human protein-protein interaction network.
- id: PMID:16286467
title: Interleukin-1beta induction of NFkappaB is partially regulated by H2O2-mediated
activation of NFkappaB-inducing kinase.
- id: PMID:20713597
title: Autophagy requires endoplasmic reticulum targeting of the PI3-kinase complex
via Atg14L.
- id: PMID:23524951
title: mTOR inhibits autophagy by controlling ULK1 ubiquitylation, self-association
and function through AMBRA1 and TRAF6.
findings:
- statement: mTOR controls autophagy through regulation of TRAF6-mediated ULK1 ubiquitination
supporting_text: mTOR inhibits autophagy by controlling ULK1 ubiquitylation, self-association
and function through AMBRA1 and TRAF6.
reference_section_type: TITLE
- id: PMID:25891078
title: IRGM governs the core autophagy machinery to conduct antimicrobial defense.
- id: PMID:30778222
title: Distinct functions of ATG16L1 isoforms in membrane binding and LC3B lipidation
in autophagy-related processes.
- id: PMID:33637724
title: VPS34 K29/K48 branched ubiquitination governed by UBE3C and TRABID regulates
autophagy, proteostasis and liver metabolism.
- id: PMID:23392225
title: FIP200 regulates targeting of Atg16L1 to the isolation membrane.
- id: PMID:28890335
title: The ER-Localized Transmembrane Protein EPG-3/VMP1 Regulates SERCA Activity
to Control ER-Isolation Membrane Contacts for Autophagosome Formation.
- id: PMID:34796041
title: Hepatitis B virus X Protein Promotes Liver Cancer Progression through Autophagy
Induction in Response to TLR4 Stimulation.
- id: PMID:25371197
title: TAK1-ECSIT-TRAF6 complex plays a key role in the TLR4 signal to activate
NF-ฮบB.
findings:
- statement: TAK1-ECSIT-TRAF6 complex is essential for TLR4-mediated NF-ฮบB activation
supporting_text: TAK1-ECSIT-TRAF6 complex plays a key role in the TLR4 signal
to activate NF-ฮบB.
reference_section_type: TITLE
- id: PMID:25355951
title: Ubiquitination of ECSIT is crucial for the activation of p65/p50 NF-ฮบBs in
Toll-like receptor 4 signaling.
- id: PMID:26189595
title: Polyubiquitination of Transforming Growth Factor ฮฒ-activated Kinase 1 (TAK1)
at Lysine 562 Residue Regulates TLR4-mediated JNK and p38 MAPK Activation.
- id: PMID:19675569
title: Direct activation of protein kinases by unanchored polyubiquitin chains.
findings:
- statement: Free K63-linked polyubiquitin chains synthesized by TRAF6 directly
activate TAK1 and IKK
supporting_text: By reconstituting TAK1 activation in vitro using purified proteins,
here we show that free Lys 63 polyubiquitin chains, which are not conjugated
to any target protein, directly activate TAK1 by binding to the ubiquitin receptor
TAB2 (also known as MAP3K7IP2).
reference_section_type: ABSTRACT
- statement: Unanchored polyubiquitin chains synthesized by TRAF6 and UBCH5C activate
the IKK complex
supporting_text: Furthermore, we found that unanchored polyubiquitin chains synthesized
by TRAF6 and UBCH5C (also known as UBE2D3) activate the IKK complex.
reference_section_type: ABSTRACT
- id: PMID:9252186
title: A cytokine-responsive IkappaB kinase that activates the transcription factor
NF-kappaB.
- id: PMID:11397809
title: IRAK1b, a novel alternative splice variant of interleukin-1 receptor-associated
kinase (IRAK), mediates interleukin-1 signaling and has prolonged stability.
- id: PMID:11238466
title: Equine herpesvirus protein E10 induces membrane recruitment and phosphorylation
of its cellular homologue, bcl-10.
- id: PMID:15121867
title: TRAF family proteins link PKR with NF-kappa B activation.
- id: PMID:12459498
title: NF-kappaB activator Act1 associates with IL-1/Toll pathway adaptor molecule
TRAF6.
- id: PMID:14530355
title: Toll/IL-1 receptor domain-containing adaptor inducing IFN-beta (TRIF) associates
with TNF receptor-associated factor 6 and TANK-binding kinase 1, and activates
two distinct transcription factors, NF-kappa B and IFN-regulatory factor-3, in
the Toll-like receptor signaling.
- id: PMID:16378096
title: Association of beta-arrestin and TRAF6 negatively regulates Toll-like receptor-interleukin
1 receptor signaling.
- id: PMID:10094049
title: The kinase TAK1 can activate the NIK-I kappaB as well as the MAP kinase cascade
in the IL-1 signalling pathway.
findings:
- statement: TAK1 acts upstream of NIK and associates with TRAF6 in IL-1 signaling
supporting_text: Here we show that the MAPKK kinase TAK1 acts upstream of NIK
in the IL-1-activated signalling pathway and that TAK1 associates with TRAF6
during IL-1 signalling.
reference_section_type: ABSTRACT
- statement: TAK1 links TRAF6 to the NIK-IKK cascade in IL-1 signaling
supporting_text: Our results indicate that TAK1 links TRAF6 to the NIK-IKK cascade
in the IL-1 signalling pathway.
reference_section_type: ABSTRACT
- id: PMID:14982987
title: Toll-like receptor 3-mediated activation of NF-kappaB and IRF3 diverges at
Toll-IL-1 receptor domain-containing adapter inducing IFN-beta.
- id: PMID:15125833
title: The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation by BCL10
and MALT1 in T lymphocytes.
- id: PMID:11244088
title: The atypical protein kinase C-interacting protein p62 is a scaffold for NF-kappaB
activation by nerve growth factor.
- id: PMID:12925853
title: SIGIRR, a negative regulator of Toll-like receptor-interleukin 1 receptor
signaling.
- id: PMID:11728344
title: A novel TNF receptor family member binds TWEAK and is implicated in angiogenesis.
- id: Reactome:R-HSA-202453
title: TRAF6 pathway
- id: PMID:12270937
title: Role of TRAF3 and -6 in the activation of the NF-kappa B and JNK pathways
by X-linked ectodermal dysplasia receptor.
findings: []
- id: PMID:17728323
title: Identification of TRAF6-dependent NEMO polyubiquitination sites through analysis
of a new NEMO mutation causing incontinentia pigmenti.
findings: []
- id: PMID:26620909
title: Reversible ubiquitination shapes NLRC5 function and modulates NF-ฮบB activation
switch.
findings: []
- id: Reactome:R-HSA-202534
title: Ubiquitination of NEMO by TRAF6
findings: []
- id: Reactome:R-HSA-2730904
title: Auto-ubiquitination of TRAF6
findings: []
- id: Reactome:R-HSA-446877
title: TRAF6 is K63 poly-ubiquitinated
findings: []
- id: Reactome:R-HSA-450358
title: 'Activated TRAF6 synthesizes unanchored polyubiquitin chains upon TLR stimulation '
findings: []
- id: Reactome:R-HSA-936942
title: Auto ubiquitination of oligo-TRAF6 bound to p-IRAK2
findings: []
- id: Reactome:R-HSA-936986
title: Activated TRAF6 synthesizes unanchored polyubiquitin chains
findings: []
- id: Reactome:R-HSA-9645394
title: 'Activated TRAF6 synthesizes unanchored polyubiquitin chains upon ALPK1:ADP-heptose
stimulation '
findings: []
- id: Reactome:R-HSA-9645414
title: Auto ubiquitination of TRAF6 bound to ALPK1:ADP-heptose:TIFA oligomer
findings: []
- id: Reactome:R-HSA-975147
title: Auto ubiquitination of oligo-TRAF6 bound to p-IRAK2 at endosome membrane
findings: []
- id: GO_REF:0000033
title: Annotation inferences using phylogenetic trees
findings: []
- id: GO_REF:0000043
title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
findings: []
- id: GO_REF:0000117
title: Electronic Gene Ontology annotations created by ARBA machine learning models
findings: []
- id: PMID:15465037
title: The coiled-coil domain of TRAF6 is essential for its auto-ubiquitination.
findings: []
- id: PMID:16874300
title: The signaling adapter p62 is an important mediator of T helper 2 cell function
and allergic airway inflammation.
findings: []
- id: PMID:16932746
title: The UL144 gene product of human cytomegalovirus activates NFkappaB via a
TRAF6-dependent mechanism.
findings: []
- id: PMID:17124500
title: Sphingosine 1-phosphate as a regulator of osteoclast differentiation and
osteoclast-osteoblast coupling.
findings: []
- id: PMID:17389358
title: Unc-51-like kinase 1/2-mediated endocytic processes regulate filopodia extension
and branching of sensory axons.
findings: []
- id: PMID:17449468
title: RBCK1 negatively regulates tumor necrosis factor- and interleukin-1-triggered
NF-kappaB activation by targeting TAB2/3 for degradation.
findings: []
- id: PMID:17703191
title: Essential role for TAX1BP1 in the termination of TNF-alpha-, IL-1- and LPS-mediated
NF-kappaB and JNK signaling.
findings: []
- id: PMID:17948050
title: Malt1 ubiquitination triggers NF-kappaB signaling upon T-cell activation.
findings: []
- id: PMID:18093978
title: Nuclear tumor necrosis factor receptor-associated factor 6 in lymphoid cells
negatively regulates c-Myb-mediated transactivation through small ubiquitin-related
modifier-1 modification.
findings: []
- id: PMID:18239685
title: Inflammatory cardiac valvulitis in TAX1BP1-deficient mice through selective
NF-kappaB activation.
findings: []
- id: PMID:18682563
title: Herpesvirus tegument protein activates NF-kappaB signaling through the TRAF6
adaptor protein.
findings: []
- id: PMID:18758450
title: The type I TGF-beta receptor engages TRAF6 to activate TAK1 in a receptor
kinase-independent manner.
findings: []
- id: PMID:19365808
title: 'NESCA: a new NEMO/IKKgamma and TRAF6 interacting protein.'
findings: []
- id: PMID:19465916
title: E2 interaction and dimerization in the crystal structure of TRAF6.
findings: []
- id: PMID:19549727
title: Analysis of the human E2 ubiquitin conjugating enzyme protein interaction
network.
findings: []
- id: PMID:19713527
title: The E3 ligase TRAF6 regulates Akt ubiquitination and activation.
findings: []
- id: PMID:19820695
title: Helicobacter pylori CagA activates NF-kappaB by targeting TAK1 for TRAF6-mediated
Lys 63 ubiquitination.
findings: []
- id: PMID:20079715
title: NUMBL interacts with TRAF6 and promotes the degradation of TRAF6.
findings: []
- id: PMID:20080758
title: WDR5 is essential for assembly of the VISA-associated signaling complex and
virus-triggered IRF3 and NF-kappaB activation.
findings: []
- id: PMID:20628368
title: Tom70 mediates activation of interferon regulatory factor 3 on mitochondria.
findings: []
- id: PMID:20676093
title: The transmembrane activator TACI triggers immunoglobulin class switching
by activating B cells through the adaptor MyD88.
findings: []
- id: PMID:21516116
title: Next-generation sequencing to generate interactome datasets.
findings: []
- id: PMID:21541365
title: Neurosteroid dehydroepiandrosterone interacts with nerve growth factor (NGF)
receptors, preventing neuronal apoptosis.
findings: []
- id: PMID:21782231
title: MAVS forms functional prion-like aggregates to activate and propagate antiviral
innate immune response.
findings: []
- id: PMID:21813773
title: IFN-induced TPR protein IFIT3 potentiates antiviral signaling by bridging
MAVS and TBK1.
findings: []
- id: PMID:21903422
title: Mapping a dynamic innate immunity protein interaction network regulating
type I interferon production.
findings: []
- id: PMID:21988832
title: Toward an understanding of the protein interaction network of the human liver.
findings: []
- id: PMID:22493164
title: Systematic analysis of dimeric E3-RING interactions reveals increased combinatorial
complexity in human ubiquitination networks.
findings: []
- id: PMID:22528498
title: Protein kinase C-ฮด negatively regulates T cell receptor-induced NF-ฮบB activation
by inhibiting the assembly of CARMA1 signalosome.
findings: []
- id: PMID:22904686
title: The germinal center kinase TNIK is required for canonical NF-ฮบB and JNK signaling
in B-cells by the EBV oncoprotein LMP1 and the CD40 receptor.
findings: []
- id: PMID:22908223
title: Tetraspanin 6 (TSPAN6) negatively regulates retinoic acid-inducible gene
I-like receptor-mediated immune signaling in a ubiquitination-dependent manner.
findings: []
- id: PMID:23015697
title: Human metapneumovirus M2-2 protein inhibits innate cellular signaling by
targeting MAVS.
findings: []
- id: PMID:23514740
title: TNFR-associated factor 6 regulates TCR signaling via interaction with and
modification of LAT adapter.
findings: []
- id: PMID:25416956
title: A proteome-scale map of the human interactome network.
findings: []
- id: PMID:25736436
title: WDFY1 mediates TLR3/4 signaling by recruiting TRIF.
findings: []
- id: PMID:25861989
title: TRAF Family Member-associated NF-ฮบB Activator (TANK) Inhibits Genotoxic Nuclear
Factor ฮบB Activation by Facilitating Deubiquitinase USP10-dependent Deubiquitination
of TRAF6 Ligase.
findings: []
- id: PMID:26068852
title: INNATE IMMUNITY. Cytosolic detection of the bacterial metabolite HBP activates
TIFA-dependent innate immunity.
findings: []
- id: PMID:26385923
title: Structural Insights into mitochondrial antiviral signaling protein (MAVS)-tumor
necrosis factor receptor-associated factor 6 (TRAF6) signaling.
findings: []
- id: PMID:26458771
title: Loss of Tifab, a del(5q) MDS gene, alters hematopoiesis through derepression
of Toll-like receptor-TRAF6 signaling.
findings: []
- id: PMID:26752465
title: Increased Expression of Interleukin-36, a Member of the Interleukin-1 Cytokine
Family, in Inflammatory Bowel Disease.
findings: []
- id: PMID:27107012
title: Pooled-matrix protein interaction screens using Barcode Fusion Genetics.
findings: []
- id: PMID:27173435
title: An organelle-specific protein landscape identifies novel diseases and molecular
mechanisms.
findings: []
- id: PMID:28514442
title: Architecture of the human interactome defines protein communities and disease
networks.
findings: []
- id: PMID:32296183
title: A reference map of the human binary protein interactome.
findings: []
- id: PMID:32814053
title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins
and Uncovers Widespread Protein Aggregation in Affected Brains.
findings: []
- id: PMID:33961781
title: Dual proteome-scale networks reveal cell-specific remodeling of the human
interactome.
findings: []
- id: GO_REF:0000024
title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
by curator judgment of sequence similarity.
findings: []
- id: GO_REF:0000044
title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
vocabulary mapping, accompanied by conservative changes to GO terms applied by
UniProt.
findings: []
- id: PMID:12296995
title: TAK1-dependent activation of AP-1 and c-Jun N-terminal kinase by receptor
activator of NF-kappaB.
findings: []
- id: PMID:18984593
title: TRAF6 and MEKK1 play a pivotal role in the RIG-I-like helicase antiviral
pathway.
findings: []
- id: PMID:19825828
title: Act1, a U-box E3 ubiquitin ligase for IL-17 signaling.
findings: []
- id: PMID:20038579
title: Lysine 63-linked polyubiquitination of TAK1 at lysine 158 is required for
tumor necrosis factor alpha- and interleukin-1beta-induced IKK/NF-kappaB and JNK/AP-1
activation.
findings: []
- id: PMID:20501938
title: TRAF6 and A20 regulate lysine 63-linked ubiquitination of Beclin-1 to control
TLR4-induced autophagy.
findings: []
- id: PMID:21068390
title: Bifunctional apoptosis regulator (BAR), an endoplasmic reticulum (ER)-associated
E3 ubiquitin ligase, modulates BI-1 protein stability and function in ER Stress.
findings: []
- id: PMID:22412986
title: Activation of interferon regulatory factor 5 by site specific phosphorylation.
findings: []
- id: PMID:22851693
title: ฮฒ-TrCP-mediated IRAK1 degradation releases TAK1-TRAF6 from the membrane to
the cytosol for TAK1-dependent NF-ฮบB activation.
findings: []
- id: PMID:25515214
title: Brain endothelial miR-146a negatively modulates T-cell adhesion through repressing
multiple targets to inhibit NF-ฮบB activation.
findings: []
- id: PMID:26456228
title: Ring finger protein 166 potentiates RNA virus-induced interferon-ฮฒ production
via enhancing the ubiquitination of TRAF3 and TRAF6.
findings: []
- id: PMID:26839314
title: Ubiquitin-specific Protease 20 Regulates the Reciprocal Functions of ฮฒ-Arrestin2
in Toll-like Receptor 4-promoted Nuclear Factor ฮบB (NFฮบB) Activation.
findings: []
- id: PMID:30927622
title: TARBP2 inhibits IRF7 activation by suppressing TRAF6-mediated K63-linked
ubiquitination of IRF7.
findings: []
- id: PMID:31435003
title: MicroRNA-146a negatively regulates IL-33 in activated group 2 innate lymphoid
cells by inhibiting IRAK1 and TRAF6.
findings: []
- id: PMID:33799071
title: The extreme C-terminus of IRAK2 assures full TRAF6 ubiquitination and optimal
TLR signaling.
findings: []
- id: PMID:35183823
title: IL-17 upregulates MCP-1 expression via Act1 / TRAF6 / TAK1 in experimental
autoimmune myocarditis.
findings: []
- id: PMID:8910514
title: Identification of TRAF6, a novel tumor necrosis factor receptor-associated
factor protein that mediates signaling from an amino-terminal domain of the CD40
cytoplasmic region.
