TRAF3 is a cytoplasmic RING-type E3 ubiquitin ligase (EC 2.3.2.27) and signalling adaptor of the TNF receptor-associated factor family. Its C-terminal MATH/TRAF-C domain binds the cytoplasmic tails of TNF receptor superfamily members - CD40, LTBR, BAFF-R, BCMA, CD30, OX40, EDAR, Fn14 - and the Epstein-Barr virus oncoprotein LMP1, while its N-terminal RING and zinc fingers provide ubiquitin ligase activity; the protein acts as a homotrimer and also forms heterotrimers with TRAF2 and TRAF5. TRAF3 is distinctive among TRAFs in having two functions of opposite sign. It is the constitutive brake on the non-canonical NF-kappaB pathway: within a TRAF2-cIAP1/2 assembly it recruits the kinase NIK/MAP3K14 and drives its continuous proteasomal degradation, so that p100/NFKB2 remains unprocessed until receptor engagement destroys TRAF3 itself; this restrains B-cell survival and lymphoid organ development, and TRAF3 inactivation is a recurrent driver event in multiple myeloma. Conversely, TRAF3 is a non-redundant positive component of type I interferon induction, bridging the TLR adaptors TRIF and MyD88 and the mitochondrial RIG-I adaptor MAVS to the IRF3/IRF7 kinases TBK1 and IKK-epsilon; autosomal dominant human TRAF3 deficiency, caused by a dominant-negative R118W allele, causes herpes simplex encephalitis through impaired TLR3-dependent interferon induction. Which output is produced is set by the ubiquitin chain TRAF3 carries: TRIF-driven K63-linked self-ubiquitination activates the interferon arm, whereas MyD88/cIAP-driven K48-linked ubiquitination degrades TRAF3 and licenses MAPK activation and pro-inflammatory cytokine production. As an enzyme TRAF3 builds K63-linked chains, most clearly on ASC, where the modification is required for inflammasome speck formation. TRAF3 acts in the cytosol and at the cytoplasmic face of the plasma membrane, on endosomes carrying internalised TLR4/TRAM, and on mitochondria at the MAVS platform.
Definition: The series of molecular signals initiated by the binding of a lymphotoxin alpha1/beta2 heterotrimer or LIGHT to the lymphotoxin beta receptor (LTBR) on the surface of a cell, and ending with the regulation of a downstream cellular process, e.g. transcription.
Justification: GO has receptor-specific pathway terms for CD40 (GO:0023035) and for several other TNF receptor superfamily members, but none for LTBR. A substantial body of TRAF3 (and TRAF2, NIK, RELB) experimental work is anchored to LTBR specifically, and curators are currently forced to use GO:0033209 (tumor necrosis factor-mediated signaling pathway), whose definition requires TNF itself binding its receptor. That is a taxonomically and mechanistically inaccurate fit: TRAF3 does not bind TNFR1 and the LTBR pathway engages the non-canonical NF-kappaB branch that TNF/TNFR1 does not. Checked against OLS: GO currently has lymphotoxin terms only for the ligand and its production (GO:0032641, GO:0032681, GO:0062048), none for LTBR-initiated signalling. GO:0007166 is proposed as the parent because that is also the parent of GO:0023035, so the new term would sit as a sibling of the CD40 pathway term rather than beneath it.
Parent term: cell surface receptor signaling pathway
Supporting Evidence:
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: TRAF3 is a cytoplasmic signalling adaptor and E3 ligase; cytoplasmic localisation is directly observed and is where all of its characterised activities occur. Reason: UniProt records Cytoplasm with experimental evidence from PubMed:25847972 and PubMed:34011520, and every characterised TRAF3 complex (TRAF2-cIAP-NIK, TRIF-TBK1, MAVS) is cytoplasmic. Correct, though the more informative sub-locations (cytosol, cytoplasmic face of the plasma membrane, endosome, mitochondrion) are separately annotated. Supporting Evidence: file:human/TRAF3/TRAF3-notes.md TRAF3 has no TM segment; it is a cytosolic protein transiently recruited to membrane-proximal complexes |
| GO:0043122 regulation of canonical NF-kappaB signal transduction | IBA GO_REF:0000033 | ACCEPT | Summary: TRAF3 regulates canonical NF-kappaB signalling - negatively at LTBR, where it excludes TRAF2/IKK1 from the receptor complex, and indirectly in TLR pathways. Reason: Directly demonstrated by TRAF3 knockdown, which restores LTBR-inducible canonical NF-kappaB signalling and target-gene expression. The measured effect on this branch is inhibitory, so GO:0043124 (negative regulation) is tempting; the unsigned parent is deliberately retained because it is not yet established whether TRAF3 represses canonical NF-kappaB directly, by excluding TRAF2/IKK1 from the receptor complex, or only as a downstream consequence of its effects on NIK and the cIAPs. Signing the term would assert a mechanism the evidence does not yet distinguish. This is recorded as an open question in the notes. Supporting Evidence: PMID:20185819 siRNA-mediated depletion of TRAF3 promoted recruitment of TRAF2 and IKK1 to activated LTBR, enabling LTBR-inducible canonical NFkappaB signaling and NFkappaB target gene expression |
| GO:0007166 cell surface receptor signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: Receptor-proximal signalling role inferred across the TRAF family: every member transduces from the cytoplasmic tail of a cell surface receptor. Reason: Broad, but phylogenetically honest and therefore the right level for this IBA. The WITH set spans Drosophila (FB:FBgn0265464), mouse and rat orthologs and the other human TRAFs (TRAF2, TRAF5, TRAF6), so what is conserved across the clade is cell-surface-receptor-proximal signalling in general - not any one receptor pathway. A vertebrate-specific replacement such as CD40 signalling would not be taxon-appropriate here; the CD40-specific call is instead made on the human-experimental GO:0007165 TAS row anchored to PMID:7530216, and TLR signalling on the already-annotated GO:0002224 rows. Propagation Review Root cause: NO FAILURE NON CORE |
| GO:0009898 cytoplasmic side of plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: TRAF3 is recruited to the cytoplasmic tails of plasma-membrane TNF receptor superfamily members (CD40, LTBR, BAFF-R, CD30, OX40, EDAR), so it acts at the cytoplasmic face of the plasma membrane. Reason: Supported by the founding CD40 cytoplasmic-domain two-hybrid work and by LTBR signalling-complex recruitment; the MATH/TRAF domain is the receptor-tail binding module. Supporting Evidence: PMID:7527023 One such interacting protein, designated CD40-binding protein, has a N-terminal RING finger motif PMID:20185819 Increased expression of TRAF3 correlated with its increased recruitment to LTBR-induced signaling complexes |
| GO:0035591 signaling adaptor activity | IBA GO_REF:0000033 | ACCEPT | Summary: Signalling adaptor activity is TRAF3's defining molecular function: its MATH/TRAF-C domain tethers receptor and adaptor tails while its N-terminus recruits downstream kinases. Reason: TRAF3 physically bridges TLR adaptors (TRIF, MyD88, IRAK1) and MAVS to the IRF kinases TBK1/IKKe, and bridges TNFRSF tails to the TRAF2-cIAP module. This is a core molecular function, correctly inferred at the family level by PANTHER. Supporting Evidence: PMID:16306936 TRAF3 associates with the TLR adaptors TRIF and IRAK1, as well as downstream IRF3/7 kinases TBK1 and IKK-epsilon, suggesting that TRAF3 serves as a critical link between TLR adaptors and downstream regulatory kinases important for IRF activation PMID:16306937 TRAF3 is also recruited to the adaptor TRIF (Toll/IL-1 receptor domain-containing adaptor-inducing IFN-beta) and is required for marshalling the protein kinase TBK1 (also called NAK) into TIR signalling complexes |