findings: []
- id: Reactome:R-HSA-166058
title: MyD88:MAL(TIRAP) cascade initiated on plasma membrane
findings: []
- id: Reactome:R-HSA-166362
title: Dissociation of hp-IRAK1:TRAF6 from the activated TLR:oligo-Myd88:TIRAP:p-IRAK4
complex
findings: []
- id: Reactome:R-HSA-166363
title: TRAF6 binds to hp- IRAK1
findings: []
- id: Reactome:R-HSA-166869
title: TRAF6 binds MEKK1
findings: []
- id: Reactome:R-HSA-168164
title: Toll Like Receptor 3 (TLR3) Cascade
findings: []
- id: Reactome:R-HSA-168184
title: Activated TAK1 mediates phosphorylation of the IKK Complex
findings: []
- id: Reactome:R-HSA-177690
title: Activated TLR3:TRIF:K63pUb-TRAF6 recruits TAK1complex
findings: []
- id: Reactome:R-HSA-177692
title: 'Activation of recruited TAK1 within the activated TLR3 complex '
findings: []
- id: Reactome:R-HSA-177694
title: Viral dsRNA:TLR3:TICAM1 complex recruits TRAF6
findings: []
- id: Reactome:R-HSA-193641
title: IKK-beta is recruited
findings: []
- id: Reactome:R-HSA-193665
title: MYD88 dissociates
findings: []
- id: Reactome:R-HSA-193669
title: TRAF6 binds to p75NTR:NRIF
findings: []
- id: Reactome:R-HSA-193684
title: p62 recruits an atypical PKC
findings: []
- id: Reactome:R-HSA-193694
title: p62 is recruited and forms a complex with TRAF6
findings: []
- id: Reactome:R-HSA-193695
title: IRAK interacts with TRAF6
findings: []
- id: Reactome:R-HSA-193700
title: p75NTR ICD signals to NF-kB
findings: []
- id: Reactome:R-HSA-193703
title: IKKbeta is activated
findings: []
- id: Reactome:R-HSA-193705
title: IKKbeta phosphorylates IkB causing NF-kB to dissociate
findings: []
- id: Reactome:R-HSA-202403
title: TCR signaling
findings: []
- id: Reactome:R-HSA-202472
title: Translocation of TRAF6 to CBM complex
findings: []
- id: Reactome:R-HSA-202500
title: Activation of IKK complex
findings: []
- id: Reactome:R-HSA-202510
title: Activation of TAK1-TAB2 complex
findings: []
- id: Reactome:R-HSA-205112
title: gamma-secretase cleaves p75NTR, releasing NRIF and TRAF6
findings: []
- id: Reactome:R-HSA-205118
title: TRAF6 polyubiquitinates NRIF
findings: []
- id: Reactome:R-HSA-209566
title: TRAF6 is auto-ubiquitinated
findings: []
- id: Reactome:R-HSA-2262775
title: Dissociation of p-IRAK2:TRAF6 from the activated TLR:oligo-Myd88:TIRAP:p-IRAK4
complex
findings: []
- id: Reactome:R-HSA-2262777
title: 'TRAF6 binds to p-IRAK2 '
findings: []
- id: Reactome:R-HSA-2454202
title: Fc epsilon receptor (FCERI) signaling
findings: []
- id: Reactome:R-HSA-2730861
title: Recruitment of TAK1 kinase complex to oligo-K63-pUb-TRAF6
findings: []
- id: Reactome:R-HSA-2730864
title: Recruitment of TRAF6 to CBM complex by binding to MALT1
findings: []
- id: Reactome:R-HSA-2730876
title: Phosphorylation of IKK-beta by TAK1
findings: []
- id: Reactome:R-HSA-2730900
title: Activation of TAK1 complex bound to pUb-TRAF6
findings: []
- id: Reactome:R-HSA-2730903
title: Oligomerization of TRAF6
findings: []
- id: Reactome:R-HSA-446862
title: Hyperphosphorylated IRAK1 associates with TRAF6
findings: []
- id: Reactome:R-HSA-446870
title: Polyubiquitinated TRAF6 binds the TAK1 complex
findings: []
- id: Reactome:R-HSA-446894
title: TRAF6 binding leads to IRAK1:TRAF6 release
findings: []
- id: Reactome:R-HSA-450173
title: IRAK1 induces oligomerisation of TRAF6
findings: []
- id: Reactome:R-HSA-450187
title: TAK1 is activated within the TAK1 complex
findings: []
- id: Reactome:R-HSA-450259
title: Auto ubiqitination of TRAF6 bound to viral dsRNS:TLR3:TICAM1 complex
findings: []
- id: Reactome:R-HSA-450337
title: Activated TAK1 phosphorylates MKK4/MKK7
findings: []
- id: Reactome:R-HSA-450346
title: activated human TAK1 phosphorylates MKK3/MKK6
findings: []
- id: Reactome:R-HSA-507719
title: p62:MEKK3 binds to TRAF6
findings: []
- id: Reactome:R-HSA-5607732
title: K63polyUb-TAK1 autophosphorylates
findings: []
- id: Reactome:R-HSA-5607742
title: K63polyUb-p-3T,1S-TAK1 phosphorylates IKK-beta
findings: []
- id: Reactome:R-HSA-5607747
title: TRAF6 binds MALT1 oligomers
findings: []
- id: Reactome:R-HSA-5607751
title: TRAF6 oligomerizes
findings: []
- id: Reactome:R-HSA-5607756
title: TRAF6 oligomer autoubiquitinates
findings: []
- id: Reactome:R-HSA-5607757
title: K63polyUb-TRAF6 ubiquitinates TAK1
findings: []
- id: Reactome:R-HSA-5607759
title: TRIKA2 binds K63polyUb-TRAF6 oligomer
findings: []
- id: Reactome:R-HSA-5621481
title: C-type lectin receptors (CLRs)
findings: []
- id: Reactome:R-HSA-5690843
title: OTUB1, (OTUB2) binds RNF128, TRAF3, TRAF6, RHOA
findings: []
- id: Reactome:R-HSA-5690870
title: OTUD7B,TNFAIP3 deubiquitinate TRAF6
findings: []
- id: Reactome:R-HSA-5696627
title: CYLD deubiquitinates K63polyUb-TRAF2,K63polyUb-TRAF6,K63polyUb-RIPK1,K63polyUb-IKBKG
findings: []
- id: Reactome:R-HSA-741386
title: RIP2 induces K63-linked ubiquitination of NEMO
findings: []
- id: Reactome:R-HSA-847070
title: Phosphorylated TAK1 dissociates from the TLR3 receptor complex
findings: []
- id: Reactome:R-HSA-8869456
title: USP4 deubiquitinate TRAF2,TRAF6
findings: []
- id: Reactome:R-HSA-8869506
title: TNFAIP3 in OTUD7B:TNFAIP3:ZRANB1 deubiquitinates K63polyUb-TRAF6
findings: []
- id: Reactome:R-HSA-8948015
title: hp-IRAK1:3xTRAF6 binds UBE2N:UBE2V1:K63-polyUb
findings: []
- id: Reactome:R-HSA-8948018
title: UBE2N:UBE2V1 dissociates from hp-IRAK1:3xK63-polyUb-TRAF6:3xUBE2N:UBE2V1
findings: []
- id: Reactome:R-HSA-9020702
title: Interleukin-1 signaling
findings: []
- id: Reactome:R-HSA-918230
title: Recruitment of TRAF6/TRAF2 to MAVS
findings: []
- id: Reactome:R-HSA-933525
title: Phosphorylation and release of IRF7
findings: []
- id: Reactome:R-HSA-933527
title: Recruitment of TBK1/IKK epsilon complex to TANK:TRAF6
findings: []
- id: Reactome:R-HSA-933530
title: Activation of IKK by MEKK1
findings: []
- id: Reactome:R-HSA-933537
title: Recruitment of TANK to TRAF6
findings: []
- id: Reactome:R-HSA-933538
title: Recruitment of IRF7 to TRAF6
findings: []
- id: Reactome:R-HSA-936947
title: Activated TLR4:TICAM1:K63pUb-TRAF6 recruits TAK1complex
findings: []
- id: Reactome:R-HSA-936951
title: Activation of TAK1 complex bound to activated TLR4 complex
findings: []
- id: Reactome:R-HSA-936952
title: Auto ubiquitination of TRAF6 bound to the activated TLR4 complex
findings: []
- id: Reactome:R-HSA-936960
title: Activated TRAF6:p-IRAK2 interacts with TAK1 complex
findings: []
- id: Reactome:R-HSA-936963
title: IRAK2 induces TRAF6 oligomerization
findings: []
- id: Reactome:R-HSA-936985
title: Activated TLR4:TICAM1 recruits TRAF6
findings: []
- id: Reactome:R-HSA-936991
title: 'Auto phosphorylation of TAK1 bound to p-IRAK2:pUb oligo-TRAF6: free K63
pUb:TAB1:TAB2/TAB3 '
findings: []
- id: Reactome:R-HSA-937032
title: NEMO subunit of IKK complex binds to activated IRAK1
findings: []
- id: Reactome:R-HSA-937034
title: IRAK1 phosphorylates Pellino
findings: []
- id: Reactome:R-HSA-937044
title: Pellino binds hp-IRAK1:TRAF6
findings: []
- id: Reactome:R-HSA-937050
title: Pellino ubiquitinates hp-IRAK1
findings: []
- id: Reactome:R-HSA-937061
title: 'TRIF (TICAM1)-mediated TLR4 signaling '
findings: []
- id: Reactome:R-HSA-937072
title: TRAF6-mediated induction of TAK1 complex within TLR4 complex
findings: []
- id: Reactome:R-HSA-937075
title: Phosphorylated TAK1 leaves activated TLR receptor complex
findings: []
- id: Reactome:R-HSA-9628444
title: 'Activated TRAF6 synthesizes unanchored polyubiquitin chains upon TLR3 stimulation '
findings: []
- id: Reactome:R-HSA-9645406
title: ALPK1:ADP-heptose:p-T9-TIFA oligomer:K63pUb-TRAF6 oligomer recruits MAP3K7
(TAK1)
findings: []
- id: Reactome:R-HSA-9645442
title: 'Auto phosphorylation of TAK1 within the ALPK1:ADP-heptose:p-T9-TIFA:pUb-TRAF6:
free K63 pUb:TAB1:TAB2/TAB3 :MAP3K7 complex'
findings: []
- id: Reactome:R-HSA-9645460
title: Alpha-protein kinase 1 signaling pathway
findings: []
- id: Reactome:R-HSA-9645501
title: TRAF6 oligomerizes within the ALPK1:ADP-heptose:TIFA oligomer complex
findings: []
- id: Reactome:R-HSA-9645520
title: ALPK1:ADP-heptose:TIFA oligomer recruits TRAF6
findings: []
- id: Reactome:R-HSA-9685219
title: SARS-CoV-1 nsp3 deubiquinates K63-linked pUb oligo-TRAF6 (TLR7/8 signaling)
findings: []
- id: Reactome:R-HSA-9705145
title: TBK1, IKBKE form homodimers
findings: []
- id: Reactome:R-HSA-9705323
title: Phosphorylation of TBK1/IKBKE
findings: []
- id: Reactome:R-HSA-9750946
title: TRAF2,6 ubiquitinates NLRC5
findings: []
- id: Reactome:R-HSA-975097
title: Activated TRAF6:p-IRAK2 interacts with TAK1 complex upon TLR7/8 or 9 stimulation
findings: []
- id: Reactome:R-HSA-975100
title: Dissociation of hp-IRAK1/or IRAK2:TRAF6-oligomer from the p-IRAK4 :oligo-Myd88:activated
TLR7/8 or 9 complex
findings: []
- id: Reactome:R-HSA-975103
title: 'Auto phosphorylation of TAK1 bound to p-IRAK2:pUb oligo-TRAF6: free K63
pUb:TAB1:TAB2/TAB3 upon TLR7/8 or 9 activation'
findings: []
- id: Reactome:R-HSA-975106
title: Phosphorylation and release of IRF7 upon TLR7/8 or 9 activation
findings: []
- id: Reactome:R-HSA-975111
title: 'TRAF6 binds to hp- IRAK1/or p-IRAK2:p-IRAK4:MyD88:activated TLR7/8 or 9 '
findings: []
- id: Reactome:R-HSA-975118
title: TRAF6 ubiquitinqtes IRF7 within the activated TLR7/8 or 9 complex
findings: []
- id: Reactome:R-HSA-975119
title: NEMO subunit of IKK complex binds to activated IRAK1 upon stimulation of
TLR7/8 or 9
findings: []
- id: Reactome:R-HSA-975122
title: Pellino ubiquitinates hp-IRAK1 upon TLR7/8 or 9 activation<br>
findings: []
- id: Reactome:R-HSA-975139
title: 'IRAK1 phosphorylates Pellino upon TLR7/8 or 9 activation '
findings: []
- id: Reactome:R-HSA-975142
title: Pellino binds hp-IRAK1:TRAF6 upon TLR7/8 or 9 activation
findings: []
- id: Reactome:R-HSA-975185
title: IRAK2 induces TRAF6 oligomerization initiated from endosomal compartments
findings: []
- id: Reactome:R-HSA-975188
title: TRAF6 interacts with IRF7 upon TLR7/8 or 9 activation
findings: []
- id: Reactome:R-HSA-975857
title: TRAF6 binds to hp- IRAK1 or p-IRAK2
findings: []
- id: Reactome:R-HSA-9758604
title: Ubiquitination of IKBKG by TRAF6
findings: []
- id: Reactome:R-HSA-975871
title: MyD88 cascade initiated on plasma membrane
findings: []
- id: Reactome:R-HSA-975879
title: Dissociation of hp-IRAK1:TRAF6 or IRAK2:TRAF6-oligomer from the activated
TLR5 or 10:oligo-Myd88:p-IRAK4 complex
findings: []
existing_annotations:
- term:
id: GO:0004842
label: ubiquitin-protein transferase activity
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: TRAF6 functions as an E3 ubiquitin ligase that catalyzes K63-linked polyubiquitination,
which is essential for its signal transduction role. This activity is well-established
through multiple experimental studies showing TRAF6 works with the Ubc13-Uev1A
E2 complex to synthesize K63-linked chains on target proteins including itself.
action: ACCEPT
reason: This is a core molecular function of TRAF6 that is extensively validated
experimentally. The IEA annotation from sequence similarity is strongly supported
by multiple experimental evidence entries (EXP, IDA) in the same dataset and
extensive literature.
supported_by:
- reference_id: PMID:11057907
supporting_text: Activation of the IkappaB kinase complex by TRAF6 requires
a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin
chain
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 functions as a ubiquitin-protein transferase (E3 ubiquitin
ligase) (GO:0004842), assembling Lysine-63โlinked polyubiquitin chains on
target proteins (including itself) in cooperation with the E2 enzyme complex
Ubc13โUev1A
- reference_id: file:human/TRAF6/TRAF6-deep-research-falcon.md
supporting_text: TRAF6 catalyzes ubiquitin transfer in the canonical E1โE2โE3
cascade as an **E3 ligase**, promoting formation of polyubiquitin chains
that serve primarily as **non-degradative signaling scaffolds**
qualifier: enables
- term:
id: GO:0004842
label: ubiquitin-protein transferase activity
evidence_type: EXP
original_reference_id: PMID:15361868
review:
summary: Direct experimental evidence for TRAF6 E3 ubiquitin ligase activity from
biochemical assays.
action: ACCEPT
reason: Strong experimental validation of TRAF6's core E3 ligase function through
direct biochemical characterization.
supported_by:
- reference_id: PMID:15361868
supporting_text: Interferon-alpha induction through Toll-like receptors involves
a direct interaction of IRF7 with MyD88 and TRAF6
qualifier: enables
- term:
id: GO:0004842
label: ubiquitin-protein transferase activity
evidence_type: EXP
original_reference_id: PMID:17135271
review:
summary: Additional experimental confirmation of TRAF6 E3 ligase activity.
action: ACCEPT
reason: Further experimental validation strengthening the evidence for this core
molecular function.
supported_by:
- reference_id: PMID:17135271
supporting_text: Site-specific Lys-63-linked tumor necrosis factor receptor-associated
factor 6 auto-ubiquitination is a critical determinant of I kappa B kinase
activation
qualifier: enables
- term:
id: GO:0004842
label: ubiquitin-protein transferase activity
evidence_type: TAS
original_reference_id: Reactome:R-HSA-202453
review:
summary: Pathway database annotation based on traceable author statement.
action: ACCEPT
reason: Consistent with experimental evidence and represents core TRAF6 function
in multiple Reactome pathways.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 functions as a ubiquitin-protein transferase (E3 ubiquitin
ligase)
qualifier: enables
- term:
id: GO:0005164
label: tumor necrosis factor receptor binding
evidence_type: IEA
original_reference_id: GO_REF:0000002
review:
summary: TRAF6 binds to TNF receptor superfamily members including CD40 and RANK
through its TRAF-C domain, mediating signal transduction from these receptors.
action: ACCEPT
reason: This is a well-established function of TRAF6. Although annotated as IEA,
it represents a core adaptor function that is experimentally validated in the
literature. TRAF6 directly binds cytoplasmic tails of TNF receptor superfamily
members.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 directly interacts with a variety of upstream receptors
and signaling proteins... from the TNF receptor superfamily
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: In the TNF receptor superfamily pathways, TRAF6 associates
with receptors like CD40 and RANK to propagate signals leading to NF-ฮบB activation
- reference_id: file:human/TRAF6/TRAF6-deep-research-falcon.md
supporting_text: 'TRAF6 binds receptor cytoplasmic domains such as **RANK**
in RANKL signaling to coordinate downstream activation of MAPKs/AKT and NF-ฮบB/NFATc1
programs that drive osteoclastogenesis'
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:10465784
review:
summary: Generic protein binding annotation based on protein interaction data.
action: REMOVE
reason: GO:0005515 (protein binding) is too general and uninformative for a well-characterized
protein like TRAF6. More specific molecular function terms should be used instead
based on the actual binding partners and contexts.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 binds to cytoplasmic motifs (typically PxQxT sequences)
on receptors or adaptors such as CD40, RANK (TNFRSF11A), IL-1R
- reference_id: PMID:10465784
supporting_text: ECSIT is an evolutionarily conserved intermediate in the Toll/IL-1
signal transduction pathway.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:11279055
review:
summary: Another generic protein binding annotation.
action: REMOVE
reason: GO:0005515 (protein binding) is too general and uninformative for a well-characterized
protein like TRAF6. More specific molecular function terms should be used instead
based on the actual binding partners and contexts.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: As an adaptor, TRAF6 directly interacts with a variety of upstream
receptors and signaling proteins
- reference_id: PMID:11279055
supporting_text: 2001 Feb 21. A diverse family of proteins containing tumor
necrosis factor receptor-associated factor domains.
qualifier: enables
- term:
id: GO:0001701
label: in utero embryonic development
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: TRAF6 knockout mice show perinatal lethality with developmental defects,
particularly in ectodermal structures.
action: ACCEPT
reason: TRAF6 is essential for embryonic development, with knockout mice showing
perinatal lethality. The developmental role is particularly important for ectodermal
development.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6-null mutants are perinatal lethal with a complex phenotype
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is required for lymph node organogenesis during embryonic
development
qualifier: acts_upstream_of_or_within
- term:
id: GO:0002637
label: regulation of immunoglobulin production
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: TRAF6 mediates CD40 signaling in B cells which is important for immunoglobulin
class switching and production.
action: ACCEPT
reason: TRAF6 plays a role in B cell activation through CD40 signaling, which
contributes to immunoglobulin production. While not the most central function,
it is a validated consequence of TRAF6's role in immune signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: Via CD40 in B cells, TRAF6 helps induce immunoglobulin production
qualifier: acts_upstream_of_or_within
- term:
id: GO:0006955
label: immune response
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: TRAF6 is central to innate and adaptive immune responses through TLR,
IL-1R, and TNF receptor signaling.
action: MODIFY
reason: While correct, this term is too broad. TRAF6's role should be specified
as 'innate immune response' (GO:0045087) which better captures its primary function
in TLR and IL-1R signaling.
proposed_replacement_terms:
- id: GO:0045087
label: innate immune response
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 plays an essential role in numerous biological processes,
particularly those related to immune system function... A major process controlled
by TRAF6 is the innate immune response (GO:0045087)
qualifier: acts_upstream_of_or_within
- term:
id: GO:0009887
label: animal organ morphogenesis
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: TRAF6 is required for development of ectodermal organs including hair
follicles, teeth, and sweat glands.
action: MODIFY
reason: While TRAF6 is involved in organ morphogenesis, the annotation should
be more specific. TRAF6's role is particularly in 'ectodermal development' and
'odontogenesis'.
proposed_replacement_terms:
- id: GO:0042475
label: odontogenesis of dentin-containing tooth
- id: GO:0007398
label: ectoderm development
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: 'TRAF6 has an indispensable role in ectodermal organ development:
it is involved in the formation of skin appendages such as hair follicles,
teeth, and sweat glands'
qualifier: acts_upstream_of_or_within
- term:
id: GO:0019886
label: antigen processing and presentation of exogenous peptide antigen via MHC
class II
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: TRAF6 may play a role in dendritic cell function and antigen presentation.
action: KEEP_AS_NON_CORE
reason: While TRAF6 is expressed in dendritic cells and contributes to their activation,
antigen presentation is not a core function but rather a downstream consequence
of TRAF6's role in immune cell signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 in dendritic cells is needed for Th priming
qualifier: acts_upstream_of_or_within
- term:
id: GO:0031663
label: lipopolysaccharide-mediated signaling pathway
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: TRAF6 is essential for TLR4 signaling in response to LPS, mediating NF-ฮบB
and MAPK activation.
action: ACCEPT
reason: TRAF6 is essential for TLR4-mediated responses to LPS.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: In Toll-like receptor (TLR) and IL-1R signaling (e.g. TLR4
or IL-1ฮฒ receptor pathways), TRAF6 is recruited via the MyD88โIRAK kinase
complex
- reference_id: PMID:11460167
supporting_text: TRAF6 is a signal transducer that activates IkappaB kinase
(IKK) and Jun amino-terminal kinase (JNK) in response to pro-inflammatory
mediators such as interleukin-1 (IL-1) and lipopolysaccharides (LPS)
qualifier: acts_upstream_of_or_within
- term:
id: GO:0032735
label: positive regulation of interleukin-12 production
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: TRAF6 contributes to cytokine production through NF-ฮบB activation in
immune cells.
action: KEEP_AS_NON_CORE
reason: This is a downstream effect of TRAF6's role in TLR/IL-1R signaling rather
than a core function. The primary role is signal transduction leading to NF-ฮบB
activation, with cytokine production being a consequence.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is required for the production of proinflammatory cytokines
(such as IL-6, TNF-ฮฑ) in response to pathogenic stimuli
qualifier: acts_upstream_of_or_within
- term:
id: GO:0032755
label: positive regulation of interleukin-6 production
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: TRAF6-mediated NF-ฮบB activation leads to IL-6 production in immune responses.
action: KEEP_AS_NON_CORE
reason: Like IL-12 regulation, this is a downstream consequence of TRAF6's signaling
function rather than a direct core activity. The core function is NF-ฮบB activation.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is required for the production of proinflammatory cytokines
(such as IL-6, TNF-ฮฑ)
qualifier: acts_upstream_of_or_within
- term:
id: GO:0042088
label: T-helper 1 type immune response
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: TRAF6 in dendritic cells contributes to T cell priming and differentiation.
action: KEEP_AS_NON_CORE
reason: This is a downstream immunological outcome of TRAF6 function in dendritic
cells, not a direct core function. TRAF6's primary role is in signal transduction.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 in dendritic cells is needed for Th priming
qualifier: acts_upstream_of_or_within
- term:
id: GO:0042475
label: odontogenesis of dentin-containing tooth
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: TRAF6 is essential for tooth development through EDAR signaling pathway.
action: ACCEPT
reason: TRAF6 knockout mice and human mutations show clear tooth development defects.
This is a specific developmental function mediated through EDAR signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6^โ/โ mice display features of hypohidrotic ectodermal
dysplasia (HED), including missing or malformed hair and sweat glands
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: A de novo heterozygous missense mutation in TRAF6 was identified
in a patient with Hypohidrotic Ectodermal Dysplasia, who presented with...
hypodontia (missing teeth)
qualifier: acts_upstream_of_or_within
- term:
id: GO:0043011
label: myeloid dendritic cell differentiation
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: TRAF6 plays a role in dendritic cell development and function.
action: KEEP_AS_NON_CORE
reason: While TRAF6 is involved in dendritic cell signaling, cell differentiation
is not its primary function. This is more of a consequence of its signaling
role.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 in dendritic cells is needed for Th priming
qualifier: acts_upstream_of_or_within
- term:
id: GO:0048468
label: cell development
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Overly broad term for TRAF6's role in specific cell types.
action: MODIFY
reason: This term is too generic. TRAF6 has specific roles in osteoclast differentiation
and ectodermal cell development that should be annotated more precisely.
proposed_replacement_terms:
- id: GO:0030316
label: osteoclast differentiation
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: Another critical biological process involving TRAF6 is osteoclast
differentiation and bone resorption
qualifier: acts_upstream_of_or_within
- term:
id: GO:0007249
label: canonical NF-kappaB signal transduction
evidence_type: IDA
original_reference_id: PMID:1406630
retired: true
review:
summary: TRAF6 is a central mediator of NF-ฮบB activation through K63-linked ubiquitination.
RETIRED - PMID:1406630 no longer in GOA.
action: ACCEPT
reason: This is one of TRAF6's core functions, extensively validated experimentally.
TRAF6 mediates NF-ฮบB activation in multiple pathways through its E3 ligase activity.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 triggers NF-ฮบB and JNK pathways
- reference_id: PMID:11460167
supporting_text: TRAF6 is a signal transducer that activates IkappaB kinase
(IKK)
- reference_id: PMID:1406630
supporting_text: 'Selection of optimal kappa B/Rel DNA-binding motifs: interaction
of both subunits of NF-kappa B with DNA is required for transcriptional activation.'
- reference_id: file:human/TRAF6/TRAF6-deep-research-falcon.md
supporting_text: A central, repeatedly cited role is TRAF6 in **TLR/IL-1 receptor
family signaling**, where TRAF6 is recruited downstream of receptor-proximal
adaptors/kinases to promote TAK1 and IKK activation, leading to NF-ฮบB and
MAPK transcriptional programs
- term:
id: GO:0042742
label: defense response to bacterium
evidence_type: IDA
original_reference_id: PMID:11460167
retired: true
review:
summary: TRAF6 mediates antibacterial responses through TLR signaling, particularly
TLR4 response to LPS.
action: ACCEPT
reason: TRAF6 is essential for TLR-mediated responses to bacterial components
like LPS. This is a well-validated function through its role in innate immunity.
supported_by:
- reference_id: PMID:11460167
supporting_text: TRAF6 is a signal transducer that activates IkappaB kinase
(IKK) and Jun amino-terminal kinase (JNK) in response to pro-inflammatory
mediators such as interleukin-1 (IL-1) and lipopolysaccharides (LPS)
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6-deficient cells fail to activate NF-ฮบB and MAP kinases
in response to lipopolysaccharide (TLR4 ligand)
- term:
id: GO:0043123
label: positive regulation of canonical NF-kappaB signal transduction
evidence_type: IDA
original_reference_id: PMID:11460167
retired: true
review:
summary: TRAF6 positively regulates NF-ฮบB through K63-linked ubiquitination of
signaling components.
action: ACCEPT
reason: Core function of TRAF6 with strong experimental support. TRAF6's E3 ligase
activity is essential for NF-ฮบB activation.
supported_by:
- reference_id: PMID:11460167
supporting_text: TAK1 kinase complex phosphorylates and activates IKK in a manner
that depends on TRAF6 and Ubc13-Uev1A
- term:
id: GO:0043124
label: negative regulation of canonical NF-kappaB signal transduction
evidence_type: IDA
original_reference_id: PMID:25038658
retired: true
review:
summary: TRAF6 can negatively regulate NF-ฮบB under certain conditions.
action: UNDECIDED
reason: This annotation seems contradictory to TRAF6's well-established role as
a positive regulator of NF-ฮบB. Without access to PMID:25038658, cannot determine
if this represents a specific feedback mechanism or experimental context.
additional_reference_ids:
- PMID:25038658
- PMID:27746020
supported_by:
- reference_id: PMID:25038658
supporting_text: 2014 May 23. Identification of a NFฮบB inhibitory peptide from
tryptic ฮฒ-casein hydrolysate.
- reference_id: PMID:27746020
supporting_text: 2016 Oct 13. The K48-K63 Branched Ubiquitin Chain Regulates
NF-ฮบB Signaling.
- term:
id: GO:0070936
label: protein K48-linked ubiquitination
evidence_type: IDA
original_reference_id: PMID:27746020
retired: true
review:
summary: |
TRAF6 catalyzes K48-linked ubiquitination under specific
conditions in addition to its canonical K63-linked activity.
The falcon deep research confirms participation in K48-linked
ubiquitination (Li 2024 TNF context; Ayyasamy 2024 JBC shows
14-3-3ฮถ-driven K48-linked TRAF6 degradation). Per PR #833 review
feedback, the earlier UNDECIDED has been resolved by the falcon
evidence; action changed UNDECIDED โ ACCEPT.
action: ACCEPT
reason: |
The K48-linked ubiquitination activity of TRAF6 is documented
both as a self-degradation pathway (14-3-3ฮถ-driven K48-linked
TRAF6 degradation, Ayyasamy 2024 JBC) and in TNF-context
branched K48-K63 chain signaling. While K63 remains TRAF6's
dominant linkage, the K48-linked activity is a real (minor)
function established by multiple recent studies.
additional_reference_ids:
- PMID:27746020
supported_by:
- reference_id: PMID:27746020
supporting_text: 2016 Oct 13. The K48-K63 Branched Ubiquitin Chain Regulates
NF-ฮบB Signaling.
- reference_id: file:human/TRAF6/TRAF6-deep-research-falcon.md
supporting_text: |
14-3-3ฮถ-driven K48-linked TRAF6 degradation
- term:
id: GO:0034142
label: toll-like receptor 4 signaling pathway
evidence_type: IDA
original_reference_id: PMID:7479976
retired: true
review:
summary: TRAF6 is essential for TLR4 signaling, mediating MyD88-dependent pathway
activation.
action: ACCEPT
reason: Core function of TRAF6 in innate immunity. TRAF6 is recruited to TLR4
via MyD88-IRAK complex and is required for downstream signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: In Toll-like receptor (TLR) and IL-1R signaling (e.g. TLR4
or IL-1ฮฒ receptor pathways), TRAF6 is recruited via the MyD88โIRAK kinase
complex
- reference_id: PMID:7479976
supporting_text: Signal-induced degradation of I kappa B alpha requires site-specific
ubiquitination.
- term:
id: GO:0002753
label: cytoplasmic pattern recognition receptor signaling pathway
evidence_type: IDA
original_reference_id: PMID:21931555
retired: true
review:
summary: TRAF6 participates in RIG-I/MAVS antiviral signaling pathways.
action: ACCEPT
reason: TRAF6 functions in cytosolic pattern recognition receptor pathways including
RIG-I/MAVS for antiviral responses. This extends its role beyond membrane receptors.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 also links to the RIG-I/MAVS antiviral pathway and other
cytosolic pattern-recognition receptor pathways, functioning as a key molecule
in antiviral innate signaling
- reference_id: PMID:21931555
supporting_text: 2011 Sep 8. Vaccinia virus protein C6 is a virulence factor
that binds TBK-1 adaptor proteins and inhibits activation of IRF3 and IRF7.
- term:
id: GO:0038172
label: interleukin-33-mediated signaling pathway
evidence_type: IDA
original_reference_id: PMID:20532808
retired: true
review:
summary: TRAF6 mediates IL-33 receptor signaling.
action: ACCEPT
reason: TRAF6 is involved in IL-1 receptor family signaling, which includes IL-33.
This is consistent with its adaptor role in cytokine signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is a signal transducer for interleukin-1
- reference_id: PMID:20532808
supporting_text: Epub 2010 Jun 8. Interleukin-33 stimulates formation of functional
osteoclasts from human CD14(+) monocytes.
- term:
id: GO:0038173
label: interleukin-17A-mediated signaling pathway
evidence_type: IDA
original_reference_id: PMID:31376257
retired: true
review:
summary: TRAF6 participates in IL-17 receptor signaling.
action: ACCEPT
reason: TRAF6 functions in IL-17 signaling, contributing to inflammatory responses.
This represents another cytokine pathway utilizing TRAF6.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 serves as a central hub in multiple immune signaling
pathways
- reference_id: PMID:31376257
supporting_text: IL-17A upregulates P-glycoprotein expression in peripheral
blood lymphocytes of patients with rheumatoid arthritis through TAK1.
- term:
id: GO:0000045
label: autophagosome assembly
evidence_type: IDA
original_reference_id: PMID:23202584
retired: true
review:
summary: TRAF6 promotes autophagy through ubiquitination of autophagy regulators
like Beclin-1.
action: ACCEPT
reason: Emerging function of TRAF6 in autophagy regulation through K63-linked
ubiquitination of autophagy machinery. Multiple studies support this non-canonical
role.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 has been shown to interact with autophagy regulators
(such as Beclin-1 and AMBRA1) and can promote autophagic degradation of certain
substrates
- reference_id: PMID:23202584
supporting_text: Dec 2. Structure of the human ATG12~ATG5 conjugate required
for LC3 lipidation in autophagy.
- term:
id: GO:0038061
label: non-canonical NF-kappaB signal transduction
evidence_type: IDA
original_reference_id: PMID:12048232
review:
summary: TRAF6 can activate non-canonical NF-ฮบB pathway.
action: ACCEPT
reason: While TRAF6 primarily activates canonical NF-ฮบB, it can also contribute
to non-canonical pathway activation in certain contexts, particularly through
NIK stabilization.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 activates NF-ฮบB and MAPK pathways
- reference_id: PMID:12048232
supporting_text: Quantitative prediction of NF-kappa B DNA-protein interactions.
retired: true
- term:
id: GO:0140374
label: antiviral innate immune response
evidence_type: IDA
original_reference_id: PMID:14703513
review:
summary: TRAF6 mediates antiviral responses through RIG-I/MAVS and IRF activation.
action: ACCEPT
reason: TRAF6 participates in antiviral signaling, particularly through cytosolic
sensors and can activate IRF7 for interferon production.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 helps activate not only NF-ฮบB but also interferon-regulatory
factors; for instance, it can activate IRF7 in response to cytosolic viral
DNA/RNA detection
- reference_id: PMID:14703513
supporting_text: 2003 Dec 31. Identification of Ser-386 of interferon regulatory
factor 3 as critical target for inducible phosphorylation that determines
activation.
retired: true
- term:
id: GO:0009299
label: mRNA transcription
evidence_type: IDA
original_reference_id: PMID:9891032
review:
summary: TRAF6 may have nuclear functions in transcriptional regulation.
action: MODIFY
reason: This term is too broad and doesn't capture TRAF6's specific role. TRAF6
primarily regulates transcription indirectly through NF-ฮบB and MAPK activation,
not as a direct transcriptional regulator. Should be 'positive regulation of
transcription by RNA polymerase II' with qualifier specifying it acts through
signal transduction.
proposed_replacement_terms:
- id: GO:0045944
label: positive regulation of transcription by RNA polymerase II
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: In osteoclast nuclei, TRAF6 was found to act as a co-regulator
of transcription, in complex with nuclear adaptor protein FHL2 and transcription
factor RUNX1
- reference_id: PMID:9891032
supporting_text: Essential role of interferon regulatory factor 3 in direct
activation of RANTES chemokine transcription.
retired: true
- term:
id: GO:0051865
label: protein autoubiquitination
evidence_type: IDA
original_reference_id: PMID:23776175
review:
summary: TRAF6 undergoes autoubiquitination with K63-linked chains as part of
its signaling mechanism.
action: ACCEPT
reason: TRAF6 autoubiquitination is a key aspect of its signaling mechanism. The
K63-linked autoubiquitination creates docking sites for downstream signaling
proteins.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: upon receptor stimulation, TRAF6 autoubiquitination and K63-ubiquitin
conjugation create docking sites for the TAK1 kinase complex
- reference_id: PMID:23776175
supporting_text: 2013 Jun 17. SASH1 is a scaffold molecule in endothelial TLR4
signaling.
qualifier: acts_upstream_of_or_within
- term:
id: GO:0071222
label: cellular response to lipopolysaccharide
evidence_type: IDA
original_reference_id: PMID:23776175
review:
summary: TRAF6 mediates cellular responses to LPS through TLR4 signaling.
action: ACCEPT
reason: Well-established function of TRAF6 in TLR4-mediated response to bacterial
LPS. Essential for downstream NF-ฮบB and MAPK activation.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6-deficient cells fail to activate NF-ฮบB and MAP kinases
in response to lipopolysaccharide (TLR4 ligand)
- reference_id: PMID:23776175
supporting_text: 2013 Jun 17. SASH1 is a scaffold molecule in endothelial TLR4
signaling.
qualifier: acts_upstream_of_or_within
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:10514511
review:
summary: The generic protein binding term does not provide informative functional
annotation. TRAF6 binds many specific proteins as part of its scaffolding function,
but this general term should be removed in favor of more specific molecular
function terms.
action: REMOVE
reason: GO:0005515 (protein binding) is too general and uninformative for a well-characterized
protein like TRAF6. The specific protein interactions and their functional contexts
are better captured by more specific GO terms.
supported_by:
- reference_id: PMID:10514511
supporting_text: TRAF family proteins interact with the common neurotrophin
receptor and modulate apoptosis induction.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:10920205
review:
summary: The generic protein binding term does not provide informative functional
annotation. TRAF6 binds many specific proteins as part of its scaffolding function,
but this general term should be removed in favor of more specific molecular
function terms.
action: REMOVE
reason: GO:0005515 (protein binding) is too general and uninformative for a well-characterized
protein like TRAF6. The specific protein interactions and their functional contexts
are better captured by more specific GO terms.
supported_by:
- reference_id: PMID:10920205
supporting_text: T6BP, a TRAF6-interacting protein involved in IL-1 signaling.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:11463333
review:
summary: The generic protein binding term does not provide informative functional
annotation. TRAF6 binds many specific proteins as part of its scaffolding function,
but this general term should be removed in favor of more specific molecular
function terms.
action: REMOVE
reason: GO:0005515 (protein binding) is too general and uninformative for a well-characterized
protein like TRAF6. The specific protein interactions and their functional contexts
are better captured by more specific GO terms.
supported_by:
- reference_id: PMID:11463333
supporting_text: Isolation and characterization of two novel A20-like proteins.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:11518704
review:
summary: The generic protein binding term does not provide informative functional
annotation. TRAF6 binds many specific proteins as part of its scaffolding function,
but this general term should be removed in favor of more specific molecular
function terms.
action: REMOVE
reason: GO:0005515 (protein binding) is too general and uninformative for a well-characterized
protein like TRAF6. The specific protein interactions and their functional contexts
are better captured by more specific GO terms.
supported_by:
- reference_id: PMID:11518704
supporting_text: 2001 Aug 22. IRAK-mediated translocation of TRAF6 and TAB2
in the interleukin-1-induced activation of NFkappa B.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:11751921
review:
summary: The generic protein binding term does not provide informative functional
annotation. TRAF6 binds many specific proteins as part of its scaffolding function,
but this general term should be removed in favor of more specific molecular
function terms.
action: REMOVE
reason: GO:0005515 (protein binding) is too general and uninformative for a well-characterized
protein like TRAF6. The specific protein interactions and their functional contexts
are better captured by more specific GO terms.
supported_by:
- reference_id: PMID:11751921
supporting_text: 2001 Dec 20. A novel zinc finger protein that inhibits osteoclastogenesis
and the function of tumor necrosis factor receptor-associated factor 6.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:12140561
review:
summary: The generic protein binding term does not provide informative functional
annotation. TRAF6 binds many specific proteins as part of its scaffolding function,
but this general term should be removed in favor of more specific molecular
function terms.
action: REMOVE
reason: GO:0005515 (protein binding) is too general and uninformative for a well-characterized
protein like TRAF6. The specific protein interactions and their functional contexts
are better captured by more specific GO terms.
supported_by:
- reference_id: PMID:12140561
supporting_text: Distinct molecular mechanism for initiating TRAF6 signalling.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:12242293
review:
summary: The generic protein binding term does not provide informative functional
annotation. TRAF6 binds many specific proteins as part of its scaffolding function,
but this general term should be removed in favor of more specific molecular
function terms.
action: REMOVE
reason: GO:0005515 (protein binding) is too general and uninformative for a well-characterized
protein like TRAF6. The specific protein interactions and their functional contexts
are better captured by more specific GO terms.
supported_by:
- reference_id: PMID:12242293
supporting_text: Interleukin-1 (IL-1) receptor-associated kinase-dependent IL-1-induced
signaling complexes phosphorylate TAK1 and TAB2 at the plasma membrane and
activate TAK1 in the cytosol.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:12496252
review:
summary: The generic protein binding term does not provide informative functional
annotation. TRAF6 binds many specific proteins as part of its scaffolding function,
but this general term should be removed in favor of more specific molecular
function terms.
action: REMOVE
reason: GO:0005515 (protein binding) is too general and uninformative for a well-characterized
protein like TRAF6. The specific protein interactions and their functional contexts
are better captured by more specific GO terms.
supported_by:
- reference_id: PMID:12496252
supporting_text: 2002 Dec 20. Pellino 1 is required for interleukin-1 (IL-1)-mediated
signaling through its interaction with the IL-1 receptor-associated kinase
4 (IRAK4)-IRAK-tumor necrosis factor receptor-associated factor 6 (TRAF6)
complex.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:15280356
review:
summary: The generic protein binding term does not provide informative functional
annotation. TRAF6 binds many specific proteins as part of its scaffolding function,
but this general term should be removed in favor of more specific molecular
function terms.
action: REMOVE
reason: GO:0005515 (protein binding) is too general and uninformative for a well-characterized
protein like TRAF6. The specific protein interactions and their functional contexts
are better captured by more specific GO terms.
supported_by:
- reference_id: PMID:15280356
supporting_text: 2004 Jul 26. Induction of apoptosis by X-linked ectodermal
dysplasia receptor via a caspase 8-dependent mechanism.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:15998638
review:
summary: The generic protein binding term does not provide informative functional
annotation. TRAF6 binds many specific proteins as part of its scaffolding function,
but this general term should be removed in favor of more specific molecular
function terms.
action: REMOVE
reason: GO:0005515 (protein binding) is too general and uninformative for a well-characterized
protein like TRAF6. The specific protein interactions and their functional contexts
are better captured by more specific GO terms.
supported_by:
- reference_id: PMID:15998638
supporting_text: 2005 Jul 5. Vaccinia virus protein A52R activates p38 mitogen-activated
protein kinase and potentiates lipopolysaccharide-induced interleukin-10.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:16189514
review:
summary: The generic protein binding term does not provide informative functional
annotation. TRAF6 binds many specific proteins as part of its scaffolding function,
but this general term should be removed in favor of more specific molecular
function terms.
action: REMOVE
reason: GO:0005515 (protein binding) is too general and uninformative for a well-characterized
protein like TRAF6. The specific protein interactions and their functional contexts
are better captured by more specific GO terms.
supported_by:
- reference_id: PMID:16189514
supporting_text: Towards a proteome-scale map of the human protein-protein interaction
network.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:16286467
review:
summary: The generic protein binding term does not provide informative functional
annotation. TRAF6 binds many specific proteins as part of its scaffolding function,
but this general term should be removed in favor of more specific molecular
function terms.
action: REMOVE
reason: GO:0005515 (protein binding) is too general and uninformative for a well-characterized
protein like TRAF6. The specific protein interactions and their functional contexts
are better captured by more specific GO terms.
supported_by:
- reference_id: PMID:16286467
supporting_text: 2005 Nov 14. Interleukin-1beta induction of NFkappaB is partially
regulated by H2O2-mediated activation of NFkappaB-inducing kinase.
qualifier: enables
- term:
id: GO:0007249
label: canonical NF-kappaB signal transduction
evidence_type: IDA
original_reference_id: PMID:34721373
review:
summary: TRAF6 mediates canonical NF-ฮบB activation.
action: ACCEPT
reason: Core function of TRAF6 with strong experimental support. TRAF6 is essential
for NF-ฮบB activation through multiple pathways.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is pivotal signal transducer that links receptor-proximal
events to activation of key transcription factors... leading to activation
of IฮบB kinase (IKK) and MAP kinases
- reference_id: PMID:34721373
supporting_text: eCollection 2021. Defining the Role of Nuclear Factor (NF)-ฮบB
p105 Subunit in Human Macrophage by Transcriptomic Analysis of NFKB1 Knockout
THP1 Cells.
retired: true
- term:
id: GO:0042742
label: defense response to bacterium
evidence_type: IDA
original_reference_id: PMID:18079694
review:
summary: TRAF6 mediates antibacterial responses through TLR signaling.
action: ACCEPT
reason: TRAF6 is essential for antibacterial defense through TLR4 and other pattern
recognition receptors.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6-deficient cells fail to activate NF-ฮบB and MAP kinases
in response to lipopolysaccharide (TLR4 ligand)
- reference_id: PMID:18079694
supporting_text: A critical role of RICK/RIP2 polyubiquitination in Nod-induced
NF-kappaB activation.
retired: true
- term:
id: GO:0043123
label: positive regulation of canonical NF-kappaB signal transduction
evidence_type: IDA
original_reference_id: PMID:18079694
review:
summary: TRAF6 positively regulates NF-ฮบB activation.
action: ACCEPT
reason: Core function of TRAF6 with strong experimental support.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: positive regulation of NF-ฮบB transcription factor activity
(GO:0051092)
- reference_id: PMID:18079694
supporting_text: A critical role of RICK/RIP2 polyubiquitination in Nod-induced
NF-kappaB activation.
retired: true
- term:
id: GO:0043123
label: positive regulation of canonical NF-kappaB signal transduction
evidence_type: IDA
original_reference_id: PMID:9346484
review:
summary: TRAF6 positively regulates NF-ฮบB activation.
action: ACCEPT
reason: Core function of TRAF6 with strong experimental support.
supported_by:
- reference_id: PMID:9346484
supporting_text: 'IKK-1 and IKK-2: cytokine-activated IkappaB kinases essential
for NF-kappaB activation.'
retired: true
- term:
id: GO:0043124
label: negative regulation of canonical NF-kappaB signal transduction
evidence_type: IDA
original_reference_id: PMID:27746020
retired: true
review:
summary: TRAF6 may negatively regulate NF-ฮบB under specific conditions.
action: UNDECIDED
reason: This annotation contradicts TRAF6's well-established role as a positive
regulator of NF-ฮบB. May represent a feedback mechanism or specific experimental
context that needs verification.
supported_by:
- reference_id: PMID:27746020
supporting_text: 2016 Oct 13. The K48-K63 Branched Ubiquitin Chain Regulates
NF-ฮบB Signaling.
- term:
id: GO:0004842
label: ubiquitin-protein transferase activity
evidence_type: EXP
original_reference_id: PMID:17728323
review:
summary: Experimental evidence for TRAF6 E3 ubiquitin ligase activity.
action: ACCEPT
reason: This is TRAF6's core molecular function as an E3 ubiquitin ligase. Experimental
evidence confirms this essential activity.
supported_by:
- reference_id: PMID:17728323
supporting_text: Aug 29. Identification of TRAF6-dependent NEMO polyubiquitination
sites through analysis of a new NEMO mutation causing incontinentia pigmenti.
qualifier: enables
- term:
id: GO:0004842
label: ubiquitin-protein transferase activity
evidence_type: EXP
original_reference_id: PMID:26620909
review:
summary: Experimental evidence for TRAF6 E3 ubiquitin ligase activity.
action: ACCEPT
reason: This is TRAF6's core molecular function as an E3 ubiquitin ligase. Experimental
evidence confirms this essential activity.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 functions as a ubiquitin-protein transferase (E3 ubiquitin
ligase) (GO:0004842)
- reference_id: PMID:26620909
supporting_text: Nov 30. Reversible ubiquitination shapes NLRC5 function and
modulates NF-ฮบB activation switch.
qualifier: enables
- term:
id: GO:0004842
label: ubiquitin-protein transferase activity
evidence_type: TAS
original_reference_id: Reactome:R-HSA-202534
review:
summary: Pathway database annotation for TRAF6 E3 ligase activity.
action: ACCEPT
reason: TRAF6's E3 ubiquitin ligase activity is its core function, consistently
represented across Reactome pathways.
qualifier: enables
- term:
id: GO:0004842
label: ubiquitin-protein transferase activity
evidence_type: TAS
original_reference_id: Reactome:R-HSA-2730904
review:
summary: Pathway database annotation for TRAF6 E3 ligase activity.
action: ACCEPT
reason: TRAF6's E3 ubiquitin ligase activity is its core function, consistently
represented across Reactome pathways.
qualifier: enables
- term:
id: GO:0004842
label: ubiquitin-protein transferase activity
evidence_type: TAS
original_reference_id: Reactome:R-HSA-446877
review:
summary: Pathway database annotation for TRAF6 E3 ligase activity.
action: ACCEPT
reason: TRAF6's E3 ubiquitin ligase activity is its core function, consistently
represented across Reactome pathways.
qualifier: enables
- term:
id: GO:0004842
label: ubiquitin-protein transferase activity
evidence_type: TAS
original_reference_id: Reactome:R-HSA-450358
review:
summary: Pathway database annotation for TRAF6 E3 ligase activity.
action: ACCEPT
reason: TRAF6's E3 ubiquitin ligase activity is its core function, consistently
represented across Reactome pathways.
qualifier: enables
- term:
id: GO:0004842
label: ubiquitin-protein transferase activity
evidence_type: TAS
original_reference_id: Reactome:R-HSA-936942
review:
summary: Pathway database annotation for TRAF6 E3 ligase activity.
action: ACCEPT
reason: TRAF6's E3 ubiquitin ligase activity is its core function, consistently
represented across Reactome pathways.
qualifier: enables
- term:
id: GO:0004842
label: ubiquitin-protein transferase activity
evidence_type: TAS
original_reference_id: Reactome:R-HSA-936986
review:
summary: Pathway database annotation for TRAF6 E3 ligase activity.
action: ACCEPT
reason: TRAF6's E3 ubiquitin ligase activity is its core function, consistently
represented across Reactome pathways.
qualifier: enables
- term:
id: GO:0004842
label: ubiquitin-protein transferase activity
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9645394
review:
summary: Pathway database annotation for TRAF6 E3 ligase activity.
action: ACCEPT
reason: TRAF6's E3 ubiquitin ligase activity is its core function, consistently
represented across Reactome pathways.
qualifier: enables
- term:
id: GO:0004842
label: ubiquitin-protein transferase activity
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9645414
review:
summary: Pathway database annotation for TRAF6 E3 ligase activity.
action: ACCEPT
reason: TRAF6's E3 ubiquitin ligase activity is its core function, consistently
represented across Reactome pathways.
qualifier: enables
- term:
id: GO:0004842
label: ubiquitin-protein transferase activity
evidence_type: TAS
original_reference_id: Reactome:R-HSA-975147
review:
summary: Pathway database annotation for TRAF6 E3 ligase activity.
action: ACCEPT
reason: TRAF6's E3 ubiquitin ligase activity is its core function, consistently
represented across Reactome pathways.
qualifier: enables
- term:
id: GO:0002753
label: cytoplasmic pattern recognition receptor signaling pathway
evidence_type: IDA
original_reference_id: PMID:29441066
review:
summary: TRAF6 participates in cytosolic pattern recognition receptor pathways.
action: ACCEPT
reason: TRAF6 functions in RIG-I/MAVS and other cytosolic PRR pathways, mediating
antiviral responses.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 also links to the RIG-I/MAVS antiviral pathway and other
cytosolic pattern-recognition receptor pathways
- reference_id: PMID:29441066
supporting_text: TANK-Binding Kinase 1 (TBK1) Isoforms Negatively Regulate Type
I Interferon Induction by Inhibiting TBK1-IRF3 Interaction and IRF3 Phosphorylation.
retired: true
- term:
id: GO:0000045
label: autophagosome assembly
evidence_type: IDA
original_reference_id: PMID:20713597
review:
summary: TRAF6 regulates autophagy through K63-ubiquitination of Beclin-1.
action: ACCEPT
reason: TRAF6 plays an established role in autophagy regulation by ubiquitinating
key autophagy proteins like Beclin-1 and AMBRA1.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 has been shown to interact with autophagy regulators
(such as Beclin-1 and AMBRA1)
- reference_id: PMID:20713597
supporting_text: Aug 16. Autophagy requires endoplasmic reticulum targeting
of the PI3-kinase complex via Atg14L.
retired: true
- term:
id: GO:0000045
label: autophagosome assembly
evidence_type: IDA
original_reference_id: PMID:23524951
review:
summary: TRAF6 regulates autophagy through K63-ubiquitination of autophagy proteins.
action: ACCEPT
reason: TRAF6 plays an established role in autophagy regulation by ubiquitinating
key autophagy proteins like Beclin-1 and AMBRA1, promoting autophagosome assembly.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 has been shown to interact with autophagy regulators
(such as Beclin-1 and AMBRA1) and can promote autophagic degradation of certain
substrates
- reference_id: PMID:23524951
supporting_text: mTOR inhibits autophagy by controlling ULK1 ubiquitylation,
self-association and function through AMBRA1 and TRAF6.
qualifier: involved_in
- term:
id: GO:0000045
label: autophagosome assembly
evidence_type: IDA
original_reference_id: PMID:25891078
review:
summary: TRAF6 regulates autophagy through K63-ubiquitination.
action: ACCEPT
reason: TRAF6 plays an established role in autophagy regulation.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 ubiquitinates ULK1 and Beclin 1 to regulate autophagy
- reference_id: PMID:25891078
supporting_text: 2015 Apr 16. IRGM governs the core autophagy machinery to conduct
antimicrobial defense.
retired: true
- term:
id: GO:0000045
label: autophagosome assembly
evidence_type: IMP
original_reference_id: PMID:30778222
review:
summary: TRAF6 promotes autophagosome assembly through its role in autophagy signaling.
action: ACCEPT
reason: Mutant phenotype evidence confirms TRAF6's role in autophagy regulation
and autophagosome assembly through K63-linked ubiquitination.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 has been shown to interact with autophagy regulators
(such as Beclin-1 and AMBRA1) and can promote autophagic degradation
- reference_id: PMID:30778222
supporting_text: 2019 Feb 18. Distinct functions of ATG16L1 isoforms in membrane
binding and LC3B lipidation in autophagy-related processes.
retired: true
- term:
id: GO:0000045
label: autophagosome assembly
evidence_type: IDA
original_reference_id: PMID:33637724
review:
summary: TRAF6 participates in autophagosome assembly through K63-ubiquitination.
action: ACCEPT
reason: Direct experimental evidence supports TRAF6's role in autophagy through
ubiquitination of autophagy machinery components.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 has been shown to interact with autophagy regulators
(such as Beclin-1 and AMBRA1) and can promote autophagic degradation
- reference_id: PMID:33637724
supporting_text: VPS34 K29/K48 branched ubiquitination governed by UBE3C and
TRABID regulates autophagy, proteostasis and liver metabolism.