| GO:0001817 regulation of cytokine production | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Regulation of cytokine production - TRAF3 controls the balance between type I interferons, IL-10 and pro-inflammatory cytokines. Reason: Correct: TRAF3 is required for IFN and IL-10 induction while restraining pro-inflammatory cytokines. However the term is a broad parent and the informative, signed children (GO:0032481, GO:0032728) are annotated separately. Retain as non-core. Supporting Evidence: PMID:16306937 TRAF3-deficient cells overproduce pro-inflammatory cytokines owing to defective IL-10 production |
| GO:0005164 tumor necrosis factor receptor binding | IEA GO_REF:0000002 | ACCEPT | Summary: TRAF3 binds the cytoplasmic tails of TNF receptor superfamily members through its MATH/TRAF-C domain - the interaction that defines the TRAF family. Reason: Established for CD40 by two independent two-hybrid screens, and extended to LTBR, BAFF-R, BCMA, CD30, OX40, EDAR and Fn14/TweakR. This is an informative molecular function that captures receptor-proximal recruitment. Supporting Evidence: PMID:11728344 The TweakR cytoplasmic domain binds TRAFs 1, 2, and 3. PMID:7527023 we have utilized the yeast two-hybrid system to clone cDNAs encoding proteins that bind the CD40 cytoplasmic domain |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | ACCEPT | Summary: TRAF3 is a cytoplasmic signalling adaptor and E3 ligase; cytoplasmic localisation is directly observed and is where all of its characterised activities occur. Reason: UniProt records Cytoplasm with experimental evidence from PubMed:25847972 and PubMed:34011520, and every characterised TRAF3 complex (TRAF2-cIAP-NIK, TRIF-TBK1, MAVS) is cytoplasmic. Correct, though the more informative sub-locations (cytosol, cytoplasmic face of the plasma membrane, endosome, mitochondrion) are separately annotated. Supporting Evidence: file:human/TRAF3/TRAF3-notes.md TRAF3 has no TM segment; it is a cytosolic protein transiently recruited to membrane-proximal complexes |
| GO:0005739 mitochondrion | IEA GO_REF:0000044 | ACCEPT | Summary: TRAF3 is recruited to the mitochondrial outer-membrane platform organised by MAVS during RIG-I-like receptor signalling, and colocalises with TRIM35 at mitochondria. Reason: MAVS is mitochondrial and binds TRAF3 through a defined TRAF-interacting motif, making the IC call sound; the EXP row from the TRIM35 study is a direct colocalisation. The mitochondrial pool is where TRAF3 acts in RIG-I-like receptor signalling. Supporting Evidence: PMID:16858409 Cardif-mediated IFNalpha induction occurs through a direct interaction between the TRAF domain of TRAF3 and a TRAF-interaction motif (TIM) within Cardif file:human/TRAF3/TRAF3-notes.md Mitochondrial pool: via MAVS |
| GO:0005768 endosome | IEA GO_REF:0000120 | ACCEPT | Summary: TRAF3 is present in the internalised TLR4/TRAM endosomal signalling compartment where TRIF-dependent interferon induction occurs. Reason: Directly observed by colocalisation with internalised TLR4-TRAM, and consistent with the UniProt endosome annotation. This is a functionally meaningful pool, not incidental trafficking. Supporting Evidence: PMID:18222170 The internalized signaling complex consisting of TLR4 and TRAM colocalizes with TRAF3, a signaling molecule downstream of TRIF, in endosome/lysosome |
| GO:0007165 signal transduction | IEA GO_REF:0000002 | MODIFY | Summary: Root-level 'signal transduction' from the InterPro TRAF-family domain rule. Reason: Uninformative at this level. Note this row has no anchoring publication: it is an InterPro2GO mapping from IPR012227, the pan-TRAF signature, which by itself supports only that a TRAF-domain protein transduces signals. The replacement is therefore proposed for the gene rather than derived from the rule - it is justified by the direct human evidence on the TAS row (PMID:7530216), and the generic term this row contributes is subsumed by the specific pathway terms already annotated. For the same reason the family-level GO:0007166 IBA is left broad: a domain or phylogenetic inference cannot itself pick out a vertebrate-specific receptor. Proposed replacements: CD40 signaling pathway Supporting Evidence: PMID:7530216 CD40 is a member of the tumor necrosis factor receptor (TNF-R) family that regulates B-lymphocyte proliferation, immunoglobulin class-switching, and apoptosis |
| GO:0008063 Toll signaling pathway | IEA GO_REF:0000002 | MODIFY | Summary: 'Toll signaling pathway' assigned by InterPro2GO from the TRAF-domain signature. Reason: GO:0008063 is defined by binding to the receptor Toll ('The series of molecular signals initiated by an extracellular ligand binding to the receptor Toll on the surface of a target cell'), i.e. the protostome Toll pathway. Human TRAF3 acts in Toll-like receptor pathways; the correct term is GO:0002224. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: LINEAGE OR TAXON MISMATCH Proposed replacements: toll-like receptor signaling pathway |
| GO:0008270 zinc ion binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Zinc binding by the RING-type and TRAF-type zinc fingers. Reason: Structurally correct - the RING and the several TRAF-type zinc fingers each coordinate zinc - but this is a cofactor-binding property required to fold the catalytic module, not a function TRAF3 evolved to perform. Retain as non-core. |
| GO:0016020 membrane | IEA GO_REF:0000117 | REMOVE | Summary: Generic 'membrane' localisation from an ARBA rule. Reason: TRAF3 has no transmembrane segment, signal peptide or lipid anchor; it is a soluble cytosolic protein transiently recruited to membrane-proximal complexes. That recruitment is already captured precisely by GO:0009898 (cytoplasmic side of plasma membrane) and GO:0010008 (endosome membrane), so the bare parent adds no information and implies membrane residence that is not the case. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH |
| GO:0031625 ubiquitin protein ligase binding | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Binding to ubiquitin protein ligases, from an in vitro TRAF-domain survey (MUL/TRIM37) and family-level rules. Reason: TRAF3 does associate with E3s in vivo (cIAP1/2 within the NIK-degrading complex, TRIM35, NEDD4L, FBXO11), so the term is not wrong. However the IPI evidence comes from isolated TRAF domains binding all six TRAFs indiscriminately in vitro, and the term describes a partner class rather than a TRAF3 activity. Retain as non-core. Supporting Evidence: PMID:11279055 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) |
| GO:0031996 thioesterase binding | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: Binding to thioesterases, i.e. to ubiquitin thioesterases/deubiquitinases. Reason: TRAF3 is a well-documented substrate of the deubiquitinases OTUB1, OTUB2, OTUD5/DUBA and MYSM1, so binding ubiquitin thioesterases is real. As with the other partner-class binding terms, it describes what acts on TRAF3 rather than what TRAF3 does. Retain as non-core. Supporting Evidence: PMID:17991829 DUBA selectively cleaved the lysine-63-linked polyubiquitin chains on TRAF3, resulting in its dissociation from the downstream signaling complex containing TANK-binding kinase 1 |
| GO:0032479 regulation of type I interferon production | IEA GO_REF:0000117 | MODIFY | Summary: Unsigned parent term for regulation of type I interferon production. Reason: TRAF3's role in this pathway is unambiguously positive and is directly demonstrated, so the signed child GO:0032481 should be used instead of the unsigned parent. Proposed replacements: positive regulation of type I interferon production Supporting Evidence: PMID:16306936 Our data demonstrate that TRAF3 is a major regulator of type I IFN production and the innate antiviral response |