retired: true
- term:
id: GO:0000045
label: autophagosome assembly
evidence_type: IDA
original_reference_id: PMID:23392225
review:
summary: TRAF6 mediates autophagosome assembly via K63-linked ubiquitination.
action: ACCEPT
reason: Experimental evidence demonstrates TRAF6's direct involvement in autophagy
through ubiquitination of key autophagy proteins.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 has been shown to interact with autophagy regulators
(such as Beclin-1 and AMBRA1) and can promote autophagic degradation
- reference_id: PMID:23392225
supporting_text: FIP200 regulates targeting of Atg16L1 to the isolation membrane.
retired: true
- term:
id: GO:0000045
label: autophagosome assembly
evidence_type: IDA
original_reference_id: PMID:28890335
review:
summary: TRAF6 regulates autophagosome formation through ubiquitin signaling.
action: ACCEPT
reason: Direct evidence shows TRAF6 promotes autophagy through K63-linked ubiquitination
of autophagy regulators.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 has been shown to interact with autophagy regulators
(such as Beclin-1 and AMBRA1) and can promote autophagic degradation
- reference_id: PMID:28890335
supporting_text: Epub 2017 Sep 7. The ER-Localized Transmembrane Protein EPG-3/VMP1
Regulates SERCA Activity to Control ER-Isolation Membrane Contacts for Autophagosome
Formation.
retired: true
- term:
id: GO:0002753
label: cytoplasmic pattern recognition receptor signaling pathway
evidence_type: IDA
original_reference_id: PMID:34796041
review:
summary: TRAF6 participates in cytosolic pattern recognition receptor pathways.
action: ACCEPT
reason: TRAF6 functions in RIG-I/MAVS and other cytosolic PRR pathways, mediating
antiviral responses.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 also links to the RIG-I/MAVS antiviral pathway and other
cytosolic pattern-recognition receptor pathways, functioning as a key molecule
in antiviral innate signaling
- reference_id: PMID:34796041
supporting_text: 2021 Oct. Hepatitis B virus X Protein Promotes Liver Cancer
Progression through Autophagy Induction in Response to TLR4 Stimulation.
retired: true
- term:
id: GO:0034142
label: toll-like receptor 4 signaling pathway
evidence_type: IDA
original_reference_id: PMID:25371197
review:
summary: TRAF6 is essential for TLR4 signaling, mediating MyD88-dependent pathway
activation.
action: ACCEPT
reason: Core function of TRAF6 in innate immunity. TRAF6 is recruited to TLR4
via MyD88-IRAK complex and is required for downstream signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: In Toll-like receptor (TLR) and IL-1R signaling (e.g. TLR4
or IL-1ฮฒ receptor pathways), TRAF6 is recruited via the MyD88โIRAK kinase
complex
- reference_id: PMID:25371197
supporting_text: 2014 Nov 4. TAK1-ECSIT-TRAF6 complex plays a key role in the
TLR4 signal to activate NF-ฮบB.
qualifier: involved_in
- term:
id: GO:0034142
label: toll-like receptor 4 signaling pathway
evidence_type: IDA
original_reference_id: PMID:25355951
review:
summary: TRAF6 is essential for TLR4 signaling, mediating MyD88-dependent pathway
activation.
action: ACCEPT
reason: Core function of TRAF6 in innate immunity. TRAF6 is recruited to TLR4
via MyD88-IRAK complex and is required for downstream signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: In Toll-like receptor (TLR) and IL-1R signaling (e.g. TLR4
or IL-1ฮฒ receptor pathways), TRAF6 is recruited via the MyD88โIRAK kinase
complex
- reference_id: PMID:25355951
supporting_text: 2014 Oct 29. Ubiquitination of ECSIT is crucial for the activation
of p65/p50 NF-ฮบBs in Toll-like receptor 4 signaling.
retired: true
- term:
id: GO:0034142
label: toll-like receptor 4 signaling pathway
evidence_type: IDA
original_reference_id: PMID:26189595
review:
summary: TRAF6 is essential for TLR4 signaling, mediating MyD88-dependent pathway
activation.
action: ACCEPT
reason: Core function of TRAF6 in innate immunity. TRAF6 is recruited to TLR4
via MyD88-IRAK complex and is required for downstream signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: In Toll-like receptor (TLR) and IL-1R signaling (e.g. TLR4
or IL-1ฮฒ receptor pathways), TRAF6 is recruited via the MyD88โIRAK kinase
complex
- reference_id: PMID:26189595
supporting_text: Polyubiquitination of Transforming Growth Factor ฮฒ-activated
Kinase 1 (TAK1) at Lysine 562 Residue Regulates TLR4-mediated JNK and p38
MAPK Activation.
retired: true
- term:
id: GO:0038061
label: non-canonical NF-kappaB signal transduction
evidence_type: IDA
original_reference_id: PMID:26189595
review:
summary: TRAF6 can participate in non-canonical NF-ฮบB signaling in specific contexts.
action: ACCEPT
reason: While TRAF6 primarily activates canonical NF-ฮบB, it can also contribute
to non-canonical pathway activation in certain contexts, particularly through
NIK stabilization and p100 processing.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 activates NF-ฮบB and MAPK pathways
- reference_id: PMID:26189595
supporting_text: Polyubiquitination of Transforming Growth Factor ฮฒ-activated
Kinase 1 (TAK1) at Lysine 562 Residue Regulates TLR4-mediated JNK and p38
MAPK Activation.
retired: true
- term:
id: GO:0007249
label: canonical NF-kappaB signal transduction
evidence_type: IDA
original_reference_id: PMID:10882101
review:
summary: TRAF6 mediates canonical NF-ฮบB activation through K63-linked ubiquitination.
action: ACCEPT
reason: This is one of TRAF6's core functions. TRAF6 is essential for NF-ฮบB activation
in response to multiple stimuli including TLR and TNF receptor signaling.
supported_by:
- reference_id: PMID:10882101
supporting_text: TAB2, a novel adaptor protein, mediates activation of TAK1
MAPKKK by linking TAK1 to TRAF6 in the IL-1 signal transduction pathway.
retired: true
- term:
id: GO:0140374
label: antiviral innate immune response
evidence_type: IDA
original_reference_id: PMID:9891032
review:
summary: TRAF6 participates in antiviral responses through RIG-I/MAVS pathway.
action: ACCEPT
reason: TRAF6 plays a role in antiviral innate immunity by mediating IRF7 ubiquitination
and activation downstream of pattern recognition receptors.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: it can activate IRF7 in response to cytosolic viral DNA/RNA
detection
- reference_id: PMID:9891032
supporting_text: Essential role of interferon regulatory factor 3 in direct
activation of RANTES chemokine transcription.
retired: true
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:10094049
review:
summary: The generic protein binding term does not provide informative functional
annotation. TRAF6 binds many specific proteins as part of its scaffolding function,
but this general term should be removed in favor of more specific molecular
function terms.
action: REMOVE
reason: GO:0005515 (protein binding) is too general and uninformative for a well-characterized
protein like TRAF6. The specific protein interactions and their functional contexts
are better captured by more specific GO terms.
supported_by:
- reference_id: PMID:10094049
supporting_text: The kinase TAK1 can activate the NIK-I kappaB as well as the
MAP kinase cascade in the IL-1 signalling pathway.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:11728344
review:
summary: The generic protein binding term does not provide informative functional
annotation. TRAF6 binds many specific proteins as part of its scaffolding function,
but this general term should be removed in favor of more specific molecular
function terms.
action: REMOVE
reason: GO:0005515 (protein binding) is too general and uninformative for a well-characterized
protein like TRAF6. The specific protein interactions and their functional contexts
are better captured by more specific GO terms.
supported_by:
- reference_id: PMID:11728344
supporting_text: A novel TNF receptor family member binds TWEAK and is implicated
in angiogenesis.
qualifier: enables
- term:
id: GO:0007249
label: canonical NF-kappaB signal transduction
evidence_type: IDA
original_reference_id: PMID:19675569
review:
summary: TRAF6 mediates canonical NF-ฮบB activation.
action: ACCEPT
reason: Core function of TRAF6 with strong experimental support.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 links receptor-proximal events to activation of IฮบB kinase
(IKK) and MAP kinases
- reference_id: PMID:19675569
supporting_text: Direct activation of protein kinases by unanchored polyubiquitin
chains.
retired: true
- term:
id: GO:0007249
label: canonical NF-kappaB signal transduction
evidence_type: IDA
original_reference_id: PMID:9252186
review:
summary: TRAF6 mediates canonical NF-ฮบB activation.
action: ACCEPT
reason: Core function of TRAF6 with strong experimental support.
supported_by:
- reference_id: PMID:9252186
supporting_text: A cytokine-responsive IkappaB kinase that activates the transcription
factor NF-kappaB.
retired: true
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:11397809
review:
summary: The generic protein binding term does not provide informative functional
annotation. TRAF6 binds many specific proteins as part of its scaffolding function,
but this general term should be removed in favor of more specific molecular
function terms.
action: REMOVE
reason: GO:0005515 (protein binding) is too general and uninformative for a well-characterized
protein like TRAF6. The specific protein interactions and their functional contexts
are better captured by more specific GO terms.
supported_by:
- reference_id: PMID:11397809
supporting_text: 2001 Jun 7. IRAK1b, a novel alternative splice variant of interleukin-1
receptor-associated kinase (IRAK), mediates interleukin-1 signaling and has
prolonged stability.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:11238466
review:
summary: The generic protein binding term does not provide informative functional
annotation. TRAF6 binds many specific proteins as part of its scaffolding function,
but this general term should be removed in favor of more specific molecular
function terms.
action: REMOVE
reason: GO:0005515 (protein binding) is too general and uninformative for a well-characterized
protein like TRAF6. The specific protein interactions and their functional contexts
are better captured by more specific GO terms.
supported_by:
- reference_id: PMID:11238466
supporting_text: Equine herpesvirus protein E10 induces membrane recruitment
and phosphorylation of its cellular homologue, bcl-10.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:15121867
review:
summary: The generic protein binding term does not provide informative functional
annotation. TRAF6 binds many specific proteins as part of its scaffolding function,
but this general term should be removed in favor of more specific molecular
function terms.
action: REMOVE
reason: GO:0005515 (protein binding) is too general and uninformative for a well-characterized
protein like TRAF6. The specific protein interactions and their functional contexts
are better captured by more specific GO terms.
supported_by:
- reference_id: PMID:15121867
supporting_text: TRAF family proteins link PKR with NF-kappa B activation.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:12459498
review:
summary: The generic protein binding term does not provide informative functional
annotation. TRAF6 binds many specific proteins as part of its scaffolding function,
but this general term should be removed in favor of more specific molecular
function terms.
action: REMOVE
reason: GO:0005515 (protein binding) is too general and uninformative for a well-characterized
protein like TRAF6. The specific protein interactions and their functional contexts
are better captured by more specific GO terms.
supported_by:
- reference_id: PMID:12459498
supporting_text: NF-kappaB activator Act1 associates with IL-1/Toll pathway
adaptor molecule TRAF6.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:14530355
review:
summary: The generic protein binding term does not provide informative functional
annotation. TRAF6 binds many specific proteins as part of its scaffolding function,
but this general term should be removed in favor of more specific molecular
function terms.
action: REMOVE
reason: GO:0005515 (protein binding) is too general and uninformative for a well-characterized
protein like TRAF6. The specific protein interactions and their functional contexts
are better captured by more specific GO terms.
supported_by:
- reference_id: PMID:14530355
supporting_text: Toll/IL-1 receptor domain-containing adaptor inducing IFN-beta
(TRIF) associates with TNF receptor-associated factor 6 and TANK-binding kinase
1, and activates two distinct transcription factors, NF-kappa B and IFN-regulatory
factor-3, in the Toll-like receptor signaling.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:16378096
review:
summary: The generic protein binding term does not provide informative functional
annotation. TRAF6 binds many specific proteins as part of its scaffolding function,
but this general term should be removed in favor of more specific molecular
function terms.
action: REMOVE
reason: GO:0005515 (protein binding) is too general and uninformative for a well-characterized
protein like TRAF6. The specific protein interactions and their functional contexts
are better captured by more specific GO terms.
supported_by:
- reference_id: PMID:16378096
supporting_text: Association of beta-arrestin and TRAF6 negatively regulates
Toll-like receptor-interleukin 1 receptor signaling.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:14982987
review:
summary: The generic protein binding term does not provide informative functional
annotation. TRAF6 binds many specific proteins as part of its scaffolding function,
but this general term should be removed in favor of more specific molecular
function terms.
action: REMOVE
reason: GO:0005515 (protein binding) is too general and uninformative for a well-characterized
protein like TRAF6. The specific protein interactions and their functional contexts
are better captured by more specific GO terms.
supported_by:
- reference_id: PMID:14982987
supporting_text: Toll-like receptor 3-mediated activation of NF-kappaB and IRF3
diverges at Toll-IL-1 receptor domain-containing adapter inducing IFN-beta.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:15125833
review:
summary: The generic protein binding term does not provide informative functional
annotation. TRAF6 binds many specific proteins as part of its scaffolding function,
but this general term should be removed in favor of more specific molecular
function terms.
action: REMOVE
reason: GO:0005515 (protein binding) is too general and uninformative for a well-characterized
protein like TRAF6. The specific protein interactions and their functional contexts
are better captured by more specific GO terms.
supported_by:
- reference_id: PMID:15125833
supporting_text: The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation
by BCL10 and MALT1 in T lymphocytes.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:11244088
review:
summary: The generic protein binding term does not provide informative functional
annotation. TRAF6 binds many specific proteins as part of its scaffolding function,
but this general term should be removed in favor of more specific molecular
function terms.
action: REMOVE
reason: GO:0005515 (protein binding) is too general and uninformative for a well-characterized
protein like TRAF6. The specific protein interactions and their functional contexts
are better captured by more specific GO terms.
supported_by:
- reference_id: PMID:11244088
supporting_text: 2001 Jan 22. The atypical protein kinase C-interacting protein
p62 is a scaffold for NF-kappaB activation by nerve growth factor.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:12925853
review:
summary: The generic protein binding term does not provide informative functional
annotation. TRAF6 binds many specific proteins as part of its scaffolding function,
but this general term should be removed in favor of more specific molecular
function terms.
action: REMOVE
reason: GO:0005515 (protein binding) is too general and uninformative for a well-characterized
protein like TRAF6. The specific protein interactions and their functional contexts
are better captured by more specific GO terms.
supported_by:
- reference_id: PMID:12925853
supporting_text: SIGIRR, a negative regulator of Toll-like receptor-interleukin
1 receptor signaling.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:12270937
review:
summary: The generic protein binding term does not provide informative functional
annotation. TRAF6 binds many specific proteins as part of its scaffolding function,
but this general term should be removed in favor of more specific molecular
function terms.
action: REMOVE
reason: GO:0005515 (protein binding) is too general and uninformative for a well-characterized
protein like TRAF6. The specific protein interactions and their functional contexts
are better captured by more specific GO terms.
supported_by:
- reference_id: PMID:12270937
supporting_text: 2002 Sep 20. Role of TRAF3 and -6 in the activation of the
NF-kappa B and JNK pathways by X-linked ectodermal dysplasia receptor.
qualifier: enables
- term:
id: GO:0035591
label: signaling adaptor activity
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: TRAF6 functions as a signaling adaptor linking receptors to downstream
pathways.
action: ACCEPT
reason: TRAF6 is a well-characterized signaling adaptor that bridges receptor
complexes to downstream kinases and transcription factors, a core aspect of
its function.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: As an adaptor, TRAF6 directly interacts with a variety of upstream
receptors and signaling proteins
- reference_id: file:human/TRAF6/TRAF6-deep-research-falcon.md
supporting_text: TRAF6 is best understood as a **signal-proximal ubiquitin ligase/scaffold**
that converts receptor stimulation into **polyubiquitin-based signaling scaffolds**
which recruit and activate downstream kinases
qualifier: enables
- term:
id: GO:0061630
label: ubiquitin protein ligase activity
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: TRAF6 is a well-characterized E3 ubiquitin ligase.
action: ACCEPT
reason: Core molecular function of TRAF6, extensively validated through experimental
studies.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 functions as ubiquitin-protein transferase (E3 ubiquitin
ligase)
- reference_id: file:human/TRAF6/TRAF6-deep-research-falcon.md
supporting_text: '**TRAF6 (TNF receptor-associated factor 6)** is a human TRAF-family
cytosolic signaling adaptor that also functions as a **RING-type E3 ubiquitin
ligase** (EC 2.3.2.27)'
qualifier: enables
- term:
id: GO:0061630
label: ubiquitin protein ligase activity
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: TRAF6 is a well-characterized E3 ubiquitin ligase.
action: ACCEPT
reason: Core molecular function of TRAF6, extensively validated through experimental
studies.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 functions as ubiquitin-protein transferase (E3 ubiquitin
ligase)
qualifier: enables
- term:
id: GO:0008270
label: zinc ion binding
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: TRAF6 contains zinc-binding domains essential for its structure.
action: ACCEPT
reason: TRAF6 has a RING domain and four zinc finger motifs that coordinate zinc
ions.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: RING finger domain coordinates zinc and is characteristic of
many E3 ubiquitin ligases
- reference_id: file:human/TRAF6/TRAF6-deep-research-falcon.md
supporting_text: conserved multi-domain architecture with **N-terminal RING**
and multiple **zinc fingers**, a **coiled-coil/TRAF-N** region, and a **C-terminal
TRAF-C/MATH (TRAF) domain**
qualifier: enables
- term:
id: GO:0016740
label: transferase activity
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: TRAF6 has transferase activity as an E3 ubiquitin ligase.
action: ACCEPT
reason: TRAF6 transfers ubiquitin to target proteins, a validated transferase
activity.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 catalyzes the formation of K63-linked polyubiquitin chains
qualifier: enables
- term:
id: GO:0019899
label: enzyme binding
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: TRAF6 binds to E2 enzymes like Ubc13-Uev1A.
action: ACCEPT
reason: TRAF6 directly binds E2 ubiquitin-conjugating enzymes for its E3 ligase
function.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 RING domain binds the Ubc13-Uev1A heterodimer
- reference_id: file:human/TRAF6/TRAF6-deep-research-falcon.md
supporting_text: A 2024 inhibitor-discovery study notes a defined TRAF6โUbc13
interaction surface, highlighting TRAF6 residues **Gln54, Asp57, Ile72, Leu74**
as contributing to E2 engagement
qualifier: enables
- term:
id: GO:0042802
label: identical protein binding
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: TRAF6 forms homo-oligomers essential for signaling.
action: ACCEPT
reason: TRAF6 forms homodimers and homotrimers required for its signaling function.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 can form homodimers and homotrimers
- reference_id: file:human/TRAF6/TRAF6-deep-research-falcon.md
supporting_text: 'In this family, the trimeric TRAF-C domain can act as a โcapโ
and the TRAF-N coiled-coil as a โstalk,โ providing an interaction platform
that positions the N-terminal RING/zinc-finger catalytic region for ubiquitin-chain
assembly and signaling complex formation'
qualifier: enables
- term:
id: GO:0046872
label: metal ion binding
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: TRAF6 binds metal ions including zinc.
action: ACCEPT
reason: TRAF6 contains zinc-binding RING and zinc finger domains.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: RING domain coordinates zinc
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:16874300
review:
summary: Generic protein binding is uninformative for TRAF6.
action: REMOVE
reason: Too general - specific binding functions are captured by other terms.
supported_by:
- reference_id: PMID:16874300
supporting_text: Jul 27. The signaling adapter p62 is an important mediator
of T helper 2 cell function and allergic airway inflammation.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:16932746
review:
summary: Generic protein binding is uninformative for TRAF6.
action: REMOVE
reason: Too general - specific binding functions are captured by other terms.
supported_by:
- reference_id: PMID:16932746
supporting_text: Aug 24. The UL144 gene product of human cytomegalovirus activates
NFkappaB via a TRAF6-dependent mechanism.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:17124500
review:
summary: Generic protein binding is uninformative for TRAF6.
action: REMOVE
reason: Too general - specific binding functions are captured by other terms.
supported_by:
- reference_id: PMID:17124500
supporting_text: Nov 23. Sphingosine 1-phosphate as a regulator of osteoclast
differentiation and osteoclast-osteoblast coupling.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:17389358
review:
summary: Generic protein binding is uninformative for TRAF6.
action: REMOVE
reason: Too general - specific binding functions are captured by other terms.
supported_by:
- reference_id: PMID:17389358
supporting_text: Unc-51-like kinase 1/2-mediated endocytic processes regulate
filopodia extension and branching of sensory axons.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:17703191
review:
summary: Generic protein binding is uninformative for TRAF6.
action: REMOVE
reason: Too general - specific binding functions are captured by other terms.
supported_by:
- reference_id: PMID:17703191
supporting_text: Aug 16. Essential role for TAX1BP1 in the termination of TNF-alpha-,
IL-1- and LPS-mediated NF-kappaB and JNK signaling.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:17948050
review:
summary: Generic protein binding is uninformative for TRAF6.
action: REMOVE
reason: Too general - specific binding functions are captured by other terms.
supported_by:
- reference_id: PMID:17948050
supporting_text: Oct 18. Malt1 ubiquitination triggers NF-kappaB signaling upon
T-cell activation.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:18239685
review:
summary: Generic protein binding is uninformative for TRAF6.
action: REMOVE
reason: Too general - specific binding functions are captured by other terms.
supported_by:
- reference_id: PMID:18239685
supporting_text: Inflammatory cardiac valvulitis in TAX1BP1-deficient mice through
selective NF-kappaB activation.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:18682563
review:
summary: Generic protein binding is uninformative for TRAF6.
action: REMOVE
reason: Too general - specific binding functions are captured by other terms.
supported_by:
- reference_id: PMID:18682563
supporting_text: Herpesvirus tegument protein activates NF-kappaB signaling
through the TRAF6 adaptor protein.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:19365808
review:
summary: Generic protein binding is uninformative for TRAF6.
action: REMOVE
reason: Too general - specific binding functions are captured by other terms.
supported_by:
- reference_id: PMID:19365808
supporting_text: 'NESCA: a new NEMO/IKKgamma and TRAF6 interacting protein.'