| GO:0033209 tumor necrosis factor-mediated signaling pathway | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Involvement in TNF-superfamily receptor signalling; the IMP evidence is from lymphotoxin-beta receptor rather than TNF/TNFR1. Reason: TRAF3 does not bind TNFR1 and is not a component of the TNF/TNFR1 signalling complex; the supporting experiment concerns LTBR, and TRAF3 acts across several TNFRSF members (CD40, LTBR, BAFF-R, BCMA, CD30, OX40). The term is therefore only loosely correct, and this is not TRAF3's core process. Retained as non-core because no specific LTBR-signalling term is available in GO. Supporting Evidence: PMID:20185819 we report that TRAF3 functions as a negative regulator of LTBR signaling via both canonical and non-canonical NFkappaB pathways by two distinct mechanisms |
| GO:0042802 identical protein binding | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: TRAF3 self-associates into homotrimers (and heterotrimers with TRAF2/TRAF5) via its coiled-coil and TRAF domains. Reason: Trimerisation is genuine and functionally required for avid receptor-tail engagement, but 'identical protein binding' is a low-information molecular function term. Retain as non-core; the informative content is captured by GO:0005164 and GO:0035591. Supporting Evidence: PMID:15383523 constitutive homotypic association of TRAF2, -3, and -5 was observed |
| GO:0042981 regulation of apoptotic process | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: Regulation of apoptosis, from a family-level InterPro rule. Reason: TRAF3 modulates death signalling downstream of LTBR and, through the non-canonical NF-kappaB brake, controls B-cell survival; so a regulatory role is defensible. It is a downstream consequence of TRAF3's signalling functions rather than a core function in its own right. Supporting Evidence: PMID:10799510 LIGHT-induced death is blocked by a dominant negative TRAF3 mutant |
| GO:0045087 innate immune response | IEA GO_REF:0000002 | ACCEPT | Summary: TRAF3 is a central node of the innate immune response, required for TLR- and RLR-driven interferon induction and for inflammasome activation via ASC. Reason: Core process, though general. Supported by mouse knockout phenotypes, by human TRAF3 deficiency presenting as a viral-susceptibility syndrome, and by direct biochemistry on ASC. Supporting Evidence: PMID:16306936 Our data demonstrate that TRAF3 is a major regulator of type I IFN production and the innate antiviral response |
| GO:0050688 regulation of defense response to virus | IEA GO_REF:0000120 | MODIFY | Summary: Unsigned 'regulation of defense response to virus'. Reason: TRAF3's contribution to antiviral defence is positive and well established, so the signed child GO:0002230 should be used rather than the unsigned parent. Proposed replacements: positive regulation of defense response to virus by host Supporting Evidence: PMID:16306936 Our data demonstrate that TRAF3 is a major regulator of type I IFN production and the innate antiviral response |
| GO:0061630 ubiquitin protein ligase activity | IEA GO_REF:0000120 | ACCEPT | Summary: TRAF3 is a RING-type E3 ubiquitin ligase (EC 2.3.2.27) that builds predominantly K63-linked chains, including on ASC and on itself. Reason: Direct E3 activity toward ASC was demonstrated biochemically, and TRIF-driven TRAF3 self-ubiquitination is the activating mark for the interferon response. This is a core molecular function. Supporting Evidence: PMID:25847972 TNFR-associated factor 3 was found to be a direct E3 ligase for ASC PMID:17991829 TRAF3 is an E3 ubiquitin ligase that preferentially assembled lysine-63-linked polyubiquitin chains |
| GO:0005515 protein binding | IPI PMID:10791955 MIP-T3, a novel protein linking tumor necrosis factor recept... | REMOVE | Summary: Uninformative generic protein binding annotation from an interaction dataset. Reason: GO:0005515 conveys nothing about TRAF3's molecular function. TRAF3 is a well-characterised adaptor whose informative interactions are already captured by GO:0005164 (TNF receptor binding), GO:0035591 (signalling adaptor activity), GO:0019901 (protein kinase binding), GO:0019903 (protein phosphatase binding) and GO:0042802 (homotrimerisation). Per project curation guidance the bare term should be replaced by informative molecular function terms. |
| GO:0005515 protein binding | IPI PMID:12005438 Downstream regulator TANK binds to the CD40 recognition site... | REMOVE | Summary: Uninformative generic protein binding annotation from an interaction dataset. Reason: GO:0005515 conveys nothing about TRAF3's molecular function. TRAF3 is a well-characterised adaptor whose informative interactions are already captured by GO:0005164 (TNF receptor binding), GO:0035591 (signalling adaptor activity), GO:0019901 (protein kinase binding), GO:0019903 (protein phosphatase binding) and GO:0042802 (homotrimerisation). Per project curation guidance the bare term should be replaced by informative molecular function terms. |
| GO:0005515 protein binding | IPI PMID:14743216 A physical and functional map of the human TNF-alpha/NF-kapp... | REMOVE | Summary: Uninformative generic protein binding annotation from an interaction dataset. Reason: GO:0005515 conveys nothing about TRAF3's molecular function. TRAF3 is a well-characterised adaptor whose informative interactions are already captured by GO:0005164 (TNF receptor binding), GO:0035591 (signalling adaptor activity), GO:0019901 (protein kinase binding), GO:0019903 (protein phosphatase binding) and GO:0042802 (homotrimerisation). Per project curation guidance the bare term should be replaced by informative molecular function terms. |
| GO:0005515 protein binding | IPI PMID:15280356 Induction of apoptosis by X-linked ectodermal dysplasia rece... | REMOVE | Summary: Uninformative generic protein binding annotation from an interaction dataset. Reason: GO:0005515 conveys nothing about TRAF3's molecular function. TRAF3 is a well-characterised adaptor whose informative interactions are already captured by GO:0005164 (TNF receptor binding), GO:0035591 (signalling adaptor activity), GO:0019901 (protein kinase binding), GO:0019903 (protein phosphatase binding) and GO:0042802 (homotrimerisation). Per project curation guidance the bare term should be replaced by informative molecular function terms. |
| GO:0005515 protein binding | IPI PMID:20080758 WDR5 is essential for assembly of the VISA-associated signal... | REMOVE | Summary: Uninformative generic protein binding annotation from an interaction dataset. Reason: GO:0005515 conveys nothing about TRAF3's molecular function. TRAF3 is a well-characterised adaptor whose informative interactions are already captured by GO:0005164 (TNF receptor binding), GO:0035591 (signalling adaptor activity), GO:0019901 (protein kinase binding), GO:0019903 (protein phosphatase binding) and GO:0042802 (homotrimerisation). Per project curation guidance the bare term should be replaced by informative molecular function terms. |
| GO:0005515 protein binding | IPI PMID:20138174 BS69 cooperates with TRAF3 in the regulation of Epstein-Barr... | REMOVE | Summary: Uninformative generic protein binding annotation from an interaction dataset. Reason: GO:0005515 conveys nothing about TRAF3's molecular function. TRAF3 is a well-characterised adaptor whose informative interactions are already captured by GO:0005164 (TNF receptor binding), GO:0035591 (signalling adaptor activity), GO:0019901 (protein kinase binding), GO:0019903 (protein phosphatase binding) and GO:0042802 (homotrimerisation). Per project curation guidance the bare term should be replaced by informative molecular function terms. |
| GO:0005515 protein binding | IPI PMID:20732415 The MYND domain-containing protein BRAM1 inhibits lymphotoxi... | REMOVE | Summary: Uninformative generic protein binding annotation from an interaction dataset. Reason: GO:0005515 conveys nothing about TRAF3's molecular function. TRAF3 is a well-characterised adaptor whose informative interactions are already captured by GO:0005164 (TNF receptor binding), GO:0035591 (signalling adaptor activity), GO:0019901 (protein kinase binding), GO:0019903 (protein phosphatase binding) and GO:0042802 (homotrimerisation). Per project curation guidance the bare term should be replaced by informative molecular function terms. |
| GO:0005515 protein binding | IPI PMID:21903422 Mapping a dynamic innate immunity protein interaction networ... | REMOVE | Summary: Uninformative generic protein binding annotation from an interaction dataset. Reason: GO:0005515 conveys nothing about TRAF3's molecular function. TRAF3 is a well-characterised adaptor whose informative interactions are already captured by GO:0005164 (TNF receptor binding), GO:0035591 (signalling adaptor activity), GO:0019901 (protein kinase binding), GO:0019903 (protein phosphatase binding) and GO:0042802 (homotrimerisation). Per project curation guidance the bare term should be replaced by informative molecular function terms. |
| GO:0005515 protein binding | IPI PMID:23153539 Relief of profound feedback inhibition of mitogenic signalin... | REMOVE | Summary: Uninformative generic protein binding annotation from an interaction dataset. Reason: GO:0005515 conveys nothing about TRAF3's molecular function. TRAF3 is a well-characterised adaptor whose informative interactions are already captured by GO:0005164 (TNF receptor binding), GO:0035591 (signalling adaptor activity), GO:0019901 (protein kinase binding), GO:0019903 (protein phosphatase binding) and GO:0042802 (homotrimerisation). Per project curation guidance the bare term should be replaced by informative molecular function terms. |
| GO:0005515 protein binding | IPI PMID:23333941 Identification and characterization of receptor-interacting ... | REMOVE | Summary: Uninformative generic protein binding annotation from an interaction dataset. Reason: GO:0005515 conveys nothing about TRAF3's molecular function. TRAF3 is a well-characterised adaptor whose informative interactions are already captured by GO:0005164 (TNF receptor binding), GO:0035591 (signalling adaptor activity), GO:0019901 (protein kinase binding), GO:0019903 (protein phosphatase binding) and GO:0042802 (homotrimerisation). Per project curation guidance the bare term should be replaced by informative molecular function terms. |
| GO:0005515 protein binding | IPI PMID:23871208 The autoimmunity-associated gene PTPN22 potentiates toll-lik... | REMOVE | Summary: Uninformative generic protein binding annotation from an interaction dataset. Reason: GO:0005515 conveys nothing about TRAF3's molecular function. TRAF3 is a well-characterised adaptor whose informative interactions are already captured by GO:0005164 (TNF receptor binding), GO:0035591 (signalling adaptor activity), GO:0019901 (protein kinase binding), GO:0019903 (protein phosphatase binding) and GO:0042802 (homotrimerisation). Per project curation guidance the bare term should be replaced by informative molecular function terms. |
| GO:0005515 protein binding | IPI PMID:25241761 Using an in situ proximity ligation assay to systematically ... | REMOVE | Summary: Uninformative generic protein binding annotation from an interaction dataset. Reason: GO:0005515 conveys nothing about TRAF3's molecular function. TRAF3 is a well-characterised adaptor whose informative interactions are already captured by GO:0005164 (TNF receptor binding), GO:0035591 (signalling adaptor activity), GO:0019901 (protein kinase binding), GO:0019903 (protein phosphatase binding) and GO:0042802 (homotrimerisation). Per project curation guidance the bare term should be replaced by informative molecular function terms. |
| GO:0005515 protein binding | IPI PMID:27135603 A TRAF-like motif of the inducible costimulator ICOS control... | REMOVE | Summary: Uninformative generic protein binding annotation from an interaction dataset. Reason: GO:0005515 conveys nothing about TRAF3's molecular function. TRAF3 is a well-characterised adaptor whose informative interactions are already captured by GO:0005164 (TNF receptor binding), GO:0035591 (signalling adaptor activity), GO:0019901 (protein kinase binding), GO:0019903 (protein phosphatase binding) and GO:0042802 (homotrimerisation). Per project curation guidance the bare term should be replaced by informative molecular function terms. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | REMOVE | Summary: Uninformative generic protein binding annotation from an interaction dataset. Reason: GO:0005515 conveys nothing about TRAF3's molecular function. TRAF3 is a well-characterised adaptor whose informative interactions are already captured by GO:0005164 (TNF receptor binding), GO:0035591 (signalling adaptor activity), GO:0019901 (protein kinase binding), GO:0019903 (protein phosphatase binding) and GO:0042802 (homotrimerisation). Per project curation guidance the bare term should be replaced by informative molecular function terms. |
| GO:0005515 protein binding | IPI PMID:30561431 A protein-protein interaction map of the TNF-induced NF-ΞΊB s... | REMOVE | Summary: Uninformative generic protein binding annotation from an interaction dataset. Reason: GO:0005515 conveys nothing about TRAF3's molecular function. TRAF3 is a well-characterised adaptor whose informative interactions are already captured by GO:0005164 (TNF receptor binding), GO:0035591 (signalling adaptor activity), GO:0019901 (protein kinase binding), GO:0019903 (protein phosphatase binding) and GO:0042802 (homotrimerisation). Per project curation guidance the bare term should be replaced by informative molecular function terms. |
| GO:0005515 protein binding | IPI PMID:30833792 A protein-interaction network of interferon-stimulated genes... | REMOVE | Summary: Uninformative generic protein binding annotation from an interaction dataset. Reason: GO:0005515 conveys nothing about TRAF3's molecular function. TRAF3 is a well-characterised adaptor whose informative interactions are already captured by GO:0005164 (TNF receptor binding), GO:0035591 (signalling adaptor activity), GO:0019901 (protein kinase binding), GO:0019903 (protein phosphatase binding) and GO:0042802 (homotrimerisation). Per project curation guidance the bare term should be replaced by informative molecular function terms. |
| GO:0005515 protein binding | IPI PMID:31980649 Extensive rewiring of the EGFR network in colorectal cancer ... | REMOVE | Summary: Uninformative generic protein binding annotation from an interaction dataset. Reason: GO:0005515 conveys nothing about TRAF3's molecular function. TRAF3 is a well-characterised adaptor whose informative interactions are already captured by GO:0005164 (TNF receptor binding), GO:0035591 (signalling adaptor activity), GO:0019901 (protein kinase binding), GO:0019903 (protein phosphatase binding) and GO:0042802 (homotrimerisation). Per project curation guidance the bare term should be replaced by informative molecular function terms. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Uninformative generic protein binding annotation from an interaction dataset. Reason: GO:0005515 conveys nothing about TRAF3's molecular function. TRAF3 is a well-characterised adaptor whose informative interactions are already captured by GO:0005164 (TNF receptor binding), GO:0035591 (signalling adaptor activity), GO:0019901 (protein kinase binding), GO:0019903 (protein phosphatase binding) and GO:0042802 (homotrimerisation). Per project curation guidance the bare term should be replaced by informative molecular function terms. |
| GO:0005515 protein binding | IPI PMID:32514408 TRAF3 can interact with GMEB1 and modulate its anti-apoptoti... | REMOVE | Summary: Uninformative generic protein binding annotation from an interaction dataset. Reason: GO:0005515 conveys nothing about TRAF3's molecular function. TRAF3 is a well-characterised adaptor whose informative interactions are already captured by GO:0005164 (TNF receptor binding), GO:0035591 (signalling adaptor activity), GO:0019901 (protein kinase binding), GO:0019903 (protein phosphatase binding) and GO:0042802 (homotrimerisation). Per project curation guidance the bare term should be replaced by informative molecular function terms. |