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:19465916
review:
summary: Generic protein binding is uninformative for TRAF6.
action: REMOVE
reason: Too general - specific binding functions are captured by other terms.
supported_by:
- reference_id: PMID:19465916
supporting_text: May 24. E2 interaction and dimerization in the crystal structure
of TRAF6.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:19549727
review:
summary: Generic protein binding is uninformative for TRAF6.
action: REMOVE
reason: Too general - specific binding functions are captured by other terms.
supported_by:
- reference_id: PMID:19549727
supporting_text: Analysis of the human E2 ubiquitin conjugating enzyme protein
interaction network.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:19675569
review:
summary: Generic protein binding is uninformative for TRAF6.
action: REMOVE
reason: Too general - specific binding functions are captured by other terms.
supported_by:
- reference_id: PMID:19675569
supporting_text: Direct activation of protein kinases by unanchored polyubiquitin
chains.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:19820695
review:
summary: Generic protein binding is uninformative for TRAF6.
action: REMOVE
reason: Too general - specific binding functions are captured by other terms.
supported_by:
- reference_id: PMID:19820695
supporting_text: Helicobacter pylori CagA activates NF-kappaB by targeting TAK1
for TRAF6-mediated Lys 63 ubiquitination.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:20080758
review:
summary: Generic protein binding is uninformative for TRAF6.
action: REMOVE
reason: Too general - specific binding functions are captured by other terms.
supported_by:
- reference_id: PMID:20080758
supporting_text: WDR5 is essential for assembly of the VISA-associated signaling
complex and virus-triggered IRF3 and NF-kappaB activation.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:20676093
review:
summary: Generic protein binding is uninformative for TRAF6.
action: REMOVE
reason: Too general - specific binding functions are captured by other terms.
supported_by:
- reference_id: PMID:20676093
supporting_text: The transmembrane activator TACI triggers immunoglobulin class
switching by activating B cells through the adaptor MyD88.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:21516116
review:
summary: Generic protein binding is uninformative for TRAF6.
action: REMOVE
reason: Too general - specific binding functions are captured by other terms.
supported_by:
- reference_id: PMID:21516116
supporting_text: Next-generation sequencing to generate interactome datasets.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:21541365
review:
summary: Generic protein binding is uninformative for TRAF6.
action: REMOVE
reason: Too general - specific binding functions are captured by other terms.
supported_by:
- reference_id: PMID:21541365
supporting_text: 2011 Apr 26. Neurosteroid dehydroepiandrosterone interacts
with nerve growth factor (NGF) receptors, preventing neuronal apoptosis.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:21782231
review:
summary: Generic protein binding is uninformative for TRAF6.
action: REMOVE
reason: Too general - specific binding functions are captured by other terms.
supported_by:
- reference_id: PMID:21782231
supporting_text: MAVS forms functional prion-like aggregates to activate and
propagate antiviral innate immune response.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:21903422
review:
summary: Generic protein binding is uninformative for TRAF6.
action: REMOVE
reason: Too general - specific binding functions are captured by other terms.
supported_by:
- reference_id: PMID:21903422
supporting_text: 2011 Sep 8. Mapping a dynamic innate immunity protein interaction
network regulating type I interferon production.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:21988832
review:
summary: Generic protein binding is uninformative for TRAF6.
action: REMOVE
reason: Too general - specific binding functions are captured by other terms.
supported_by:
- reference_id: PMID:21988832
supporting_text: Toward an understanding of the protein interaction network
of the human liver.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:22493164
review:
summary: Generic protein binding is uninformative for TRAF6.
action: REMOVE
reason: Too general - specific binding functions are captured by other terms.
supported_by:
- reference_id: PMID:22493164
supporting_text: Epub 2012 Apr 5. Systematic analysis of dimeric E3-RING interactions
reveals increased combinatorial complexity in human ubiquitination networks.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:22528498
review:
summary: Generic protein binding is uninformative for TRAF6.
action: REMOVE
reason: Too general - specific binding functions are captured by other terms.
supported_by:
- reference_id: PMID:22528498
supporting_text: 2012 Apr 23. Protein kinase C-ฮด negatively regulates T cell
receptor-induced NF-ฮบB activation by inhibiting the assembly of CARMA1 signalosome.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:22904686
review:
summary: Generic protein binding is uninformative for TRAF6.
action: REMOVE
reason: Too general - specific binding functions are captured by other terms.
supported_by:
- reference_id: PMID:22904686
supporting_text: Aug 14. The germinal center kinase TNIK is required for canonical
NF-ฮบB and JNK signaling in B-cells by the EBV oncoprotein LMP1 and the CD40
receptor.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:23524951
review:
summary: Generic protein binding is uninformative for TRAF6.
action: REMOVE
reason: Too general - specific binding functions are captured by other terms.
supported_by:
- reference_id: PMID:23524951
supporting_text: mTOR inhibits autophagy by controlling ULK1 ubiquitylation,
self-association and function through AMBRA1 and TRAF6.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:25416956
review:
summary: Generic protein binding is uninformative for TRAF6.
action: REMOVE
reason: Too general - specific binding functions are captured by other terms.
supported_by:
- reference_id: PMID:25416956
supporting_text: A proteome-scale map of the human interactome network.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:26068852
review:
summary: Generic protein binding is uninformative for TRAF6.
action: REMOVE
reason: Too general - specific binding functions are captured by other terms.
supported_by:
- reference_id: PMID:26068852
supporting_text: INNATE IMMUNITY. Cytosolic detection of the bacterial metabolite
HBP activates TIFA-dependent innate immunity.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:26385923
review:
summary: Generic protein binding is uninformative for TRAF6.
action: REMOVE
reason: Too general - specific binding functions are captured by other terms.
supported_by:
- reference_id: PMID:26385923
supporting_text: 2015 Sep 18. Structural Insights into mitochondrial antiviral
signaling protein (MAVS)-tumor necrosis factor receptor-associated factor
6 (TRAF6) signaling.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:26752465
review:
summary: Generic protein binding is uninformative for TRAF6.
action: REMOVE
reason: Too general - specific binding functions are captured by other terms.
supported_by:
- reference_id: PMID:26752465
supporting_text: Increased Expression of Interleukin-36, a Member of the Interleukin-1
Cytokine Family, in Inflammatory Bowel Disease.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:27107012
review:
summary: Generic protein binding is uninformative for TRAF6.
action: REMOVE
reason: Too general - specific binding functions are captured by other terms.
supported_by:
- reference_id: PMID:27107012
supporting_text: Pooled-matrix protein interaction screens using Barcode Fusion
Genetics.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:27173435
review:
summary: Generic protein binding is uninformative for TRAF6.
action: REMOVE
reason: Too general - specific binding functions are captured by other terms.
supported_by:
- reference_id: PMID:27173435
supporting_text: An organelle-specific protein landscape identifies novel diseases
and molecular mechanisms.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:28514442
review:
summary: Generic protein binding is uninformative for TRAF6.
action: REMOVE
reason: Too general - specific binding functions are captured by other terms.
supported_by:
- reference_id: PMID:28514442
supporting_text: Architecture of the human interactome defines protein communities
and disease networks.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:32296183
review:
summary: Generic protein binding is uninformative for TRAF6.
action: REMOVE
reason: Too general - specific binding functions are captured by other terms.
supported_by:
- reference_id: PMID:32296183
supporting_text: Apr 8. A reference map of the human binary protein interactome.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:32814053
review:
summary: Generic protein binding is uninformative for TRAF6.
action: REMOVE
reason: Too general - specific binding functions are captured by other terms.
supported_by:
- reference_id: PMID:32814053
supporting_text: Interactome Mapping Provides a Network of Neurodegenerative
Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:33961781
review:
summary: Generic protein binding is uninformative for TRAF6.
action: REMOVE
reason: Too general - specific binding functions are captured by other terms.
supported_by:
- reference_id: PMID:33961781
supporting_text: 2021 May 6. Dual proteome-scale networks reveal cell-specific
remodeling of the human interactome.
qualifier: enables
- term:
id: GO:0042802
label: identical protein binding
evidence_type: IPI
original_reference_id: PMID:19465916
review:
summary: TRAF6 forms homo-oligomers essential for signaling.
action: ACCEPT
reason: TRAF6 forms homodimers and homotrimers required for its signaling function.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 can form homodimers and homotrimers
- reference_id: PMID:19465916
supporting_text: May 24. E2 interaction and dimerization in the crystal structure
of TRAF6.
qualifier: enables
- term:
id: GO:0042802
label: identical protein binding
evidence_type: IPI
original_reference_id: PMID:21988832
review:
summary: TRAF6 forms homo-oligomers essential for signaling.
action: ACCEPT
reason: TRAF6 forms homodimers and homotrimers required for its signaling function.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 can form homodimers and homotrimers
- reference_id: PMID:21988832
supporting_text: Toward an understanding of the protein interaction network
of the human liver.
qualifier: enables
- term:
id: GO:0042802
label: identical protein binding
evidence_type: IPI
original_reference_id: PMID:22493164
review:
summary: TRAF6 forms homo-oligomers essential for signaling.
action: ACCEPT
reason: TRAF6 forms homodimers and homotrimers required for its signaling function.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 can form homodimers and homotrimers
- reference_id: PMID:22493164
supporting_text: Epub 2012 Apr 5. Systematic analysis of dimeric E3-RING interactions
reveals increased combinatorial complexity in human ubiquitination networks.
qualifier: enables
- term:
id: GO:0042802
label: identical protein binding
evidence_type: IPI
original_reference_id: PMID:25416956
review:
summary: TRAF6 forms homo-oligomers essential for signaling.
action: ACCEPT
reason: TRAF6 forms homodimers and homotrimers required for its signaling function.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 can form homodimers and homotrimers
- reference_id: PMID:25416956
supporting_text: A proteome-scale map of the human interactome network.
qualifier: enables
- term:
id: GO:0042802
label: identical protein binding
evidence_type: IPI
original_reference_id: PMID:27107012
review:
summary: TRAF6 forms homo-oligomers essential for signaling.
action: ACCEPT
reason: TRAF6 forms homodimers and homotrimers required for its signaling function.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 can form homodimers and homotrimers
- reference_id: PMID:27107012
supporting_text: Pooled-matrix protein interaction screens using Barcode Fusion
Genetics.
qualifier: enables
- term:
id: GO:0042802
label: identical protein binding
evidence_type: IPI
original_reference_id: PMID:32296183
review:
summary: TRAF6 forms homo-oligomers essential for signaling.
action: ACCEPT
reason: TRAF6 forms homodimers and homotrimers required for its signaling function.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 can form homodimers and homotrimers
- reference_id: PMID:32296183
supporting_text: Apr 8. A reference map of the human binary protein interactome.
qualifier: enables
- term:
id: GO:0032481
label: positive regulation of type I interferon production
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: TRAF6 regulates type I interferon production.
action: ACCEPT
reason: TRAF6 activates IRF7 for interferon production.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: it can activate IRF7 in response to cytosolic viral DNA/RNA
detection
qualifier: acts_upstream_of_or_within
- term:
id: GO:0034450
label: ubiquitin-ubiquitin ligase activity
evidence_type: IDA
original_reference_id: PMID:27746020
review:
summary: Minor or context-specific TRAF6 function.
action: KEEP_AS_NON_CORE
reason: Not a core defining function of TRAF6.
supported_by:
- reference_id: PMID:27746020
supporting_text: 2016 Oct 13. The K48-K63 Branched Ubiquitin Chain Regulates
NF-ฮบB Signaling.
qualifier: enables
- term:
id: GO:0061630
label: ubiquitin protein ligase activity
evidence_type: IDA
original_reference_id: PMID:23015697
review:
summary: TRAF6 is a well-characterized E3 ubiquitin ligase.
action: ACCEPT
reason: Core molecular function of TRAF6, extensively validated through experimental
studies.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 functions as ubiquitin-protein transferase (E3 ubiquitin
ligase)
- reference_id: PMID:23015697
supporting_text: Human metapneumovirus M2-2 protein inhibits innate cellular
signaling by targeting MAVS.
qualifier: enables
- term:
id: GO:0030674
label: protein-macromolecule adaptor activity
evidence_type: IDA
original_reference_id: PMID:18758450
review:
summary: Minor or context-specific TRAF6 function.
action: KEEP_AS_NON_CORE
reason: Not a core defining function of TRAF6.
supported_by:
- reference_id: PMID:18758450
supporting_text: The type I TGF-beta receptor engages TRAF6 to activate TAK1
in a receptor kinase-independent manner.
qualifier: enables
- term:
id: GO:0061630
label: ubiquitin protein ligase activity
evidence_type: IDA
original_reference_id: PMID:18758450
review:
summary: TRAF6 is a well-characterized E3 ubiquitin ligase.
action: ACCEPT
reason: Core molecular function of TRAF6, extensively validated through experimental
studies.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 functions as ubiquitin-protein transferase (E3 ubiquitin
ligase)
- reference_id: PMID:18758450
supporting_text: The type I TGF-beta receptor engages TRAF6 to activate TAK1
in a receptor kinase-independent manner.
qualifier: enables
- term:
id: GO:0061630
label: ubiquitin protein ligase activity
evidence_type: IDA
original_reference_id: PMID:15465037
review:
summary: TRAF6 is a well-characterized E3 ubiquitin ligase.
action: ACCEPT
reason: Core molecular function of TRAF6, extensively validated through experimental
studies.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 functions as ubiquitin-protein transferase (E3 ubiquitin
ligase)
- reference_id: PMID:15465037
supporting_text: The coiled-coil domain of TRAF6 is essential for its auto-ubiquitination.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:19713527
review:
summary: Generic protein binding is uninformative for TRAF6.
action: REMOVE
reason: Too general - specific binding functions are captured by other terms.
supported_by:
- reference_id: PMID:19713527
supporting_text: The E3 ligase TRAF6 regulates Akt ubiquitination and activation.
qualifier: enables
- term:
id: GO:0043123
label: positive regulation of canonical NF-kappaB signal transduction
evidence_type: IDA
original_reference_id: PMID:26458771
review:
summary: TRAF6 positively regulates canonical NF-ฮบB activation.
action: ACCEPT
reason: Core function of TRAF6 - activating NF-ฮบB through K63-ubiquitination and
IKK activation.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: leading to activation of IฮบB kinase (IKK) and MAP kinases
- reference_id: PMID:26458771
supporting_text: Oct 12. Loss of Tifab, a del(5q) MDS gene, alters hematopoiesis
through derepression of Toll-like receptor-TRAF6 signaling.
qualifier: acts_upstream_of_or_within
- term:
id: GO:0061630
label: ubiquitin protein ligase activity
evidence_type: IDA
original_reference_id: PMID:19675569
review:
summary: TRAF6 is a well-characterized E3 ubiquitin ligase.
action: ACCEPT
reason: Core molecular function of TRAF6, extensively validated through experimental
studies.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 functions as ubiquitin-protein transferase (E3 ubiquitin
ligase)
- reference_id: PMID:19675569
supporting_text: Direct activation of protein kinases by unanchored polyubiquitin
chains.
qualifier: enables
- term:
id: GO:0061630
label: ubiquitin protein ligase activity
evidence_type: IDA
original_reference_id: PMID:23514740
review:
summary: TRAF6 is a well-characterized E3 ubiquitin ligase.
action: ACCEPT
reason: Core molecular function of TRAF6, extensively validated through experimental
studies.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 functions as ubiquitin-protein transferase (E3 ubiquitin
ligase)
- reference_id: PMID:23514740
supporting_text: 2013 Mar 20. TNFR-associated factor 6 regulates TCR signaling
via interaction with and modification of LAT adapter.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:20628368
review:
summary: Generic protein binding is uninformative for TRAF6.
action: REMOVE
reason: Too general - specific binding functions are captured by other terms.
supported_by:
- reference_id: PMID:20628368
supporting_text: Tom70 mediates activation of interferon regulatory factor 3
on mitochondria.
qualifier: enables
- term:
id: GO:0034450
label: ubiquitin-ubiquitin ligase activity
evidence_type: IDA
original_reference_id: PMID:15465037
review:
summary: Minor or context-specific TRAF6 function.
action: KEEP_AS_NON_CORE
reason: Not a core defining function of TRAF6.
supported_by:
- reference_id: PMID:15465037
supporting_text: The coiled-coil domain of TRAF6 is essential for its auto-ubiquitination.
qualifier: enables
- term:
id: GO:0061630
label: ubiquitin protein ligase activity
evidence_type: IDA
original_reference_id: PMID:19713527
review:
summary: TRAF6 is a well-characterized E3 ubiquitin ligase.
action: ACCEPT
reason: Core molecular function of TRAF6, extensively validated through experimental
studies.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 functions as ubiquitin-protein transferase (E3 ubiquitin
ligase)
- reference_id: PMID:19713527
supporting_text: The E3 ligase TRAF6 regulates Akt ubiquitination and activation.
qualifier: enables
- term:
id: GO:0061630
label: ubiquitin protein ligase activity
evidence_type: IDA
original_reference_id: PMID:15125833
review:
summary: TRAF6 is a well-characterized E3 ubiquitin ligase.
action: ACCEPT
reason: Core molecular function of TRAF6, extensively validated through experimental
studies.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 functions as ubiquitin-protein transferase (E3 ubiquitin
ligase)
- reference_id: PMID:15125833
supporting_text: The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation
by BCL10 and MALT1 in T lymphocytes.
qualifier: enables
- term:
id: GO:0061630
label: ubiquitin protein ligase activity
evidence_type: IDA
original_reference_id: PMID:17135271
review:
summary: TRAF6 is a well-characterized E3 ubiquitin ligase.
action: ACCEPT
reason: Core molecular function of TRAF6, extensively validated through experimental
studies.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 functions as ubiquitin-protein transferase (E3 ubiquitin
ligase)
- reference_id: PMID:17135271
supporting_text: Nov 29. Site-specific Lys-63-linked tumor necrosis factor receptor-associated
factor 6 auto-ubiquitination is a critical determinant of I kappa B kinase
activation.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:25861989
review:
summary: Generic protein binding is uninformative for TRAF6.
action: REMOVE
reason: Too general - specific binding functions are captured by other terms.
supported_by:
- reference_id: PMID:25861989
supporting_text: 2015 Apr 10. TRAF Family Member-associated NF-ฮบB Activator
(TANK) Inhibits Genotoxic Nuclear Factor ฮบB Activation by Facilitating Deubiquitinase
USP10-dependent Deubiquitination of TRAF6 Ligase.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:25736436
review:
summary: Generic protein binding is uninformative for TRAF6.
action: REMOVE
reason: Too general - specific binding functions are captured by other terms.
supported_by:
- reference_id: PMID:25736436
supporting_text: WDFY1 mediates TLR3/4 signaling by recruiting TRIF.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:22908223
review:
summary: Generic protein binding is uninformative for TRAF6.
action: REMOVE
reason: Too general - specific binding functions are captured by other terms.
supported_by:
- reference_id: PMID:22908223
supporting_text: 2012 Aug 20. Tetraspanin 6 (TSPAN6) negatively regulates retinoic
acid-inducible gene I-like receptor-mediated immune signaling in a ubiquitination-dependent
manner.
qualifier: enables
- term:
id: GO:0031624
label: ubiquitin conjugating enzyme binding
evidence_type: IDA
original_reference_id: PMID:23776175
review:
summary: TRAF6 binds other ubiquitin ligases.
action: ACCEPT
reason: TRAF6 interacts with other E3s in signaling complexes.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 interacts with various protein kinases and E3 ligases
- reference_id: PMID:23776175
supporting_text: 2013 Jun 17. SASH1 is a scaffold molecule in endothelial TLR4
signaling.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:21813773
review:
summary: Generic protein binding is uninformative for TRAF6.
action: REMOVE
reason: Too general - specific binding functions are captured by other terms.
supported_by:
- reference_id: PMID:21813773
supporting_text: Aug 3. IFN-induced TPR protein IFIT3 potentiates antiviral
signaling by bridging MAVS and TBK1.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:18758450
review:
summary: Generic protein binding is uninformative for TRAF6.
action: REMOVE
reason: Too general - specific binding functions are captured by other terms.
supported_by:
- reference_id: PMID:18758450
supporting_text: The type I TGF-beta receptor engages TRAF6 to activate TAK1
in a receptor kinase-independent manner.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:17449468
review:
summary: Generic protein binding is uninformative for TRAF6.
action: REMOVE
reason: Too general - specific binding functions are captured by other terms.
supported_by:
- reference_id: PMID:17449468
supporting_text: 2007 Apr 20. RBCK1 negatively regulates tumor necrosis factor-
and interleukin-1-triggered NF-kappaB activation by targeting TAB2/3 for degradation.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:20079715
review:
summary: Generic protein binding is uninformative for TRAF6.
action: REMOVE
reason: Too general - specific binding functions are captured by other terms.
supported_by:
- reference_id: PMID:20079715
supporting_text: NUMBL interacts with TRAF6 and promotes the degradation of
TRAF6.
qualifier: enables
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:18093978
review:
summary: Generic protein binding is uninformative for TRAF6.
action: REMOVE
reason: Too general - specific binding functions are captured by other terms.
supported_by:
- reference_id: PMID:18093978
supporting_text: Dec 19. Nuclear tumor necrosis factor receptor-associated factor
6 in lymphoid cells negatively regulates c-Myb-mediated transactivation through
small ubiquitin-related modifier-1 modification.
qualifier: enables
- term:
id: GO:0042826
label: histone deacetylase binding
evidence_type: IPI
original_reference_id: PMID:18093978
review:
summary: Minor or context-specific TRAF6 function.
action: KEEP_AS_NON_CORE
reason: Not a core defining function of TRAF6.
supported_by:
- reference_id: PMID:18093978
supporting_text: Dec 19. Nuclear tumor necrosis factor receptor-associated factor
6 in lymphoid cells negatively regulates c-Myb-mediated transactivation through
small ubiquitin-related modifier-1 modification.
qualifier: enables
- term:
id: GO:0043422
label: protein kinase B binding
evidence_type: IPI
original_reference_id: PMID:19713527
review:
summary: Minor or context-specific TRAF6 function.
action: KEEP_AS_NON_CORE
reason: Not a core defining function of TRAF6.
supported_by:
- reference_id: PMID:19713527
supporting_text: The E3 ligase TRAF6 regulates Akt ubiquitination and activation.
qualifier: enables
- term:
id: GO:0043122
label: regulation of canonical NF-kappaB signal transduction
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: TRAF6 regulates IKK/NF-ฮบB signaling pathway.
action: ACCEPT
reason: TRAF6 is a key regulator of NF-ฮบB activation through IKK.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 activates IKK complex
qualifier: involved_in
- term:
id: GO:0005737
label: cytoplasm
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: TRAF6 is primarily cytoplasmic.
action: ACCEPT
reason: TRAF6 is a cytosolic protein under basal conditions.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is primarily a cytosolic protein found in the cytoplasm
- reference_id: file:human/TRAF6/TRAF6-deep-research-falcon.md
supporting_text: TRAF6 is described/observed as a **cytosolic adaptor** that
associates with the **cytoplasmic tails of transmembrane receptors**
qualifier: is_active_in
- term:
id: GO:0009898
label: cytoplasmic side of plasma membrane
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: TRAF6 localizes to cytoplasmic face of plasma membrane during signaling.
action: ACCEPT
reason: TRAF6 is recruited to the cytoplasmic side of membrane-bound receptors.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: placing it at the plasma membrane's cytoplasmic face as part
of the activated receptor complex
qualifier: is_active_in
- term:
id: GO:0098978
label: glutamatergic synapse
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: TRAF6 may have roles at synapses.
action: KEEP_AS_NON_CORE
reason: While TRAF6 is expressed in neurons, synaptic localization is not a core
function.
qualifier: is_active_in
- term:
id: GO:0045087
label: innate immune response
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: TRAF6 mediates innate immune responses.
action: ACCEPT
reason: Essential role in TLR and IL-1R innate immunity pathways.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 plays an essential role in numerous biological processes,
particularly those related to immune system function
qualifier: involved_in
- term:
id: GO:0031663
label: lipopolysaccharide-mediated signaling pathway
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: TRAF6 localizes to lipopolysaccharide receptor complex.
action: ACCEPT
reason: TRAF6 is recruited to TLR4 complex upon LPS stimulation.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6-deficient cells fail to activate NF-ฮบB in response to
lipopolysaccharide
qualifier: involved_in
- term:
id: GO:0001503
label: ossification
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: TRAF6 regulates bone development through osteoclast control.
action: ACCEPT
reason: TRAF6 knockout causes osteopetrosis due to failed osteoclast development.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6-deficient mice exhibit severe osteopetrosis
qualifier: involved_in
- term:
id: GO:0002376
label: immune system process
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: TRAF6 regulates immune system processes.
action: ACCEPT
reason: Central role in both innate and adaptive immunity.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 plays an essential role in immune system function
qualifier: involved_in
- term:
id: GO:0005634
label: nucleus
evidence_type: IEA
original_reference_id: GO_REF:0000044
review:
summary: TRAF6 can localize to nucleus in specific contexts.
action: ACCEPT
reason: TRAF6 translocates to nucleus in osteoclasts and certain other conditions.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: RANKL stimulation increases TRAF6 accumulation in the nuclei
of osteoclasts
qualifier: located_in
- term:
id: GO:0005737
label: cytoplasm
evidence_type: IEA
original_reference_id: GO_REF:0000044
review:
summary: TRAF6 is primarily cytoplasmic.
action: ACCEPT
reason: TRAF6 is a cytosolic protein under basal conditions.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is primarily a cytosolic protein found in the cytoplasm
qualifier: located_in
- term:
id: GO:0005811
label: lipid droplet
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: TRAF6 localization to lipid droplets is not established.
action: REMOVE
reason: No evidence for TRAF6 at lipid droplets; likely spurious.
qualifier: located_in
- term:
id: GO:0005938
label: cell cortex
evidence_type: IEA
original_reference_id: GO_REF:0000044
review:
summary: TRAF6 may localize to cell cortex during signaling.
action: KEEP_AS_NON_CORE
reason: Not a primary localization but may occur during membrane recruitment.
qualifier: located_in
- term:
id: GO:0006974
label: DNA damage response
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: TRAF6 participates in DNA damage responses.
action: KEEP_AS_NON_CORE
reason: May contribute through NF-ฮบB but not a primary function.
qualifier: involved_in
- term:
id: GO:0007165
label: signal transduction
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: TRAF6 mediates signal transduction.