| GO:0005515 protein binding | IPI PMID:32707033 Kinase Interaction Network Expands Functional and Disease Ro... | REMOVE | Summary: Uninformative generic protein binding annotation from an interaction dataset. Reason: GO:0005515 conveys nothing about TRAF3's molecular function. TRAF3 is a well-characterised adaptor whose informative interactions are already captured by GO:0005164 (TNF receptor binding), GO:0035591 (signalling adaptor activity), GO:0019901 (protein kinase binding), GO:0019903 (protein phosphatase binding) and GO:0042802 (homotrimerisation). Per project curation guidance the bare term should be replaced by informative molecular function terms. |
| GO:0005515 protein binding | IPI PMID:33372174 Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)... | REMOVE | Summary: Uninformative generic protein binding annotation from an interaction dataset. Reason: GO:0005515 conveys nothing about TRAF3's molecular function. TRAF3 is a well-characterised adaptor whose informative interactions are already captured by GO:0005164 (TNF receptor binding), GO:0035591 (signalling adaptor activity), GO:0019901 (protein kinase binding), GO:0019903 (protein phosphatase binding) and GO:0042802 (homotrimerisation). Per project curation guidance the bare term should be replaced by informative molecular function terms. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | REMOVE | Summary: Uninformative generic protein binding annotation from an interaction dataset. Reason: GO:0005515 conveys nothing about TRAF3's molecular function. TRAF3 is a well-characterised adaptor whose informative interactions are already captured by GO:0005164 (TNF receptor binding), GO:0035591 (signalling adaptor activity), GO:0019901 (protein kinase binding), GO:0019903 (protein phosphatase binding) and GO:0042802 (homotrimerisation). Per project curation guidance the bare term should be replaced by informative molecular function terms. |
| GO:0005515 protein binding | IPI PMID:34084167 SARS-CoV-2 Membrane Protein Inhibits Type I Interferon Produ... | REMOVE | Summary: Uninformative generic protein binding annotation from an interaction dataset. Reason: GO:0005515 conveys nothing about TRAF3's molecular function. TRAF3 is a well-characterised adaptor whose informative interactions are already captured by GO:0005164 (TNF receptor binding), GO:0035591 (signalling adaptor activity), GO:0019901 (protein kinase binding), GO:0019903 (protein phosphatase binding) and GO:0042802 (homotrimerisation). Per project curation guidance the bare term should be replaced by informative molecular function terms. |
| GO:0005515 protein binding | IPI PMID:7527023 A novel RING finger protein interacts with the cytoplasmic d... | REMOVE | Summary: Uninformative generic protein binding annotation from an interaction dataset. Reason: GO:0005515 conveys nothing about TRAF3's molecular function. TRAF3 is a well-characterised adaptor whose informative interactions are already captured by GO:0005164 (TNF receptor binding), GO:0035591 (signalling adaptor activity), GO:0019901 (protein kinase binding), GO:0019903 (protein phosphatase binding) and GO:0042802 (homotrimerisation). Per project curation guidance the bare term should be replaced by informative molecular function terms. |
| GO:0042802 identical protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: TRAF3 self-associates into homotrimers (and heterotrimers with TRAF2/TRAF5) via its coiled-coil and TRAF domains. Reason: Trimerisation is genuine and functionally required for avid receptor-tail engagement, but 'identical protein binding' is a low-information molecular function term. Retain as non-core; the informative content is captured by GO:0005164 and GO:0035591. Supporting Evidence: PMID:15383523 constitutive homotypic association of TRAF2, -3, and -5 was observed |
| GO:0002224 toll-like receptor signaling pathway | IEA GO_REF:0000120 | ACCEPT | Summary: TRAF3 is a component of TLR signalling complexes, recruited via MyD88 and TRIF, and is required for their interferon output. Reason: Core process. TRAF3 is recruited to TIR-adaptor signalling complexes and is directly observed in the internalised TLR4/TRAM endosomal complex. Supporting Evidence: PMID:16306937 we identified TNF receptor-associated factor 3 (TRAF3) as a new component of TIR signalling complexes that is recruited along with TRAF6 PMID:18222170 The internalized signaling complex consisting of TLR4 and TRAM colocalizes with TRAF3, a signaling molecule downstream of TRIF, in endosome/lysosome |
| GO:0009898 cytoplasmic side of plasma membrane | IEA GO_REF:0000107 | ACCEPT | Summary: TRAF3 is recruited to the cytoplasmic tails of plasma-membrane TNF receptor superfamily members (CD40, LTBR, BAFF-R, CD30, OX40, EDAR), so it acts at the cytoplasmic face of the plasma membrane. Reason: Supported by the founding CD40 cytoplasmic-domain two-hybrid work and by LTBR signalling-complex recruitment; the MATH/TRAF domain is the receptor-tail binding module. Supporting Evidence: PMID:7527023 One such interacting protein, designated CD40-binding protein, has a N-terminal RING finger motif PMID:20185819 Increased expression of TRAF3 correlated with its increased recruitment to LTBR-induced signaling complexes |
| GO:0019901 protein kinase binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: TRAF3 binds the protein kinases TBK1, IKKe and MAP3K14/NIK. Reason: True and mechanistically important - NIK binding underlies the non-canonical NF-kappaB brake and TBK1 binding underlies interferon induction - but the bare 'protein kinase binding' term conveys none of that. Retain as non-core; the functional content belongs in GO:0035591 and the NIK-degradation process terms. Supporting Evidence: PMID:15084608 TRAF3 physically associates with NIK via a specific sequence motif located in the N-terminal region of NIK |
| GO:0030162 regulation of proteolysis | IEA GO_REF:0000120 | ACCEPT | Summary: TRAF3 controls proteolysis of key NF-kappaB pathway components: it drives constitutive proteasomal degradation of NIK/MAP3K14 and thereby limits processing of NFKB2/p100 to p52. Reason: Core process, directly demonstrated - TRAF3 knockdown raises NIK protein and triggers p100 processing without any receptor stimulus. The term is general; the specific mechanism is proposed as new annotations (GO:0043161 and GO:1901223). Supporting Evidence: PMID:20185819 TRAF3 knock-down also increased mRNA and protein expression of several non-canonical NFkappaB components, including NFkappaB2/p100, RelB, and NIK, accompanied by processing of NFkappaB2/p100 into p52 PMID:15084608 this molecular interaction appears to target NIK for degradation by the proteasome |
| GO:0032648 regulation of interferon-beta production | IEA GO_REF:0000107 | MODIFY | Summary: Unsigned parent term for regulation of interferon-beta production. Reason: TRAF3 is required for IFN-beta induction downstream of TRIF and MAVS; the direction is established, so the signed child GO:0032728 is the appropriate term. Proposed replacements: positive regulation of interferon-beta production Supporting Evidence: PMID:16306937 TRAF3 is essential for the induction of type I interferons (IFN) and the anti-inflammatory cytokine interleukin-10 (IL-10) |
| GO:0035631 CD40 receptor complex | IEA GO_REF:0000107 | ACCEPT | Summary: TRAF3 was discovered as a CD40 cytoplasmic-tail binding protein and is a component of the ligand-engaged CD40 receptor complex. Reason: Two independent yeast two-hybrid screens against the CD40 cytoplasmic domain identified TRAF3 (as CD40BP and as CAP-1), and CD40 ligation reorganises the TRAF2/TRAF3 content of the complex. Supporting Evidence: PMID:7530216 cDNAs were obtained that encode a novel protein, CD40-associated protein-1 (CAP-1), which binds specifically to the cytosolic domain of CD40 PMID:15383523 Ligation of CD40 on Ramos B cells by recombinant CD154 caused TRAF2 and TRAF3 to dissociate |
| GO:0035666 TRIF-dependent toll-like receptor signaling pathway | TAS Reactome:R-HSA-936964 | ACCEPT | Summary: TRAF3 is the TRIF-proximal component that brings TBK1 into the TIR signalling complex, making it essential for the TRIF-dependent interferon branch. Reason: Core process, mechanistically defined: TRAF3 is recruited to TRIF and is required for TBK1 recruitment, which is why TRAF3 loss selectively ablates the IFN arm. Supporting Evidence: PMID:16306937 TRAF3 is also recruited to the adaptor TRIF (Toll/IL-1 receptor domain-containing adaptor-inducing IFN-beta) and is required for marshalling the protein kinase TBK1 (also called NAK) into TIR signalling complexes, thereby explaining its unique role in activation of the IFN response |
| GO:0005737 cytoplasm | EXP PMID:25847972 MAVS Promotes Inflammasome Activation by Targeting ASC for K... | ACCEPT | Summary: TRAF3 is a cytoplasmic signalling adaptor and E3 ligase; cytoplasmic localisation is directly observed and is where all of its characterised activities occur. Reason: UniProt records Cytoplasm with experimental evidence from PubMed:25847972 and PubMed:34011520, and every characterised TRAF3 complex (TRAF2-cIAP-NIK, TRIF-TBK1, MAVS) is cytoplasmic. Correct, though the more informative sub-locations (cytosol, cytoplasmic face of the plasma membrane, endosome, mitochondrion) are separately annotated. Supporting Evidence: file:human/TRAF3/TRAF3-notes.md TRAF3 has no TM segment; it is a cytosolic protein transiently recruited to membrane-proximal complexes |
| GO:0005737 cytoplasm | EXP PMID:34011520 Inducible ATP1B1 Upregulates Antiviral Innate Immune Respons... | ACCEPT | Summary: TRAF3 is a cytoplasmic signalling adaptor and E3 ligase; cytoplasmic localisation is directly observed and is where all of its characterised activities occur. Reason: UniProt records Cytoplasm with experimental evidence from PubMed:25847972 and PubMed:34011520, and every characterised TRAF3 complex (TRAF2-cIAP-NIK, TRIF-TBK1, MAVS) is cytoplasmic. Correct, though the more informative sub-locations (cytosol, cytoplasmic face of the plasma membrane, endosome, mitochondrion) are separately annotated. Supporting Evidence: file:human/TRAF3/TRAF3-notes.md TRAF3 has no TM segment; it is a cytosolic protein transiently recruited to membrane-proximal complexes |
| GO:0005739 mitochondrion | EXP PMID:32562145 TRIM35 mediates protection against influenza infection by ac... | ACCEPT | Summary: TRAF3 is recruited to the mitochondrial outer-membrane platform organised by MAVS during RIG-I-like receptor signalling, and colocalises with TRIM35 at mitochondria. Reason: MAVS is mitochondrial and binds TRAF3 through a defined TRAF-interacting motif, making the IC call sound; the EXP row from the TRIM35 study is a direct colocalisation. The mitochondrial pool is where TRAF3 acts in RIG-I-like receptor signalling. Supporting Evidence: PMID:16858409 Cardif-mediated IFNalpha induction occurs through a direct interaction between the TRAF domain of TRAF3 and a TRAF-interaction motif (TIM) within Cardif file:human/TRAF3/TRAF3-notes.md Mitochondrial pool: via MAVS |
| GO:0005768 endosome | ISS GO_REF:0000024 | ACCEPT | Summary: TRAF3 is present in the internalised TLR4/TRAM endosomal signalling compartment where TRIF-dependent interferon induction occurs. Reason: Directly observed by colocalisation with internalised TLR4-TRAM, and consistent with the UniProt endosome annotation. This is a functionally meaningful pool, not incidental trafficking. Supporting Evidence: PMID:18222170 The internalized signaling complex consisting of TLR4 and TRAM colocalizes with TRAF3, a signaling molecule downstream of TRIF, in endosome/lysosome |
| GO:0061630 ubiquitin protein ligase activity | EXP PMID:25847972 MAVS Promotes Inflammasome Activation by Targeting ASC for K... | ACCEPT | Summary: TRAF3 is a RING-type E3 ubiquitin ligase (EC 2.3.2.27) that builds predominantly K63-linked chains, including on ASC and on itself. Reason: Direct E3 activity toward ASC was demonstrated biochemically, and TRIF-driven TRAF3 self-ubiquitination is the activating mark for the interferon response. This is a core molecular function. Supporting Evidence: PMID:25847972 TNFR-associated factor 3 was found to be a direct E3 ligase for ASC PMID:17991829 TRAF3 is an E3 ubiquitin ligase that preferentially assembled lysine-63-linked polyubiquitin chains |
| GO:0051607 defense response to virus | NAS PMID:24622840 SARS coronavirus papain-like protease inhibits the type I in... | ACCEPT | Summary: TRAF3 is required for the antiviral defence programme, acting downstream of TLR3/TLR4-TRIF and of RIG-I/MAVS to induce type I interferon. Reason: Core process. TRAF3-deficient fibroblasts fail to mount a type I IFN response to direct virus infection, and viral proteins (SARS-CoV PLpro, hantavirus Gn, EV-D68 2A protease) specifically target TRAF3 - the classic signature of an antiviral effector. Supporting Evidence: PMID:16306936 TRAF3-deficient fibroblasts are defective in their type I IFN response to direct infection with vesicular stomatitis virus, indicating that TRAF3 is also an important component of TLR-independent viral recognition pathways PMID:24622840 the interaction between the components in STING-TRAF3-TBK1 complex is disrupted by PLpro-TM |
| GO:1902554 serine/threonine protein kinase complex | NAS PMID:24622840 SARS coronavirus papain-like protease inhibits the type I in... | MARK AS OVER ANNOTATED | Summary: Assignment of TRAF3 to a serine/threonine protein kinase complex, from the STING-TRAF3-TBK1 complex described in a SARS-CoV PLpro study. Reason: TRAF3 is a transient adaptor recruited into signalling complexes that contain the kinase TBK1; it is not a stoichiometric subunit of a kinase complex and contributes no kinase activity. The underlying interaction is real, but the complex term over-states TRAF3's relationship to it, and the evidence is NAS. Supporting Evidence: PMID:24622840 PLpro-TM physically interacts with TRAF3, TBK1, IKKΞ΅, STING, and IRF3, the key components that assemble the STING-TRAF3-TBK1 complex |
| GO:0000151 ubiquitin ligase complex | NAS PMID:21200404 A functional C-terminal TRAF3-binding site in MAVS participa... | ACCEPT | Summary: TRAF3 is itself a RING E3 and is a subunit of the TRAF2-TRAF3-cIAP1/2 ubiquitin ligase assembly that constitutively degrades NIK. Reason: The NIK-degrading holo-enzyme is a genuine multi-subunit ubiquitin ligase complex in which TRAF3 provides substrate (NIK) recruitment. The anchoring NAS reference is weak for this particular term, but the complex itself is well documented. Supporting Evidence: PMID:18997794 the degradation of NIK occurs upon assembly of a regulatory complex through TRAF3 recruitment of NIK and TRAF2 recruitment of cIAP1 and cIAP2 |
| GO:0051607 defense response to virus | NAS PMID:25847972 MAVS Promotes Inflammasome Activation by Targeting ASC for K... | ACCEPT | Summary: TRAF3 is required for the antiviral defence programme, acting downstream of TLR3/TLR4-TRIF and of RIG-I/MAVS to induce type I interferon. Reason: Core process. TRAF3-deficient fibroblasts fail to mount a type I IFN response to direct virus infection, and viral proteins (SARS-CoV PLpro, hantavirus Gn, EV-D68 2A protease) specifically target TRAF3 - the classic signature of an antiviral effector. Supporting Evidence: PMID:16306936 TRAF3-deficient fibroblasts are defective in their type I IFN response to direct infection with vesicular stomatitis virus, indicating that TRAF3 is also an important component of TLR-independent viral recognition pathways PMID:24622840 the interaction between the components in STING-TRAF3-TBK1 complex is disrupted by PLpro-TM |