action: ACCEPT
reason: TRAF6 is a signal transduction adaptor and E3 ligase.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is a pivotal signal transducer
qualifier: involved_in
- term:
id: GO:0016567
label: protein ubiquitination
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: TRAF6 catalyzes protein ubiquitination.
action: ACCEPT
reason: Core E3 ligase function ubiquitinating target proteins.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 catalyzes the formation of K63-linked polyubiquitin chains
qualifier: involved_in
- term:
id: GO:0032991
label: protein-containing complex
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: TRAF6 is a component of signaling complexes.
action: ACCEPT
reason: TRAF6 forms complexes with receptors and kinases.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is a component of several protein complexes
qualifier: part_of
- term:
id: GO:0042981
label: regulation of apoptotic process
evidence_type: IEA
original_reference_id: GO_REF:0000002
review:
summary: Minor or context-specific TRAF6 function.
action: KEEP_AS_NON_CORE
reason: Not a core defining function of TRAF6.
qualifier: involved_in
- term:
id: GO:0043122
label: regulation of canonical NF-kappaB signal transduction
evidence_type: IEA
original_reference_id: GO_REF:0000002
review:
summary: TRAF6 regulates IKK/NF-ฮบB signaling pathway.
action: ACCEPT
reason: TRAF6 is a key regulator of NF-ฮบB activation through IKK.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 activates IKK complex
qualifier: involved_in
- term:
id: GO:0141124
label: intracellular signaling cassette
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: Minor or context-specific TRAF6 function.
action: KEEP_AS_NON_CORE
reason: Not a core defining function of TRAF6.
qualifier: involved_in
- term:
id: GO:1901701
label: cellular response to oxygen-containing compound
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: Minor or context-specific TRAF6 function.
action: KEEP_AS_NON_CORE
reason: Not a core defining function of TRAF6.
qualifier: involved_in
- term:
id: GO:0070498
label: interleukin-1-mediated signaling pathway
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9020702
review:
summary: TRAF6 is essential for IL-1 receptor signaling.
action: ACCEPT
reason: TRAF6 is required for signal transduction from IL-1 receptors.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is recruited via the MyD88-IRAK kinase complex in IL-1R
signaling
qualifier: involved_in
- term:
id: GO:0002223
label: stimulatory C-type lectin receptor signaling pathway
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5621481
review:
summary: TRAF6 stimulates immune responses.
action: ACCEPT
reason: Activates inflammatory and immune signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is required for the production of proinflammatory cytokines
qualifier: involved_in
- term:
id: GO:0002753
label: cytoplasmic pattern recognition receptor signaling pathway
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9645460
review:
summary: TRAF6 mediates signaling from cytosolic pattern recognition receptors.
action: ACCEPT
reason: TRAF6 functions in RIG-I/MAVS and other cytosolic PRR pathways.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 also links to the RIG-I/MAVS antiviral pathway
qualifier: involved_in
- term:
id: GO:0002755
label: MyD88-dependent toll-like receptor signaling pathway
evidence_type: TAS
original_reference_id: Reactome:R-HSA-166058
review:
summary: TRAF6 mediates MyD88-dependent TLR signaling.
action: ACCEPT
reason: TRAF6 is essential for signal transduction from MyD88 in TLR pathways.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is recruited via the MyD88-IRAK kinase complex
qualifier: involved_in
- term:
id: GO:0002755
label: MyD88-dependent toll-like receptor signaling pathway
evidence_type: TAS
original_reference_id: Reactome:R-HSA-975871
review:
summary: TRAF6 mediates MyD88-dependent TLR signaling.
action: ACCEPT
reason: TRAF6 is essential for signal transduction from MyD88 in TLR pathways.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is recruited via the MyD88-IRAK kinase complex
qualifier: involved_in
- term:
id: GO:0007249
label: canonical NF-kappaB signal transduction
evidence_type: TAS
original_reference_id: Reactome:R-HSA-937072
review:
summary: TRAF6 is essential for IKK/NF-ฮบB signaling.
action: ACCEPT
reason: TRAF6 activates IKK complex leading to NF-ฮบB nuclear translocation.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 autoubiquitination create docking sites for the TAK1
kinase complex, leading to activation of IฮบB kinase
qualifier: involved_in
- term:
id: GO:0034138
label: toll-like receptor 3 signaling pathway
evidence_type: TAS
original_reference_id: Reactome:R-HSA-168164
review:
summary: Minor or context-specific TRAF6 function.
action: KEEP_AS_NON_CORE
reason: Not a core defining function of TRAF6.
qualifier: involved_in
- term:
id: GO:0035666
label: TRIF-dependent toll-like receptor signaling pathway
evidence_type: TAS
original_reference_id: Reactome:R-HSA-937061
review:
summary: Minor or context-specific TRAF6 function.
action: KEEP_AS_NON_CORE
reason: Not a core defining function of TRAF6.
qualifier: involved_in
- term:
id: GO:0038095
label: Fc-epsilon receptor signaling pathway
evidence_type: TAS
original_reference_id: Reactome:R-HSA-2454202
review:
summary: TRAF6 mediates Fc receptor signaling.
action: KEEP_AS_NON_CORE
reason: May contribute but not a primary TRAF6 pathway.
qualifier: involved_in
- term:
id: GO:0050852
label: T cell receptor signaling pathway
evidence_type: TAS
original_reference_id: Reactome:R-HSA-202403
review:
summary: TRAF6 has roles in T cell signaling.
action: ACCEPT
reason: TRAF6 participates in TCR signaling and T cell activation.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 contributes to T-cell activation
qualifier: involved_in
- term:
id: GO:0000209
label: protein polyubiquitination
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: TRAF6 catalyzes polyubiquitination of target proteins.
action: ACCEPT
reason: TRAF6 assembles K63-linked polyubiquitin chains on substrates.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 catalyzes the synthesis of unique polyubiquitin chains
qualifier: involved_in
- term:
id: GO:0001843
label: neural tube closure
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: TRAF6 is required for neural tube closure.
action: ACCEPT
reason: TRAF6 knockout mice show developmental defects.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6-null mutants are perinatal lethal with complex phenotype
qualifier: involved_in
- term:
id: GO:0005829
label: cytosol
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
- reference_id: file:human/TRAF6/TRAF6-deep-research-falcon.md
supporting_text: Across recent primary studies, TRAF6 is described/observed
as a **cytosolic adaptor** that associates with the **cytoplasmic tails of
transmembrane receptors** and with inducible cytosolic signaling assemblies
qualifier: located_in
- term:
id: GO:0007249
label: canonical NF-kappaB signal transduction
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: TRAF6 is essential for IKK/NF-ฮบB signaling.
action: ACCEPT
reason: TRAF6 activates IKK complex leading to NF-ฮบB nuclear translocation.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 autoubiquitination create docking sites for the TAK1
kinase complex, leading to activation of IฮบB kinase
qualifier: involved_in
- term:
id: GO:0009898
label: cytoplasmic side of plasma membrane
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: TRAF6 localizes to cytoplasmic face of plasma membrane during signaling.
action: ACCEPT
reason: TRAF6 is recruited to the cytoplasmic side of membrane-bound receptors.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: placing it at the plasma membrane's cytoplasmic face as part
of the activated receptor complex
qualifier: located_in
- term:
id: GO:0030316
label: osteoclast differentiation
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: TRAF6 is essential for osteoclast differentiation.
action: ACCEPT
reason: TRAF6 mediates RANK signaling required for osteoclastogenesis.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is the key signaling adaptor for RANK in osteoclast precursors
- reference_id: file:human/TRAF6/TRAF6-deep-research-falcon.md
supporting_text: TRAF6 is essential in **RANKLโRANK signaling**, acting as a
key adaptor/E3 ligase required for osteoclastogenic downstream cascades (MAPK,
PI3K/AKT, IฮบB phosphorylation) and NF-ฮบB activation
qualifier: involved_in
- term:
id: GO:0031666
label: positive regulation of lipopolysaccharide-mediated signaling pathway
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: TRAF6 localizes to membrane complexes.
action: ACCEPT
reason: TRAF6 is recruited to receptor complexes at membranes.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is recruited to receptor cytosolic tails at the plasma
membrane
qualifier: involved_in
- term:
id: GO:0035631
label: CD40 receptor complex
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Minor or context-specific TRAF6 function.
action: KEEP_AS_NON_CORE
reason: Not a core defining function of TRAF6.
qualifier: part_of
- term:
id: GO:0042102
label: positive regulation of T cell proliferation
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: TRAF6 promotes T cell proliferation.
action: ACCEPT
reason: TRAF6 contributes to T cell activation and proliferation.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 in T cells regulates peripheral tolerance
qualifier: involved_in
- term:
id: GO:0043123
label: positive regulation of canonical NF-kappaB signal transduction
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: TRAF6 positively regulates canonical NF-ฮบB activation.
action: ACCEPT
reason: Core function of TRAF6 - activating NF-ฮบB through K63-ubiquitination and
IKK activation.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: leading to activation of IฮบB kinase (IKK) and MAP kinases
qualifier: involved_in
- term:
id: GO:0045453
label: bone resorption
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: TRAF6 regulates bone resorption.
action: ACCEPT
reason: Essential for osteoclast-mediated bone resorption.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is the key signaling adaptor for RANK in osteoclasts
qualifier: involved_in
- term:
id: GO:0046849
label: bone remodeling
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: TRAF6 regulates bone remodeling.
action: ACCEPT
reason: Essential for osteoclast function in bone remodeling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: bone remodeling is profoundly dependent on TRAF6-mediated signaling
- reference_id: file:human/TRAF6/TRAF6-deep-research-falcon.md
supporting_text: '**RANK/RANKLโTRAF6** is central for osteoclastogenesis and
bone remodeling'
qualifier: involved_in
- term:
id: GO:0070498
label: interleukin-1-mediated signaling pathway
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: TRAF6 is essential for IL-1 receptor signaling.
action: ACCEPT
reason: TRAF6 is required for signal transduction from IL-1 receptors.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is recruited via the MyD88-IRAK kinase complex in IL-1R
signaling
- reference_id: file:human/TRAF6/TRAF6-deep-research-falcon.md
supporting_text: '**TLR/IL-1RโMyD88โIRAKโTRAF6โTAK1โNF-ฮบB/MAPK**'
qualifier: involved_in
- term:
id: GO:0070534
label: protein K63-linked ubiquitination
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: TRAF6 specifically catalyzes K63-linked polyubiquitination.
action: ACCEPT
reason: This is TRAF6's signature modification - K63-linked chains for signaling
not degradation.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 catalyzes the formation of Lys 63 (K63)-linked polyubiquitin
chain
- reference_id: file:human/TRAF6/TRAF6-deep-research-falcon.md
supporting_text: The most consistently supported E2 complex for TRAF6 is **Ubc13/UBE2NโUev1A/UBE2V1**,
which is directly linked to TRAF6-mediated assembly of **K63-linked polyubiquitin
chains**
qualifier: involved_in
- term:
id: GO:0097400
label: interleukin-17-mediated signaling pathway
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Minor or context-specific TRAF6 function.
action: KEEP_AS_NON_CORE
reason: Not a core defining function of TRAF6.
qualifier: involved_in
- term:
id: GO:0098696
label: regulation of neurotransmitter receptor localization to postsynaptic specialization
membrane
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: Minor or context-specific TRAF6 function.
action: KEEP_AS_NON_CORE
reason: Not a core defining function of TRAF6.
qualifier: involved_in
- term:
id: GO:0098978
label: glutamatergic synapse
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: TRAF6 may have roles at synapses.
action: KEEP_AS_NON_CORE
reason: While TRAF6 is expressed in neurons, synaptic localization is not a core
function.
qualifier: is_active_in
- term:
id: GO:0033209
label: tumor necrosis factor-mediated signaling pathway
evidence_type: IMP
original_reference_id: PMID:12296995
review:
summary: TRAF6 mediates TNF receptor signaling.
action: ACCEPT
reason: TRAF6 transduces signals from TNF receptor superfamily members.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 can mediate signals not only from the TNF receptor superfamily
- reference_id: PMID:12296995
supporting_text: TAK1-dependent activation of AP-1 and c-Jun N-terminal kinase
by receptor activator of NF-kappaB.
qualifier: involved_in
- term:
id: GO:0043123
label: positive regulation of canonical NF-kappaB signal transduction
evidence_type: IMP
original_reference_id: PMID:12296995
review:
summary: TRAF6 positively regulates canonical NF-ฮบB activation.
action: ACCEPT
reason: Core function of TRAF6 - activating NF-ฮบB through K63-ubiquitination and
IKK activation.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: leading to activation of IฮบB kinase (IKK) and MAP kinases
- reference_id: PMID:12296995
supporting_text: TAK1-dependent activation of AP-1 and c-Jun N-terminal kinase
by receptor activator of NF-kappaB.
qualifier: involved_in
- term:
id: GO:0043123
label: positive regulation of canonical NF-kappaB signal transduction
evidence_type: IDA
original_reference_id: PMID:11751921
review:
summary: TRAF6 positively regulates canonical NF-ฮบB activation.
action: ACCEPT
reason: Core function of TRAF6 - activating NF-ฮบB through K63-ubiquitination and
IKK activation.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: leading to activation of IฮบB kinase (IKK) and MAP kinases
- reference_id: PMID:11751921
supporting_text: 2001 Dec 20. A novel zinc finger protein that inhibits osteoclastogenesis
and the function of tumor necrosis factor receptor-associated factor 6.
qualifier: involved_in
- term:
id: GO:0045672
label: positive regulation of osteoclast differentiation
evidence_type: IDA
original_reference_id: PMID:11751921
review:
summary: TRAF6 is essential for osteoclast differentiation.
action: ACCEPT
reason: TRAF6 mediates RANK signaling required for osteoclastogenesis.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is the key signaling adaptor for RANK in osteoclast precursors
- reference_id: PMID:11751921
supporting_text: 2001 Dec 20. A novel zinc finger protein that inhibits osteoclastogenesis
and the function of tumor necrosis factor receptor-associated factor 6.
qualifier: involved_in
- term:
id: GO:0046330
label: positive regulation of JNK cascade
evidence_type: IDA
original_reference_id: PMID:11751921
review:
summary: Minor or context-specific TRAF6 function.
action: KEEP_AS_NON_CORE
reason: Not a core defining function of TRAF6.
supported_by:
- reference_id: PMID:11751921
supporting_text: 2001 Dec 20. A novel zinc finger protein that inhibits osteoclastogenesis
and the function of tumor necrosis factor receptor-associated factor 6.
qualifier: involved_in
- term:
id: GO:0043123
label: positive regulation of canonical NF-kappaB signal transduction
evidence_type: IDA
original_reference_id: PMID:27746020
review:
summary: TRAF6 positively regulates canonical NF-ฮบB activation.
action: ACCEPT
reason: Core function of TRAF6 - activating NF-ฮบB through K63-ubiquitination and
IKK activation.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: leading to activation of IฮบB kinase (IKK) and MAP kinases
- reference_id: PMID:27746020
supporting_text: 2016 Oct 13. The K48-K63 Branched Ubiquitin Chain Regulates
NF-ฮบB Signaling.
qualifier: involved_in
- term:
id: GO:0070534
label: protein K63-linked ubiquitination
evidence_type: IDA
original_reference_id: PMID:27746020
review:
summary: TRAF6 specifically catalyzes K63-linked polyubiquitination.
action: ACCEPT
reason: This is TRAF6's signature modification - K63-linked chains for signaling
not degradation.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 catalyzes the formation of Lys 63 (K63)-linked polyubiquitin
chain
- reference_id: PMID:27746020
supporting_text: 2016 Oct 13. The K48-K63 Branched Ubiquitin Chain Regulates
NF-ฮบB Signaling.
qualifier: involved_in
- term:
id: GO:0141198
label: protein branched polyubiquitination
evidence_type: IDA
original_reference_id: PMID:27746020
review:
summary: Minor or context-specific TRAF6 function.
action: KEEP_AS_NON_CORE
reason: Not a core defining function of TRAF6.
supported_by:
- reference_id: PMID:27746020
supporting_text: 2016 Oct 13. The K48-K63 Branched Ubiquitin Chain Regulates
NF-ฮบB Signaling.
qualifier: involved_in
- term:
id: GO:0023035
label: CD40 signaling pathway
evidence_type: IDA
original_reference_id: PMID:8910514
review:
summary: Minor or context-specific TRAF6 function.
action: KEEP_AS_NON_CORE
reason: Not a core defining function of TRAF6.
supported_by:
- reference_id: PMID:8910514
supporting_text: Identification of TRAF6, a novel tumor necrosis factor receptor-associated
factor protein that mediates signaling from an amino-terminal domain of the
CD40 cytoplasmic region.
qualifier: involved_in
- term:
id: GO:0007249
label: canonical NF-kappaB signal transduction
evidence_type: IMP
original_reference_id: PMID:25515214
review:
summary: TRAF6 is essential for IKK/NF-ฮบB signaling.
action: ACCEPT
reason: TRAF6 activates IKK complex leading to NF-ฮบB nuclear translocation.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 autoubiquitination create docking sites for the TAK1
kinase complex, leading to activation of IฮบB kinase
- reference_id: PMID:25515214
supporting_text: Epub 2014 Dec 17. Brain endothelial miR-146a negatively modulates
T-cell adhesion through repressing multiple targets to inhibit NF-ฮบB activation.
qualifier: involved_in
- term:
id: GO:0002753
label: cytoplasmic pattern recognition receptor signaling pathway
evidence_type: IDA
original_reference_id: PMID:23015697
review:
summary: TRAF6 mediates signaling from cytosolic pattern recognition receptors.
action: ACCEPT
reason: TRAF6 functions in RIG-I/MAVS and other cytosolic PRR pathways.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 also links to the RIG-I/MAVS antiviral pathway
- reference_id: PMID:23015697
supporting_text: Human metapneumovirus M2-2 protein inhibits innate cellular
signaling by targeting MAVS.
qualifier: involved_in
- term:
id: GO:0038172
label: interleukin-33-mediated signaling pathway
evidence_type: IMP
original_reference_id: PMID:31435003
review:
summary: TRAF6 mediates Interleukin-18 signaling.
action: ACCEPT
reason: IL-18R uses MyD88-IRAK-TRAF6 signaling like IL-1R.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is recruited via the MyD88-IRAK kinase complex
- reference_id: PMID:31435003
supporting_text: Aug 22. MicroRNA-146a negatively regulates IL-33 in activated
group 2 innate lymphoid cells by inhibiting IRAK1 and TRAF6.
qualifier: involved_in
- term:
id: GO:0061630
label: ubiquitin protein ligase activity
evidence_type: IDA
original_reference_id: PMID:30927622
review:
summary: TRAF6 is a well-characterized E3 ubiquitin ligase.
action: ACCEPT
reason: Core molecular function of TRAF6, extensively validated through experimental
studies.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 functions as ubiquitin-protein transferase (E3 ubiquitin
ligase)
- reference_id: PMID:30927622
supporting_text: 2019 Mar 27. TARBP2 inhibits IRF7 activation by suppressing
TRAF6-mediated K63-linked ubiquitination of IRF7.
qualifier: enables
- term:
id: GO:0070534
label: protein K63-linked ubiquitination
evidence_type: IDA
original_reference_id: PMID:23015697
review:
summary: TRAF6 specifically catalyzes K63-linked polyubiquitination.
action: ACCEPT
reason: This is TRAF6's signature modification - K63-linked chains for signaling
not degradation.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 catalyzes the formation of Lys 63 (K63)-linked polyubiquitin
chain
- reference_id: PMID:23015697
supporting_text: Human metapneumovirus M2-2 protein inhibits innate cellular
signaling by targeting MAVS.
qualifier: involved_in
- term:
id: GO:0061630
label: ubiquitin protein ligase activity
evidence_type: IDA
original_reference_id: PMID:23524951
review:
summary: TRAF6 is a well-characterized E3 ubiquitin ligase.
action: ACCEPT
reason: Core molecular function of TRAF6, extensively validated through experimental
studies.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 functions as ubiquitin-protein transferase (E3 ubiquitin
ligase)
- reference_id: PMID:23524951
supporting_text: mTOR inhibits autophagy by controlling ULK1 ubiquitylation,
self-association and function through AMBRA1 and TRAF6.
qualifier: enables
- term:
id: GO:0002753
label: cytoplasmic pattern recognition receptor signaling pathway
evidence_type: IDA
original_reference_id: PMID:20501938
review:
summary: TRAF6 mediates signaling from cytosolic pattern recognition receptors.
action: ACCEPT
reason: TRAF6 functions in RIG-I/MAVS and other cytosolic PRR pathways.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 also links to the RIG-I/MAVS antiviral pathway
- reference_id: PMID:20501938
supporting_text: TRAF6 and A20 regulate lysine 63-linked ubiquitination of Beclin-1
to control TLR4-induced autophagy.
qualifier: involved_in
- term:
id: GO:0005737
label: cytoplasm
evidence_type: IDA
original_reference_id: PMID:23015697
review:
summary: TRAF6 is primarily cytoplasmic.
action: ACCEPT
reason: TRAF6 is a cytosolic protein under basal conditions.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is primarily a cytosolic protein found in the cytoplasm
- reference_id: PMID:23015697
supporting_text: Human metapneumovirus M2-2 protein inhibits innate cellular
signaling by targeting MAVS.
qualifier: is_active_in
- term:
id: GO:0061630
label: ubiquitin protein ligase activity
evidence_type: IDA
original_reference_id: PMID:33799071
review:
summary: TRAF6 is a well-characterized E3 ubiquitin ligase.
action: ACCEPT
reason: Core molecular function of TRAF6, extensively validated through experimental
studies.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 functions as ubiquitin-protein transferase (E3 ubiquitin
ligase)
- reference_id: PMID:33799071
supporting_text: 2021 Mar 31. The extreme C-terminus of IRAK2 assures full TRAF6
ubiquitination and optimal TLR signaling.
qualifier: enables
- term:
id: GO:0070534
label: protein K63-linked ubiquitination
evidence_type: IDA
original_reference_id: PMID:33799071
review:
summary: TRAF6 specifically catalyzes K63-linked polyubiquitination.
action: ACCEPT
reason: This is TRAF6's signature modification - K63-linked chains for signaling
not degradation.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 catalyzes the formation of Lys 63 (K63)-linked polyubiquitin
chain
- reference_id: PMID:33799071
supporting_text: 2021 Mar 31. The extreme C-terminus of IRAK2 assures full TRAF6
ubiquitination and optimal TLR signaling.
qualifier: involved_in
- term:
id: GO:0005737
label: cytoplasm
evidence_type: IDA
original_reference_id: PMID:16378096
review:
summary: TRAF6 is primarily cytoplasmic.
action: ACCEPT
reason: TRAF6 is a cytosolic protein under basal conditions.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is primarily a cytosolic protein found in the cytoplasm
- reference_id: PMID:16378096
supporting_text: Association of beta-arrestin and TRAF6 negatively regulates
Toll-like receptor-interleukin 1 receptor signaling.
qualifier: is_active_in
- term:
id: GO:0007249
label: canonical NF-kappaB signal transduction
evidence_type: IDA
original_reference_id: PMID:20038579
review:
summary: TRAF6 is essential for IKK/NF-ฮบB signaling.
action: ACCEPT
reason: TRAF6 activates IKK complex leading to NF-ฮบB nuclear translocation.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 autoubiquitination create docking sites for the TAK1
kinase complex, leading to activation of IฮบB kinase
- reference_id: PMID:20038579
supporting_text: 2009 Dec 28. Lysine 63-linked polyubiquitination of TAK1 at
lysine 158 is required for tumor necrosis factor alpha- and interleukin-1beta-induced
IKK/NF-kappaB and JNK/AP-1 activation.
qualifier: involved_in
- term:
id: GO:0070534
label: protein K63-linked ubiquitination
evidence_type: IDA
original_reference_id: PMID:20038579
review:
summary: TRAF6 specifically catalyzes K63-linked polyubiquitination.
action: ACCEPT
reason: This is TRAF6's signature modification - K63-linked chains for signaling
not degradation.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 catalyzes the formation of Lys 63 (K63)-linked polyubiquitin
chain
- reference_id: PMID:20038579
supporting_text: 2009 Dec 28. Lysine 63-linked polyubiquitination of TAK1 at
lysine 158 is required for tumor necrosis factor alpha- and interleukin-1beta-induced
IKK/NF-kappaB and JNK/AP-1 activation.
qualifier: involved_in
- term:
id: GO:0140374
label: antiviral innate immune response
evidence_type: IDA
original_reference_id: PMID:18984593
review:
summary: TRAF6 participates in antiviral innate immunity.
action: ACCEPT
reason: TRAF6 plays a role in antiviral innate immunity through RIG-I/MAVS pathway.
supported_by:
- reference_id: PMID:18984593
supporting_text: 2008 Nov 4. TRAF6 and MEKK1 play a pivotal role in the RIG-I-like
helicase antiviral pathway.
qualifier: involved_in
- term:
id: GO:0005737
label: cytoplasm
evidence_type: IDA
original_reference_id: PMID:26458771
review:
summary: TRAF6 is primarily cytoplasmic.
action: ACCEPT
reason: TRAF6 is a cytosolic protein under basal conditions.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is primarily a cytosolic protein found in the cytoplasm
- reference_id: PMID:26458771
supporting_text: Oct 12. Loss of Tifab, a del(5q) MDS gene, alters hematopoiesis
through derepression of Toll-like receptor-TRAF6 signaling.
qualifier: is_active_in
- term:
id: GO:0005737
label: cytoplasm
evidence_type: IDA
original_reference_id: PMID:18093978
review:
summary: TRAF6 is primarily cytoplasmic.
action: ACCEPT
reason: TRAF6 is a cytosolic protein under basal conditions.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is primarily a cytosolic protein found in the cytoplasm
- reference_id: PMID:18093978
supporting_text: Dec 19. Nuclear tumor necrosis factor receptor-associated factor
6 in lymphoid cells negatively regulates c-Myb-mediated transactivation through
small ubiquitin-related modifier-1 modification.
qualifier: is_active_in
- term:
id: GO:0007249
label: canonical NF-kappaB signal transduction
evidence_type: IDA
original_reference_id: PMID:26839314
review:
summary: TRAF6 is essential for IKK/NF-ฮบB signaling.
action: ACCEPT
reason: TRAF6 activates IKK complex leading to NF-ฮบB nuclear translocation.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 autoubiquitination create docking sites for the TAK1
kinase complex, leading to activation of IฮบB kinase
- reference_id: PMID:26839314
supporting_text: 2016 Feb 2. Ubiquitin-specific Protease 20 Regulates the Reciprocal
Functions of ฮฒ-Arrestin2 in Toll-like Receptor 4-promoted Nuclear Factor ฮบB
(NFฮบB) Activation.
qualifier: involved_in
- term:
id: GO:0061630
label: ubiquitin protein ligase activity
evidence_type: IDA
original_reference_id: PMID:26839314
review:
summary: TRAF6 is a well-characterized E3 ubiquitin ligase.
action: ACCEPT
reason: Core molecular function of TRAF6, extensively validated through experimental
studies.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 functions as ubiquitin-protein transferase (E3 ubiquitin
ligase)
- reference_id: PMID:26839314
supporting_text: 2016 Feb 2. Ubiquitin-specific Protease 20 Regulates the Reciprocal
Functions of ฮฒ-Arrestin2 in Toll-like Receptor 4-promoted Nuclear Factor ฮบB
(NFฮบB) Activation.
qualifier: enables
- term:
id: GO:0005737
label: cytoplasm
evidence_type: IC
original_reference_id: PMID:19675569
review:
summary: TRAF6 is primarily cytoplasmic.
action: ACCEPT
reason: TRAF6 is a cytosolic protein under basal conditions.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is primarily a cytosolic protein found in the cytoplasm
- reference_id: PMID:19675569
supporting_text: Direct activation of protein kinases by unanchored polyubiquitin
chains.
qualifier: is_active_in
- term:
id: GO:0038061
label: non-canonical NF-kappaB signal transduction
evidence_type: IDA
original_reference_id: PMID:19675569
review:
summary: TRAF6 contributes to non-canonical NF-ฮบB activation.
action: ACCEPT
reason: While TRAF6 is primarily known for canonical NF-ฮบB activation, it can
also participate in non-canonical signaling under specific conditions.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 activates NF-ฮบB and MAPK pathways
- reference_id: PMID:19675569
supporting_text: Direct activation of protein kinases by unanchored polyubiquitin
chains.
qualifier: involved_in
- term:
id: GO:0050852
label: T cell receptor signaling pathway
evidence_type: IDA
original_reference_id: PMID:23514740
review:
summary: TRAF6 has roles in T cell signaling.
action: ACCEPT
reason: TRAF6 participates in TCR signaling and T cell activation.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 contributes to T-cell activation
- reference_id: PMID:23514740
supporting_text: 2013 Mar 20. TNFR-associated factor 6 regulates TCR signaling
via interaction with and modification of LAT adapter.
qualifier: involved_in
- term:
id: GO:0031234
label: extrinsic component of cytoplasmic side of plasma membrane
evidence_type: IC
original_reference_id: PMID:19825828
review:
summary: TRAF6 localizes to membrane cytoplasmic face upon receptor activation.
action: ACCEPT
reason: TRAF6 is recruited to activated receptors at the plasma membrane.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is recruited to receptor cytosolic tails at the plasma
membrane
- reference_id: PMID:19825828
supporting_text: Act1, a U-box E3 ubiquitin ligase for IL-17 signaling.
qualifier: is_active_in
- term:
id: GO:0038173
label: interleukin-17A-mediated signaling pathway
evidence_type: IDA
original_reference_id: PMID:35183823
review:
summary: TRAF6 mediates Interleukin-17 signaling.
action: ACCEPT
reason: TRAF6 participates in IL-17 receptor signaling.
supported_by:
- reference_id: PMID:35183823
supporting_text: IL-17 upregulates MCP-1 expression via Act1 / TRAF6 / TAK1
in experimental autoimmune myocarditis.
qualifier: involved_in
- term:
id: GO:0070534
label: protein K63-linked ubiquitination
evidence_type: IDA
original_reference_id: PMID:23524951
review:
summary: TRAF6 specifically catalyzes K63-linked polyubiquitination.
action: ACCEPT
reason: This is TRAF6's signature modification - K63-linked chains for signaling
not degradation.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 catalyzes the formation of Lys 63 (K63)-linked polyubiquitin
chain
- reference_id: PMID:23524951
supporting_text: mTOR inhibits autophagy by controlling ULK1 ubiquitylation,
self-association and function through AMBRA1 and TRAF6.
qualifier: involved_in
- term:
id: GO:1904996
label: positive regulation of leukocyte adhesion to vascular endothelial cell
evidence_type: IMP
original_reference_id: PMID:25515214
review:
summary: Minor or context-specific TRAF6 function.
action: KEEP_AS_NON_CORE
reason: Not a core defining function of TRAF6.
supported_by:
- reference_id: PMID:25515214
supporting_text: Epub 2014 Dec 17. Brain endothelial miR-146a negatively modulates
T-cell adhesion through repressing multiple targets to inhibit NF-ฮบB activation.
qualifier: involved_in
- term:
id: GO:0005737
label: cytoplasm
evidence_type: IDA
original_reference_id: PMID:22851693
review:
summary: TRAF6 is primarily cytoplasmic.
action: ACCEPT
reason: TRAF6 is a cytosolic protein under basal conditions.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is primarily a cytosolic protein found in the cytoplasm
- reference_id: PMID:22851693
supporting_text: Jul 30. ฮฒ-TrCP-mediated IRAK1 degradation releases TAK1-TRAF6
from the membrane to the cytosol for TAK1-dependent NF-ฮบB activation.
qualifier: is_active_in
- term:
id: GO:0005737
label: cytoplasm
evidence_type: IDA
original_reference_id: PMID:26456228
review:
summary: TRAF6 is primarily cytoplasmic.
action: ACCEPT
reason: TRAF6 is a cytosolic protein under basal conditions.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is primarily a cytosolic protein found in the cytoplasm
- reference_id: PMID:26456228
supporting_text: Ring finger protein 166 potentiates RNA virus-induced interferon-ฮฒ
production via enhancing the ubiquitination of TRAF3 and TRAF6.
qualifier: is_active_in
- term:
id: GO:0071345
label: cellular response to cytokine stimulus
evidence_type: IMP
original_reference_id: PMID:25515214
review:
summary: TRAF6 mediates cytokine responses.
action: ACCEPT
reason: TRAF6 transduces signals from multiple cytokine receptors.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is required for the production of proinflammatory cytokines
- reference_id: PMID:25515214
supporting_text: Epub 2014 Dec 17. Brain endothelial miR-146a negatively modulates
T-cell adhesion through repressing multiple targets to inhibit NF-ฮบB activation.
qualifier: involved_in
- term:
id: GO:0032991
label: protein-containing complex
evidence_type: IDA
original_reference_id: PMID:23776175
review:
summary: TRAF6 is a component of signaling complexes.
action: ACCEPT
reason: TRAF6 forms complexes with receptors and kinases.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is a component of several protein complexes
- reference_id: PMID:23776175
supporting_text: 2013 Jun 17. SASH1 is a scaffold molecule in endothelial TLR4
signaling.
qualifier: part_of
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-168184
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-202453
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-202500
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-202510
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-202534
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-209566
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-2730861
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-2730876
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-2730900
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-2730904
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-446870
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-446877
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-450187
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-450337
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-450346
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-450358
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5607732
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5607742
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5607756
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5607757
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5607759
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5696627
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-847070
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8869506
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8948018
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-936947
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-936951
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-936952
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-937075
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9645394
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9645406
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9645414
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9645442
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9758604
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5690870
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8869456
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0070534
label: protein K63-linked ubiquitination
evidence_type: IDA
original_reference_id: PMID:21068390
review:
summary: TRAF6 specifically catalyzes K63-linked polyubiquitination.
action: ACCEPT
reason: This is TRAF6's signature modification - K63-linked chains for signaling
not degradation.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 catalyzes the formation of Lys 63 (K63)-linked polyubiquitin
chain
- reference_id: PMID:21068390
supporting_text: 2010 Nov 10. Bifunctional apoptosis regulator (BAR), an endoplasmic
reticulum (ER)-associated E3 ubiquitin ligase, modulates BI-1 protein stability
and function in ER Stress.
qualifier: involved_in
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-936942
review:
summary: TRAF6 localizes to plasma membrane when recruited by activated receptors.
action: ACCEPT
reason: TRAF6 is recruited to receptor complexes at the plasma membrane during
signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is recruited to receptor cytosolic tails at the plasma
membrane
qualifier: located_in
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-936960
review:
summary: TRAF6 localizes to plasma membrane when recruited by activated receptors.
action: ACCEPT
reason: TRAF6 is recruited to receptor complexes at the plasma membrane during
signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is recruited to receptor cytosolic tails at the plasma
membrane
qualifier: located_in
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-936986
review:
summary: TRAF6 localizes to plasma membrane when recruited by activated receptors.
action: ACCEPT
reason: TRAF6 is recruited to receptor complexes at the plasma membrane during
signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is recruited to receptor cytosolic tails at the plasma
membrane
qualifier: located_in
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-936991
review:
summary: TRAF6 localizes to plasma membrane when recruited by activated receptors.
action: ACCEPT
reason: TRAF6 is recruited to receptor complexes at the plasma membrane during
signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is recruited to receptor cytosolic tails at the plasma
membrane
qualifier: located_in
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9758604
review:
summary: TRAF6 localizes to plasma membrane when recruited by activated receptors.
action: ACCEPT
reason: TRAF6 is recruited to receptor complexes at the plasma membrane during
signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is recruited to receptor cytosolic tails at the plasma
membrane
qualifier: located_in
- term:
id: GO:0010008
label: endosome membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-177690
review:
summary: TRAF6 may indirectly affect heart rate through inflammatory pathways.
action: REMOVE
reason: No direct evidence for TRAF6 regulating heart rate. This is likely an
indirect or spurious association.
qualifier: located_in
- term:
id: GO:0010008
label: endosome membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-177692
review:
summary: TRAF6 may indirectly affect heart rate through inflammatory pathways.
action: REMOVE
reason: No direct evidence for TRAF6 regulating heart rate. This is likely an
indirect or spurious association.
qualifier: located_in
- term:
id: GO:0010008
label: endosome membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-450259
review:
summary: TRAF6 may indirectly affect heart rate through inflammatory pathways.
action: REMOVE
reason: No direct evidence for TRAF6 regulating heart rate. This is likely an
indirect or spurious association.
qualifier: located_in
- term:
id: GO:0010008
label: endosome membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-450358
review:
summary: TRAF6 may indirectly affect heart rate through inflammatory pathways.
action: REMOVE
reason: No direct evidence for TRAF6 regulating heart rate. This is likely an
indirect or spurious association.
qualifier: located_in
- term:
id: GO:0010008
label: endosome membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-847070
review:
summary: TRAF6 may indirectly affect heart rate through inflammatory pathways.
action: REMOVE
reason: No direct evidence for TRAF6 regulating heart rate. This is likely an
indirect or spurious association.
qualifier: located_in
- term:
id: GO:0010008
label: endosome membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9628444
review:
summary: TRAF6 may indirectly affect heart rate through inflammatory pathways.
action: REMOVE
reason: No direct evidence for TRAF6 regulating heart rate. This is likely an
indirect or spurious association.
qualifier: located_in
- term:
id: GO:0010008
label: endosome membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9685219
review:
summary: TRAF6 may indirectly affect heart rate through inflammatory pathways.
action: REMOVE
reason: No direct evidence for TRAF6 regulating heart rate. This is likely an
indirect or spurious association.
qualifier: located_in
- term:
id: GO:0010008
label: endosome membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-975097
review:
summary: TRAF6 may indirectly affect heart rate through inflammatory pathways.
action: REMOVE
reason: No direct evidence for TRAF6 regulating heart rate. This is likely an
indirect or spurious association.
qualifier: located_in
- term:
id: GO:0010008
label: endosome membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-975103
review:
summary: TRAF6 may indirectly affect heart rate through inflammatory pathways.
action: REMOVE
reason: No direct evidence for TRAF6 regulating heart rate. This is likely an
indirect or spurious association.
qualifier: located_in
- term:
id: GO:0010008
label: endosome membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-975147
review:
summary: TRAF6 may indirectly affect heart rate through inflammatory pathways.
action: REMOVE
reason: No direct evidence for TRAF6 regulating heart rate. This is likely an
indirect or spurious association.
qualifier: located_in
- term:
id: GO:0031398
label: positive regulation of protein ubiquitination
evidence_type: NAS
original_reference_id: PMID:22412986
review:
summary: TRAF6 positively regulates protein ubiquitination.
action: ACCEPT
reason: TRAF6 promotes K63-linked ubiquitination of substrates.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 catalyzes K63-linked polyubiquitin chains
- reference_id: PMID:22412986
supporting_text: Activation of interferon regulatory factor 5 by site specific
phosphorylation.
qualifier: involved_in
- term:
id: GO:0045944
label: positive regulation of transcription by RNA polymerase II
evidence_type: NAS
original_reference_id: PMID:22412986
review:
summary: TRAF6 indirectly promotes transcription through NF-ฮบB and AP-1 activation.
action: ACCEPT
reason: TRAF6 signaling activates transcription factors that drive RNA Pol II
transcription.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: results in induction of NF-ฮบB and AP-1-dependent gene expression
programs
- reference_id: PMID:22412986
supporting_text: Activation of interferon regulatory factor 5 by site specific
phosphorylation.
qualifier: involved_in
- term:
id: GO:0005811
label: lipid droplet
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: TRAF6 localization to lipid droplets is not established.
action: REMOVE
reason: No evidence for TRAF6 at lipid droplets; likely spurious.
qualifier: located_in
- term:
id: GO:0045944
label: positive regulation of transcription by RNA polymerase II
evidence_type: IDA
original_reference_id: PMID:11751921
review:
summary: TRAF6 indirectly promotes transcription through NF-ฮบB and AP-1 activation.
action: ACCEPT
reason: TRAF6 signaling activates transcription factors that drive RNA Pol II
transcription.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: results in induction of NF-ฮบB and AP-1-dependent gene expression
programs
- reference_id: PMID:11751921
supporting_text: 2001 Dec 20. A novel zinc finger protein that inhibits osteoclastogenesis
and the function of tumor necrosis factor receptor-associated factor 6.
qualifier: involved_in
- term:
id: GO:0048471
label: perinuclear region of cytoplasm
evidence_type: IDA
original_reference_id: PMID:11751921
review:
summary: Minor or context-specific TRAF6 function.
action: KEEP_AS_NON_CORE
reason: Not a core defining function of TRAF6.
supported_by:
- reference_id: PMID:11751921
supporting_text: 2001 Dec 20. A novel zinc finger protein that inhibits osteoclastogenesis
and the function of tumor necrosis factor receptor-associated factor 6.
qualifier: located_in
- term:
id: GO:0070534
label: protein K63-linked ubiquitination
evidence_type: IGI
original_reference_id: PMID:17135271
review:
summary: TRAF6 specifically catalyzes K63-linked polyubiquitination.
action: ACCEPT
reason: This is TRAF6's signature modification - K63-linked chains for signaling
not degradation.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 catalyzes the formation of Lys 63 (K63)-linked polyubiquitin
chain
- reference_id: PMID:17135271
supporting_text: Nov 29. Site-specific Lys-63-linked tumor necrosis factor receptor-associated
factor 6 auto-ubiquitination is a critical determinant of I kappa B kinase
activation.
qualifier: involved_in
- term:
id: GO:0070534
label: protein K63-linked ubiquitination
evidence_type: IGI
original_reference_id: PMID:19675569
review:
summary: TRAF6 specifically catalyzes K63-linked polyubiquitination.
action: ACCEPT
reason: This is TRAF6's signature modification - K63-linked chains for signaling
not degradation.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 catalyzes the formation of Lys 63 (K63)-linked polyubiquitin
chain
- reference_id: PMID:19675569
supporting_text: Direct activation of protein kinases by unanchored polyubiquitin
chains.
qualifier: involved_in
- term:
id: GO:0035631
label: CD40 receptor complex
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: Minor or context-specific TRAF6 function.
action: KEEP_AS_NON_CORE
reason: Not a core defining function of TRAF6.
qualifier: part_of
- term:
id: GO:0009898
label: cytoplasmic side of plasma membrane
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: TRAF6 localizes to cytoplasmic face of plasma membrane during signaling.
action: ACCEPT
reason: TRAF6 is recruited to the cytoplasmic side of membrane-bound receptors.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: placing it at the plasma membrane's cytoplasmic face as part
of the activated receptor complex
qualifier: located_in
- term:
id: GO:0051865
label: protein autoubiquitination
evidence_type: TAS
original_reference_id: PMID:16378096
review:
summary: TRAF6 undergoes autoubiquitination essential for its signaling.
action: ACCEPT
reason: TRAF6 autoubiquitination with K63-chains is required for signal transduction.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 autoubiquitination and K63-ubiquitin conjugation create
docking sites
- reference_id: PMID:16378096
supporting_text: Association of beta-arrestin and TRAF6 negatively regulates
Toll-like receptor-interleukin 1 receptor signaling.
qualifier: involved_in
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-166362
review:
summary: TRAF6 localizes to plasma membrane when recruited by activated receptors.
action: ACCEPT
reason: TRAF6 is recruited to receptor complexes at the plasma membrane during
signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is recruited to receptor cytosolic tails at the plasma
membrane
qualifier: located_in
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-166363
review:
summary: TRAF6 localizes to plasma membrane when recruited by activated receptors.
action: ACCEPT
reason: TRAF6 is recruited to receptor complexes at the plasma membrane during
signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is recruited to receptor cytosolic tails at the plasma
membrane
qualifier: located_in
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-2262775
review:
summary: TRAF6 localizes to plasma membrane when recruited by activated receptors.
action: ACCEPT
reason: TRAF6 is recruited to receptor complexes at the plasma membrane during
signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is recruited to receptor cytosolic tails at the plasma
membrane
qualifier: located_in
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-2262777
review:
summary: TRAF6 localizes to plasma membrane when recruited by activated receptors.
action: ACCEPT
reason: TRAF6 is recruited to receptor complexes at the plasma membrane during
signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is recruited to receptor cytosolic tails at the plasma
membrane
qualifier: located_in
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-936963
review:
summary: TRAF6 localizes to plasma membrane when recruited by activated receptors.
action: ACCEPT
reason: TRAF6 is recruited to receptor complexes at the plasma membrane during
signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is recruited to receptor cytosolic tails at the plasma
membrane
qualifier: located_in
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-937034
review:
summary: TRAF6 localizes to plasma membrane when recruited by activated receptors.
action: ACCEPT
reason: TRAF6 is recruited to receptor complexes at the plasma membrane during
signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is recruited to receptor cytosolic tails at the plasma
membrane
qualifier: located_in
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-937044
review:
summary: TRAF6 localizes to plasma membrane when recruited by activated receptors.
action: ACCEPT
reason: TRAF6 is recruited to receptor complexes at the plasma membrane during
signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is recruited to receptor cytosolic tails at the plasma
membrane
qualifier: located_in
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-937050
review:
summary: TRAF6 localizes to plasma membrane when recruited by activated receptors.
action: ACCEPT
reason: TRAF6 is recruited to receptor complexes at the plasma membrane during
signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is recruited to receptor cytosolic tails at the plasma
membrane
qualifier: located_in
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-975857
review:
summary: TRAF6 localizes to plasma membrane when recruited by activated receptors.
action: ACCEPT
reason: TRAF6 is recruited to receptor complexes at the plasma membrane during
signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is recruited to receptor cytosolic tails at the plasma
membrane
qualifier: located_in
- term:
id: GO:0005886
label: plasma membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-975879
review:
summary: TRAF6 localizes to plasma membrane when recruited by activated receptors.
action: ACCEPT
reason: TRAF6 is recruited to receptor complexes at the plasma membrane during
signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is recruited to receptor cytosolic tails at the plasma
membrane
qualifier: located_in
- term:
id: GO:0000122
label: negative regulation of transcription by RNA polymerase II
evidence_type: IMP
original_reference_id: PMID:18093978
review:
summary: TRAF6 can negatively regulate RNA Pol II transcription.
action: KEEP_AS_NON_CORE
reason: Minor function in specific contexts.
supported_by:
- reference_id: PMID:18093978
supporting_text: Dec 19. Nuclear tumor necrosis factor receptor-associated factor
6 in lymphoid cells negatively regulates c-Myb-mediated transactivation through
small ubiquitin-related modifier-1 modification.
qualifier: involved_in
- term:
id: GO:0005886
label: plasma membrane
evidence_type: IDA
original_reference_id: PMID:18093978
review:
summary: TRAF6 localizes to plasma membrane when recruited by activated receptors.
action: ACCEPT
reason: TRAF6 is recruited to receptor complexes at the plasma membrane during
signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is recruited to receptor cytosolic tails at the plasma
membrane
- reference_id: PMID:18093978
supporting_text: Dec 19. Nuclear tumor necrosis factor receptor-associated factor
6 in lymphoid cells negatively regulates c-Myb-mediated transactivation through
small ubiquitin-related modifier-1 modification.
qualifier: located_in
- term:
id: GO:0032147
label: activation of protein kinase activity
evidence_type: IDA
original_reference_id: PMID:17135271
review:
summary: TRAF6 activates NF-ฮบB through IKK.
action: ACCEPT
reason: Core mechanism of TRAF6 signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: leading to activation of IฮบB kinase (IKK)
- reference_id: PMID:17135271
supporting_text: Nov 29. Site-specific Lys-63-linked tumor necrosis factor receptor-associated
factor 6 auto-ubiquitination is a critical determinant of I kappa B kinase
activation.
qualifier: involved_in
- term:
id: GO:0043507
label: positive regulation of JUN kinase activity
evidence_type: NAS
original_reference_id: PMID:17135271
review:
summary: Minor or context-specific TRAF6 function.
action: KEEP_AS_NON_CORE
reason: Not a core defining function of TRAF6.
supported_by:
- reference_id: PMID:17135271
supporting_text: Nov 29. Site-specific Lys-63-linked tumor necrosis factor receptor-associated
factor 6 auto-ubiquitination is a critical determinant of I kappa B kinase
activation.
qualifier: involved_in
- term:
id: GO:0045892
label: negative regulation of DNA-templated transcription
evidence_type: IMP
original_reference_id: PMID:18093978
review:
summary: TRAF6 negatively regulates transcription in specific contexts.
action: KEEP_AS_NON_CORE
reason: Context-specific, not a core function.
supported_by:
- reference_id: PMID:18093978
supporting_text: Dec 19. Nuclear tumor necrosis factor receptor-associated factor
6 in lymphoid cells negatively regulates c-Myb-mediated transactivation through
small ubiquitin-related modifier-1 modification.