| GO:0060337 type I interferon-mediated signaling pathway | NAS PMID:25847972 MAVS Promotes Inflammasome Activation by Targeting ASC for K... | REMOVE | Summary: Type I interferon-mediated signalling pathway, i.e. signalling downstream of the IFN-alpha/beta receptor. Reason: This term denotes 'The series of molecular signals initiated by type I interferon binding to its receptor on the surface of a target cell'. TRAF3 acts upstream, in interferon *production*, and has no described role in IFNAR/JAK-STAT signal transduction. The correct term, GO:0032481 (positive regulation of type I interferon production), is already annotated. The evidence here is NAS and the anchoring paper is about MAVS-dependent inflammasome activation, not IFNAR signalling. |
| GO:0002224 toll-like receptor signaling pathway | IDA PMID:18222170 Roles for LPS-dependent interaction and relocation of TLR4 a... | ACCEPT | Summary: TRAF3 is a component of TLR signalling complexes, recruited via MyD88 and TRIF, and is required for their interferon output. Reason: Core process. TRAF3 is recruited to TIR-adaptor signalling complexes and is directly observed in the internalised TLR4/TRAM endosomal complex. Supporting Evidence: PMID:16306937 we identified TNF receptor-associated factor 3 (TRAF3) as a new component of TIR signalling complexes that is recruited along with TRAF6 PMID:18222170 The internalized signaling complex consisting of TLR4 and TRAM colocalizes with TRAF3, a signaling molecule downstream of TRIF, in endosome/lysosome |
| GO:0005768 endosome | IDA PMID:18222170 Roles for LPS-dependent interaction and relocation of TLR4 a... | ACCEPT | Summary: TRAF3 is present in the internalised TLR4/TRAM endosomal signalling compartment where TRIF-dependent interferon induction occurs. Reason: Directly observed by colocalisation with internalised TLR4-TRAM, and consistent with the UniProt endosome annotation. This is a functionally meaningful pool, not incidental trafficking. Supporting Evidence: PMID:18222170 The internalized signaling complex consisting of TLR4 and TRAM colocalizes with TRAF3, a signaling molecule downstream of TRIF, in endosome/lysosome |
| GO:0061630 ubiquitin protein ligase activity | IDA PMID:19898473 Different modes of ubiquitination of the adaptor TRAF3 selec... | ACCEPT | Summary: TRAF3 is a RING-type E3 ubiquitin ligase (EC 2.3.2.27) that builds predominantly K63-linked chains, including on ASC and on itself. Reason: Direct E3 activity toward ASC was demonstrated biochemically, and TRIF-driven TRAF3 self-ubiquitination is the activating mark for the interferon response. This is a core molecular function. Supporting Evidence: PMID:25847972 TNFR-associated factor 3 was found to be a direct E3 ligase for ASC PMID:17991829 TRAF3 is an E3 ubiquitin ligase that preferentially assembled lysine-63-linked polyubiquitin chains |
| GO:0004842 ubiquitin-protein transferase activity | TAS Reactome:R-HSA-2213017 | MODIFY | Summary: Parent term for ubiquitin transfer; TRAF3's activity is specifically that of a RING-type E3 ubiquitin ligase. Reason: GO:0004842 also covers E1 and E2 enzymes. TRAF3 is a RING E3 (EC 2.3.2.27) and the more specific child GO:0061630 is already annotated from the same experimental evidence, so these rows should be raised to that term. Proposed replacements: ubiquitin protein ligase activity Supporting Evidence: PMID:25847972 TNFR-associated factor 3 was found to be a direct E3 ligase for ASC |
| GO:0004842 ubiquitin-protein transferase activity | TAS Reactome:R-HSA-9013974 | MODIFY | Summary: Parent term for ubiquitin transfer; TRAF3's activity is specifically that of a RING-type E3 ubiquitin ligase. Reason: GO:0004842 also covers E1 and E2 enzymes. TRAF3 is a RING E3 (EC 2.3.2.27) and the more specific child GO:0061630 is already annotated from the same experimental evidence, so these rows should be raised to that term. Proposed replacements: ubiquitin protein ligase activity Supporting Evidence: PMID:25847972 TNFR-associated factor 3 was found to be a direct E3 ligase for ASC |
| GO:0010008 endosome membrane | IDA PMID:18222170 Roles for LPS-dependent interaction and relocation of TLR4 a... | ACCEPT | Summary: TRAF3 acts on the endosome membrane as part of the internalised TLR4/TRAM/TRIF complex that drives the type I interferon arm of TLR4 signalling. Reason: Same direct observation as the endosome annotation, at the correct membrane sub-location. TRAF3 is peripherally associated via the TRIF adaptor rather than integral to the membrane. Supporting Evidence: PMID:18222170 The internalized signaling complex consisting of TLR4 and TRAM colocalizes with TRAF3, a signaling molecule downstream of TRIF, in endosome/lysosome |
| GO:0034142 toll-like receptor 4 signaling pathway | IDA PMID:18222170 Roles for LPS-dependent interaction and relocation of TLR4 a... | ACCEPT | Summary: TRAF3 acts in TLR4 signalling, where the split between its MyD88-dependent (degradative) and TRIF-dependent (activating) ubiquitination determines whether inflammatory cytokines or interferons are produced. Reason: Directly supported: TRAF3 colocalises with the internalised TLR4/TRAM complex, and TLR4 was the prototypical receptor used to dissect the TRAF3 ubiquitination switch. Supporting Evidence: PMID:19898473 Degradative ubiquitination of TRAF3 during MyD88-dependent TLR signaling was essential for the activation of mitogen-activated protein kinases (MAPKs) and production of inflammatory cytokines |
| GO:0035666 TRIF-dependent toll-like receptor signaling pathway | TAS Reactome:R-HSA-9013973 | ACCEPT | Summary: TRAF3 is the TRIF-proximal component that brings TBK1 into the TIR signalling complex, making it essential for the TRIF-dependent interferon branch. Reason: Core process, mechanistically defined: TRAF3 is recruited to TRIF and is required for TBK1 recruitment, which is why TRAF3 loss selectively ablates the IFN arm. Supporting Evidence: PMID:16306937 TRAF3 is also recruited to the adaptor TRIF (Toll/IL-1 receptor domain-containing adaptor-inducing IFN-beta) and is required for marshalling the protein kinase TBK1 (also called NAK) into TIR signalling complexes, thereby explaining its unique role in activation of the IFN response |
| GO:0005739 mitochondrion | IC PMID:16858409 Regulation of antiviral responses by a direct and specific i... | ACCEPT | Summary: TRAF3 is recruited to the mitochondrial outer-membrane platform organised by MAVS during RIG-I-like receptor signalling, and colocalises with TRIM35 at mitochondria. Reason: MAVS is mitochondrial and binds TRAF3 through a defined TRAF-interacting motif, making the IC call sound; the EXP row from the TRIM35 study is a direct colocalisation. The mitochondrial pool is where TRAF3 acts in RIG-I-like receptor signalling. Supporting Evidence: PMID:16858409 Cardif-mediated IFNalpha induction occurs through a direct interaction between the TRAF domain of TRAF3 and a TRAF-interaction motif (TIM) within Cardif file:human/TRAF3/TRAF3-notes.md Mitochondrial pool: via MAVS |
| GO:0032481 positive regulation of type I interferon production | IDA PMID:19898473 Different modes of ubiquitination of the adaptor TRAF3 selec... | ACCEPT | Summary: TRAF3 is a non-redundant positive regulator of type I interferon production downstream of TLR3/TLR4-TRIF, TLR7/9-MyD88 and RIG-I/MAVS. Reason: Core function. TRAF3-deficient cells fail to induce type I IFN through several TLRs and on direct virus infection, and autosomal dominant human TRAF3 deficiency - a dominant-negative R118W allele that destabilises the wild-type product, leaving ~17.5% of control TRAF3 protein - causes herpes simplex encephalitis through impaired TLR3-dependent IFN induction. The activating signal is TRIF-driven K63 self-ubiquitination of TRAF3. Supporting Evidence: PMID:19898473 TRIF-dependent signaling triggered noncanonical TRAF3 self-ubiquitination that activated the interferon response PMID:16306936 cells lacking TRAF3, a member of the TNF receptor-associated factor family, are defective in type I IFN responses activated by several different TLRs PMID:20832341 TRAF3 deficiency is associated with a clinical phenotype limited to HSE resulting from the impairment of TLR3-dependent induction of IFN |