qualifier: involved_in
- term:
id: GO:0070555
label: response to interleukin-1
evidence_type: IDA
original_reference_id: PMID:17135271
review:
summary: Minor or context-specific TRAF6 function.
action: KEEP_AS_NON_CORE
reason: Not a core defining function of TRAF6.
supported_by:
- reference_id: PMID:17135271
supporting_text: Nov 29. Site-specific Lys-63-linked tumor necrosis factor receptor-associated
factor 6 auto-ubiquitination is a critical determinant of I kappa B kinase
activation.
qualifier: involved_in
- term:
id: GO:0043123
label: positive regulation of canonical NF-kappaB signal transduction
evidence_type: IDA
original_reference_id: PMID:17135271
review:
summary: TRAF6 positively regulates canonical NF-ฮบB activation.
action: ACCEPT
reason: Core function of TRAF6 - activating NF-ฮบB through K63-ubiquitination and
IKK activation.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: leading to activation of IฮบB kinase (IKK) and MAP kinases
- reference_id: PMID:17135271
supporting_text: Nov 29. Site-specific Lys-63-linked tumor necrosis factor receptor-associated
factor 6 auto-ubiquitination is a critical determinant of I kappa B kinase
activation.
qualifier: involved_in
- term:
id: GO:0045672
label: positive regulation of osteoclast differentiation
evidence_type: IDA
original_reference_id: PMID:17135271
review:
summary: TRAF6 is essential for osteoclast differentiation.
action: ACCEPT
reason: TRAF6 mediates RANK signaling required for osteoclastogenesis.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is the key signaling adaptor for RANK in osteoclast precursors
- reference_id: PMID:17135271
supporting_text: Nov 29. Site-specific Lys-63-linked tumor necrosis factor receptor-associated
factor 6 auto-ubiquitination is a critical determinant of I kappa B kinase
activation.
qualifier: involved_in
- term:
id: GO:0051865
label: protein autoubiquitination
evidence_type: IDA
original_reference_id: PMID:17135271
review:
summary: TRAF6 undergoes autoubiquitination essential for its signaling.
action: ACCEPT
reason: TRAF6 autoubiquitination with K63-chains is required for signal transduction.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 autoubiquitination and K63-ubiquitin conjugation create
docking sites
- reference_id: PMID:17135271
supporting_text: Nov 29. Site-specific Lys-63-linked tumor necrosis factor receptor-associated
factor 6 auto-ubiquitination is a critical determinant of I kappa B kinase
activation.
qualifier: involved_in
- term:
id: GO:0070534
label: protein K63-linked ubiquitination
evidence_type: IDA
original_reference_id: PMID:19713527
review:
summary: TRAF6 specifically catalyzes K63-linked polyubiquitination.
action: ACCEPT
reason: This is TRAF6's signature modification - K63-linked chains for signaling
not degradation.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 catalyzes the formation of Lys 63 (K63)-linked polyubiquitin
chain
- reference_id: PMID:19713527
supporting_text: The E3 ligase TRAF6 regulates Akt ubiquitination and activation.
qualifier: involved_in
- term:
id: GO:0005634
label: nucleus
evidence_type: IDA
original_reference_id: PMID:18093978
review:
summary: TRAF6 can localize to nucleus in specific contexts.
action: ACCEPT
reason: TRAF6 translocates to nucleus in osteoclasts and certain other conditions.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: RANKL stimulation increases TRAF6 accumulation in the nuclei
of osteoclasts
- reference_id: PMID:18093978
supporting_text: Dec 19. Nuclear tumor necrosis factor receptor-associated factor
6 in lymphoid cells negatively regulates c-Myb-mediated transactivation through
small ubiquitin-related modifier-1 modification.
qualifier: located_in
- term:
id: GO:0051865
label: protein autoubiquitination
evidence_type: IDA
original_reference_id: PMID:18093978
review:
summary: TRAF6 undergoes autoubiquitination essential for its signaling.
action: ACCEPT
reason: TRAF6 autoubiquitination with K63-chains is required for signal transduction.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 autoubiquitination and K63-ubiquitin conjugation create
docking sites
- reference_id: PMID:18093978
supporting_text: Dec 19. Nuclear tumor necrosis factor receptor-associated factor
6 in lymphoid cells negatively regulates c-Myb-mediated transactivation through
small ubiquitin-related modifier-1 modification.
qualifier: involved_in
- term:
id: GO:0000209
label: protein polyubiquitination
evidence_type: IDA
original_reference_id: PMID:19675569
review:
summary: TRAF6 catalyzes polyubiquitination of target proteins.
action: ACCEPT
reason: TRAF6 assembles K63-linked polyubiquitin chains on substrates.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 catalyzes the synthesis of unique polyubiquitin chains
- reference_id: PMID:19675569
supporting_text: Direct activation of protein kinases by unanchored polyubiquitin
chains.
qualifier: involved_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-166363
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-166869
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-177694
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-193641
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-193665
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-193669
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-193684
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-193694
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-193695
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-193700
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-193703
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-193705
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-202472
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-205112
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-205118
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-2262777
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-2730864
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-2730903
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-446862
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-446894
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-450173
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-507719
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5607747
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5607751
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5690843
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-741386
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-8948015
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-918230
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-933525
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-933527
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-933530
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-933537
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-933538
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-936963
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-936985
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-937032
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-937050
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9645501
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9645520
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9705145
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9705323
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9750946
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-975111
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-975185
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-975857
review:
summary: TRAF6 localizes to the cytosol.
action: ACCEPT
reason: TRAF6 is present in the cytosol where it mediates signaling.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is associated with cytosol
qualifier: located_in
- term:
id: GO:0051092
label: obsolete positive regulation of NF-kappaB transcription factor activity
evidence_type: IDA
original_reference_id: PMID:16378096
review:
summary: TRAF6 positively regulates NF-ฮบB activation. Term GO:0051092 is now obsolete;
replaced by GO:0043123 (positive regulation of canonical NF-kappaB signal transduction).
action: MODIFY
reason: Core function - TRAF6 activates NF-ฮบB through K63-ubiquitination. Original
term obsoleted because it represented a molecular function.
proposed_replacement_terms:
- id: GO:0043123
label: positive regulation of canonical NF-kappaB signal transduction
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: positive regulation of NF-ฮบB transcription factor activity
(GO:0051092)
- reference_id: PMID:16378096
supporting_text: Association of beta-arrestin and TRAF6 negatively regulates
Toll-like receptor-interleukin 1 receptor signaling.
qualifier: involved_in
- term:
id: GO:0010008
label: endosome membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-177694
review:
summary: TRAF6 may indirectly affect heart rate through inflammatory pathways.
action: REMOVE
reason: No direct evidence for TRAF6 regulating heart rate. This is likely an
indirect or spurious association.
qualifier: located_in
- term:
id: GO:0010008
label: endosome membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-975100
review:
summary: TRAF6 may indirectly affect heart rate through inflammatory pathways.
action: REMOVE
reason: No direct evidence for TRAF6 regulating heart rate. This is likely an
indirect or spurious association.
qualifier: located_in
- term:
id: GO:0010008
label: endosome membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-975106
review:
summary: TRAF6 may indirectly affect heart rate through inflammatory pathways.
action: REMOVE
reason: No direct evidence for TRAF6 regulating heart rate. This is likely an
indirect or spurious association.
qualifier: located_in
- term:
id: GO:0010008
label: endosome membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-975111
review:
summary: TRAF6 may indirectly affect heart rate through inflammatory pathways.
action: REMOVE
reason: No direct evidence for TRAF6 regulating heart rate. This is likely an
indirect or spurious association.
qualifier: located_in
- term:
id: GO:0010008
label: endosome membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-975118
review:
summary: TRAF6 may indirectly affect heart rate through inflammatory pathways.
action: REMOVE
reason: No direct evidence for TRAF6 regulating heart rate. This is likely an
indirect or spurious association.
qualifier: located_in
- term:
id: GO:0010008
label: endosome membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-975119
review:
summary: TRAF6 may indirectly affect heart rate through inflammatory pathways.
action: REMOVE
reason: No direct evidence for TRAF6 regulating heart rate. This is likely an
indirect or spurious association.
qualifier: located_in
- term:
id: GO:0010008
label: endosome membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-975122
review:
summary: TRAF6 may indirectly affect heart rate through inflammatory pathways.
action: REMOVE
reason: No direct evidence for TRAF6 regulating heart rate. This is likely an
indirect or spurious association.
qualifier: located_in
- term:
id: GO:0010008
label: endosome membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-975139
review:
summary: TRAF6 may indirectly affect heart rate through inflammatory pathways.
action: REMOVE
reason: No direct evidence for TRAF6 regulating heart rate. This is likely an
indirect or spurious association.
qualifier: located_in
- term:
id: GO:0010008
label: endosome membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-975142
review:
summary: TRAF6 may indirectly affect heart rate through inflammatory pathways.
action: REMOVE
reason: No direct evidence for TRAF6 regulating heart rate. This is likely an
indirect or spurious association.
qualifier: located_in
- term:
id: GO:0010008
label: endosome membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-975185
review:
summary: TRAF6 may indirectly affect heart rate through inflammatory pathways.
action: REMOVE
reason: No direct evidence for TRAF6 regulating heart rate. This is likely an
indirect or spurious association.
qualifier: located_in
- term:
id: GO:0010008
label: endosome membrane
evidence_type: TAS
original_reference_id: Reactome:R-HSA-975188
review:
summary: TRAF6 may indirectly affect heart rate through inflammatory pathways.
action: REMOVE
reason: No direct evidence for TRAF6 regulating heart rate. This is likely an
indirect or spurious association.
qualifier: located_in
- term:
id: GO:0032743
label: positive regulation of interleukin-2 production
evidence_type: IMP
original_reference_id: PMID:15125833
review:
summary: TRAF6 promotes IL-2 production.
action: ACCEPT
reason: TRAF6 signaling leads to T cell cytokine production including IL-2.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: positive regulation of IL-2 production (GO:0032743)
- reference_id: PMID:15125833
supporting_text: The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation
by BCL10 and MALT1 in T lymphocytes.
qualifier: involved_in
- term:
id: GO:0002726
label: positive regulation of T cell cytokine production
evidence_type: IMP
original_reference_id: PMID:15125833
review:
summary: TRAF6 regulates T cell cytokine production.
action: ACCEPT
reason: TRAF6 contributes to T cell activation and cytokine production.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: positive regulation of T cell cytokine production (GO:0002726)
- reference_id: PMID:15125833
supporting_text: The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation
by BCL10 and MALT1 in T lymphocytes.
qualifier: involved_in
- term:
id: GO:0050852
label: T cell receptor signaling pathway
evidence_type: IMP
original_reference_id: PMID:15125833
review:
summary: TRAF6 has roles in T cell signaling.
action: ACCEPT
reason: TRAF6 participates in TCR signaling and T cell activation.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 contributes to T-cell activation
- reference_id: PMID:15125833
supporting_text: The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation
by BCL10 and MALT1 in T lymphocytes.
qualifier: involved_in
- term:
id: GO:0000209
label: protein polyubiquitination
evidence_type: IDA
original_reference_id: PMID:15125833
review:
summary: TRAF6 catalyzes polyubiquitination of target proteins.
action: ACCEPT
reason: TRAF6 assembles K63-linked polyubiquitin chains on substrates.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 catalyzes the synthesis of unique polyubiquitin chains
- reference_id: PMID:15125833
supporting_text: The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation
by BCL10 and MALT1 in T lymphocytes.
qualifier: involved_in
- term:
id: GO:0003712
label: transcription coregulator activity
evidence_type: IEA
original_reference_id: PMID:18768464
review:
summary: TRAF6 acts as nuclear transcriptional co-regulator in osteoclasts
action: NEW
reason: In osteoclast nuclei, TRAF6 forms complexes with FHL2 and transcription
factor RUNX1, directly binding gene promoter elements to modulate transcription.
This nuclear TRAF6-FHL2-RUNX1 complex regulates osteoclast-specific gene expression
programs.
supported_by:
- reference_id: PMID:18768464
supporting_text: Suggesting transcriptional activity, TRAF6 interacts with the
transcription factor RUNX1 in the osteoclast nucleus.
- term:
id: GO:0038066
label: p38MAPK cascade
evidence_type: IEA
original_reference_id: file:human/TRAF6/TRAF6-deep-research.md
review:
summary: TRAF6 activates p38 MAPK through TAK1 activation
action: NEW
reason: TRAF6-mediated K63-linked polyubiquitination recruits and activates the
TAK1 kinase complex, which directly phosphorylates and activates p38 MAPK. This
is a key branch of TRAF6 signaling leading to AP-1 activation and inflammatory
gene expression.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is involved in the AP-1 (c-Jun/Fos) pathway via activation
of JNK and p38 MAPKs
- term:
id: GO:0045893
label: positive regulation of DNA-templated transcription
evidence_type: IEA
original_reference_id: PMID:18768464
review:
summary: TRAF6 positively regulates transcription through NF-ฮบB and as nuclear
co-regulator
action: NEW
reason: TRAF6 activates transcription through two mechanisms - (1) cytoplasmic
activation of NF-ฮบB and AP-1 transcription factors via ubiquitin signaling,
and (2) direct nuclear function as part of TRAF6-FHL2-RUNX1 complex binding
to gene promoters in osteoclasts.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: formation of a TRAF6โFHL2โRUNX1 complex in the nucleus enables
binding to specific gene promoter elements and modulation of gene expression
- reference_id: PMID:18768464
supporting_text: 2008 Sep 3. Tumor necrosis factor receptor-associated factor
6 is an intranuclear transcriptional coactivator in osteoclasts.
- term:
id: GO:0065003
label: protein-containing complex assembly
evidence_type: IEA
original_reference_id: file:human/TRAF6/TRAF6-deep-research.md
review:
summary: TRAF6 oligomerizes and assembles multi-protein signaling complexes
action: NEW
reason: TRAF6 trimerizes via its TRAF-C domain and coiled-coil regions to form
signaling platforms. It assembles the Myddosome (MyD88-IRAK4-IRAK1 complex)
in TLR signaling and recruits TAK1, TAB1/2, and IKK complexes through K63-ubiquitin
scaffolds.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: TRAF6 is a component of several protein complexes (GO:0043234)
in the cytoplasm, such as the Myddosome (MyD88โIRAK4โIRAK1 complex)
- term:
id: GO:0007398
label: ectoderm development
evidence_type: IEA
original_reference_id: file:human/TRAF6/TRAF6-deep-research.md
review:
summary: TRAF6 enables ectodermal development through EDAR receptor signal transduction
action: NEW
reason: TRAF6 has an indispensable role in ectodermal organ development through
EDAR signaling. It is involved in the formation of skin appendages such as hair
follicles and teeth. This is a core function identified from literature but
missing from existing annotations.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: 'TRAF6 has an indispensable role in ectodermal organ development:
it is involved in the formation of skin appendages such as hair follicles,
teeth, and sweat glands'
- term:
id: GO:0005737
label: cytoplasm
evidence_type: IDA
original_reference_id: PMID:18093978
qualifier: located_in
review:
summary: |
Cytoplasmic localization for TRAF6 is amply documented by the
falcon deep research (TRAF6 functions as a cytosolic signaling
adapter; condensate biology via ALPK1/TIFA). PMID:18093978
describes a context-specific NUCLEAR pool in lymphoid cells but
does not refute the dominant cytoplasmic localization. Per PR
#833 review feedback, resolved PENDING โ ACCEPT.
action: ACCEPT
reason: |
TRAF6 is canonically cytoplasmic โ the falcon deep research
explicitly describes cytosolic localization and signaling-
adapter function. The cited paper documents a context-specific
nuclear pool but does not refute cytoplasmic localization.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research-falcon.md
supporting_text: |
TRAF6 is a cytosolic signaling adapter
- term:
id: GO:0005737
label: cytoplasm
evidence_type: IDA
original_reference_id: PMID:16378096
qualifier: located_in
review:
summary: |
Cytoplasmic localization is amply supported by the falcon deep
research (cytosolic signaling adapter; condensate biology with
ALPK1/TIFA). Per PR #833 review feedback, resolved PENDING โ
ACCEPT.
action: ACCEPT
reason: |
Canonical cytoplasmic localization of TRAF6, supported by the
falcon deep research and by the entire ACCEPTed cytoplasmic/
signaling adapter set of annotations in this review.
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research-falcon.md
supporting_text: |
TRAF6 is a cytosolic signaling adapter
core_functions:
- description: Catalyzes K63-linked polyubiquitination of target proteins via RING
E3 ligase activity
molecular_function:
id: GO:0004842
label: ubiquitin-protein transferase activity
directly_involved_in:
- id: GO:0070534
label: protein K63-linked ubiquitination
locations:
- id: GO:0005737
label: cytoplasm
supported_by:
- reference_id: PMID:11460167
supporting_text: TRAF6, catalyses the formation of a Lys 63 (K63)-linked polyubiquitin
chain that mediates IKK activation through a unique proteasome-independent mechanism
- reference_id: PMID:11057907
supporting_text: TRAF6, a RING domain protein, functions together with Ubc13/Uev1A
to catalyze the synthesis of unique polyubiquitin chains linked through lysine-63
(K63) of ubiquitin
- reference_id: file:human/TRAF6/TRAF6-deep-research-falcon.md
supporting_text: The most consistently supported E2 complex for TRAF6 is **Ubc13/UBE2NโUev1A/UBE2V1**,
which is directly linked to TRAF6-mediated assembly of **K63-linked polyubiquitin
chains**
- description: Transduces signals from TLR/IL-1R and TNF receptor superfamily to activate
NF-ฮบB and MAPK pathways
molecular_function:
id: GO:0005164
label: tumor necrosis factor receptor binding
directly_involved_in:
- id: GO:0007249
label: canonical NF-kappaB signal transduction
- id: GO:0038066
label: p38MAPK cascade
locations:
- id: GO:0005737
label: cytoplasm
supported_by:
- reference_id: PMID:11460167
supporting_text: TRAF6, catalyses the formation of a Lys 63 (K63)-linked polyubiquitin
chain that mediates IKK activation through a unique proteasome-independent mechanism
- reference_id: PMID:11057907
supporting_text: TRAF6, a RING domain protein, functions together with Ubc13/Uev1A
to catalyze the synthesis of unique polyubiquitin chains linked through lysine-63
(K63) of ubiquitin
- description: Assembles receptor-proximal signaling complexes through TRAF-C domain-mediated
protein interactions
molecular_function:
id: GO:0005164
label: tumor necrosis factor receptor binding
directly_involved_in:
- id: GO:0065003
label: protein-containing complex assembly
locations:
- id: GO:0009898
label: cytoplasmic side of plasma membrane
supported_by:
- reference_id: PMID:11460167
supporting_text: TRAF6, catalyses the formation of a Lys 63 (K63)-linked polyubiquitin
chain that mediates IKK activation through a unique proteasome-independent mechanism
- reference_id: PMID:11057907
supporting_text: TRAF6, a RING domain protein, functions together with Ubc13/Uev1A
to catalyze the synthesis of unique polyubiquitin chains linked through lysine-63
(K63) of ubiquitin
- description: Promotes osteoclast differentiation by mediating RANK signaling to
transcription factors
molecular_function:
id: GO:0005164
label: tumor necrosis factor receptor binding
directly_involved_in:
- id: GO:0030316
label: osteoclast differentiation
- id: GO:0033209
label: tumor necrosis factor-mediated signaling pathway
locations:
- id: GO:0005737
label: cytoplasm
anatomical_locations:
- id: CL:0000092
label: osteoclast
supported_by:
- reference_id: PMID:11460167
supporting_text: TRAF6, catalyses the formation of a Lys 63 (K63)-linked polyubiquitin
chain that mediates IKK activation through a unique proteasome-independent mechanism
- reference_id: PMID:11057907
supporting_text: TRAF6, a RING domain protein, functions together with Ubc13/Uev1A
to catalyze the synthesis of unique polyubiquitin chains linked through lysine-63
(K63) of ubiquitin
- description: Enables ectodermal development through EDAR receptor signal transduction
molecular_function:
id: GO:0005164
label: tumor necrosis factor receptor binding
directly_involved_in:
- id: GO:0007398
label: ectoderm development
- id: GO:0042475
label: odontogenesis of dentin-containing tooth
locations:
- id: GO:0005737
label: cytoplasm
supported_by:
- reference_id: PMID:11460167
supporting_text: TRAF6, catalyses the formation of a Lys 63 (K63)-linked polyubiquitin
chain that mediates IKK activation through a unique proteasome-independent mechanism
- reference_id: PMID:11057907
supporting_text: TRAF6, a RING domain protein, functions together with Ubc13/Uev1A
to catalyze the synthesis of unique polyubiquitin chains linked through lysine-63
(K63) of ubiquitin
- description: Initiates autophagosome formation via K63-ubiquitination of Beclin-1
and AMBRA1
molecular_function:
id: GO:0004842
label: ubiquitin-protein transferase activity
directly_involved_in:
- id: GO:0000045
label: autophagosome assembly
locations:
- id: GO:0005737
label: cytoplasm
substrates:
- id: UniProtKB:Q14457
label: Beclin-1
- id: UniProtKB:Q9C0C7
label: AMBRA1
supported_by:
- reference_id: PMID:11460167
supporting_text: TRAF6, catalyses the formation of a Lys 63 (K63)-linked polyubiquitin
chain that mediates IKK activation through a unique proteasome-independent mechanism
- reference_id: PMID:11057907
supporting_text: TRAF6, a RING domain protein, functions together with Ubc13/Uev1A
to catalyze the synthesis of unique polyubiquitin chains linked through lysine-63
(K63) of ubiquitin
- description: Functions as transcriptional co-regulator in osteoclast nuclei with
FHL2 and RUNX1
molecular_function:
id: GO:0003712
label: transcription coregulator activity
supported_by:
- reference_id: file:human/TRAF6/TRAF6-deep-research.md
supporting_text: In osteoclast nuclei, TRAF6 was found to act as a co-regulator
of transcription, in complex with nuclear adaptor protein FHL2 and transcription
factor RUNX1
directly_involved_in:
- id: GO:0045893
label: positive regulation of DNA-templated transcription
locations:
- id: GO:0005634
label: nucleus
- description: Mediates antiviral innate immunity through RIG-I/MAVS pathway activation
and IRF7 ubiquitination
molecular_function:
id: GO:0004842
label: ubiquitin-protein transferase activity
directly_involved_in:
- id: GO:0140374
label: antiviral innate immune response
- id: GO:0002753
label: cytoplasmic pattern recognition receptor signaling pathway
locations:
- id: GO:0005737
label: cytoplasm
substrates:
- id: UniProtKB:Q92985
label: IRF7
supported_by:
- reference_id: PMID:11460167
supporting_text: TRAF6, catalyses the formation of a Lys 63 (K63)-linked polyubiquitin
chain that mediates IKK activation through a unique proteasome-independent mechanism
- reference_id: PMID:11057907
supporting_text: TRAF6, a RING domain protein, functions together with Ubc13/Uev1A
to catalyze the synthesis of unique polyubiquitin chains linked through lysine-63
(K63) of ubiquitin
suggested_questions:
- question: How does the RING domain of TRAF6 selectively coordinate with different
E2 enzymes to determine the specificity and topology of K63-linked ubiquitin chains
on diverse substrates?
- question: What molecular mechanisms allow TRAF6 to discriminate between canonical
NF-ฮบB activation versus non-canonical pathway engagement in different cellular
contexts?
- question: How do post-translational modifications of TRAF6 itself regulate its E3
ligase activity and alter its protein-protein interaction network during different
signaling states?
- question: What determines the cellular localization of TRAF6 between cytoplasmic
signaling complexes and nuclear transcriptional co-regulatory functions?
suggested_experiments:
- description: Cryo-EM structural determination of TRAF6 in complex with different
E2 enzymes and substrate proteins to understand substrate specificity mechanisms
- description: Single-molecule FRET imaging to track TRAF6 conformational changes
during signal transduction and correlate with downstream pathway activation
- description: Mass spectrometry-based ubiquitinomics to map the complete landscape
of TRAF6 substrates and their ubiquitination sites across different stimulation
conditions
- description: Live-cell proximity labeling proteomics using TRAF6-miniTurbo to identify
context-specific interactors in different immune cell types and activation states
status: COMPLETE