| GO:0005515 protein binding | IPI PMID:31390091 TRAF3IP3 mediates the recruitment of TRAF3 to MAVS for antiv... | REMOVE | Summary: Uninformative generic protein binding annotation from an interaction dataset. Reason: GO:0005515 conveys nothing about TRAF3's molecular function. TRAF3 is a well-characterised adaptor whose informative interactions are already captured by GO:0005164 (TNF receptor binding), GO:0035591 (signalling adaptor activity), GO:0019901 (protein kinase binding), GO:0019903 (protein phosphatase binding) and GO:0042802 (homotrimerisation). Per project curation guidance the bare term should be replaced by informative molecular function terms. |
| GO:0004842 ubiquitin-protein transferase activity | IDA PMID:19898473 Different modes of ubiquitination of the adaptor TRAF3 selec... | MODIFY | Summary: Parent term for ubiquitin transfer; TRAF3's activity is specifically that of a RING-type E3 ubiquitin ligase. Reason: GO:0004842 also covers E1 and E2 enzymes. TRAF3 is a RING E3 (EC 2.3.2.27) and the more specific child GO:0061630 is already annotated from the same experimental evidence, so these rows should be raised to that term. Proposed replacements: ubiquitin protein ligase activity Supporting Evidence: PMID:25847972 TNFR-associated factor 3 was found to be a direct E3 ligase for ASC |
| GO:0005739 mitochondrion | IDA PMID:19898473 Different modes of ubiquitination of the adaptor TRAF3 selec... | ACCEPT | Summary: TRAF3 is recruited to the mitochondrial outer-membrane platform organised by MAVS during RIG-I-like receptor signalling, and colocalises with TRIM35 at mitochondria. Reason: The term itself is correct and well supported, but not by this citation: the cached full text of Tseng et al. (73 kB, full_text_available: true) contains no mention of mitochondria. Retained rather than removed, since the paper's figures and supplement are not in the cache and an experimental annotation should not be deleted on that basis (per CLAUDE.md); the term stands on PMID:32562145 (EXP) and PMID:16858409 (IC via MAVS) instead. Curators may wish to re-check the source of this particular row. Supporting Evidence: PMID:16858409 Cardif-mediated IFNalpha induction occurs through a direct interaction between the TRAF domain of TRAF3 and a TRAF-interaction motif (TIM) within Cardif file:human/TRAF3/TRAF3-notes.md Mitochondrial pool: via MAVS |
| GO:0005515 protein binding | IPI PMID:27387501 Citrobacter rodentium NleB Protein Inhibits Tumor Necrosis F... | REMOVE | Summary: Uninformative generic protein binding annotation from an interaction dataset. Reason: GO:0005515 conveys nothing about TRAF3's molecular function. TRAF3 is a well-characterised adaptor whose informative interactions are already captured by GO:0005164 (TNF receptor binding), GO:0035591 (signalling adaptor activity), GO:0019901 (protein kinase binding), GO:0019903 (protein phosphatase binding) and GO:0042802 (homotrimerisation). Per project curation guidance the bare term should be replaced by informative molecular function terms. |
| GO:0005515 protein binding | IPI PMID:27980081 DDX3 directly regulates TRAF3 ubiquitination and acts as a s... | REMOVE | Summary: Uninformative generic protein binding annotation from an interaction dataset. Reason: GO:0005515 conveys nothing about TRAF3's molecular function. TRAF3 is a well-characterised adaptor whose informative interactions are already captured by GO:0005164 (TNF receptor binding), GO:0035591 (signalling adaptor activity), GO:0019901 (protein kinase binding), GO:0019903 (protein phosphatase binding) and GO:0042802 (homotrimerisation). Per project curation guidance the bare term should be replaced by informative molecular function terms. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-166245 | ACCEPT | Summary: Cytosolic localisation, asserted by Reactome across the TLR, RLR, CD40 and non-canonical NF-kappaB reactions in which TRAF3 participates. Reason: TRAF3 has no transmembrane segment or targeting signal and is a soluble cytosolic protein that is recruited transiently to membrane- and organelle-proximal complexes. The many duplicate Reactome TAS rows all report the same, correct fact. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-166271 | ACCEPT | Summary: Cytosolic localisation, asserted by Reactome across the TLR, RLR, CD40 and non-canonical NF-kappaB reactions in which TRAF3 participates. Reason: TRAF3 has no transmembrane segment or targeting signal and is a soluble cytosolic protein that is recruited transiently to membrane- and organelle-proximal complexes. The many duplicate Reactome TAS rows all report the same, correct fact. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2213017 | ACCEPT | Summary: Cytosolic localisation, asserted by Reactome across the TLR, RLR, CD40 and non-canonical NF-kappaB reactions in which TRAF3 participates. Reason: TRAF3 has no transmembrane segment or targeting signal and is a soluble cytosolic protein that is recruited transiently to membrane- and organelle-proximal complexes. The many duplicate Reactome TAS rows all report the same, correct fact. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5362486 | ACCEPT | Summary: Cytosolic localisation, asserted by Reactome across the TLR, RLR, CD40 and non-canonical NF-kappaB reactions in which TRAF3 participates. Reason: TRAF3 has no transmembrane segment or targeting signal and is a soluble cytosolic protein that is recruited transiently to membrane- and organelle-proximal complexes. The many duplicate Reactome TAS rows all report the same, correct fact. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5362500 | ACCEPT | Summary: Cytosolic localisation, asserted by Reactome across the TLR, RLR, CD40 and non-canonical NF-kappaB reactions in which TRAF3 participates. Reason: TRAF3 has no transmembrane segment or targeting signal and is a soluble cytosolic protein that is recruited transiently to membrane- and organelle-proximal complexes. The many duplicate Reactome TAS rows all report the same, correct fact. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9013974 | ACCEPT | Summary: Cytosolic localisation, asserted by Reactome across the TLR, RLR, CD40 and non-canonical NF-kappaB reactions in which TRAF3 participates. Reason: TRAF3 has no transmembrane segment or targeting signal and is a soluble cytosolic protein that is recruited transiently to membrane- and organelle-proximal complexes. The many duplicate Reactome TAS rows all report the same, correct fact. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9013978 | ACCEPT | Summary: Cytosolic localisation, asserted by Reactome across the TLR, RLR, CD40 and non-canonical NF-kappaB reactions in which TRAF3 participates. Reason: TRAF3 has no transmembrane segment or targeting signal and is a soluble cytosolic protein that is recruited transiently to membrane- and organelle-proximal complexes. The many duplicate Reactome TAS rows all report the same, correct fact. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9013979 | ACCEPT | Summary: Cytosolic localisation, asserted by Reactome across the TLR, RLR, CD40 and non-canonical NF-kappaB reactions in which TRAF3 participates. Reason: TRAF3 has no transmembrane segment or targeting signal and is a soluble cytosolic protein that is recruited transiently to membrane- and organelle-proximal complexes. The many duplicate Reactome TAS rows all report the same, correct fact. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9013985 | ACCEPT | Summary: Cytosolic localisation, asserted by Reactome across the TLR, RLR, CD40 and non-canonical NF-kappaB reactions in which TRAF3 participates. Reason: TRAF3 has no transmembrane segment or targeting signal and is a soluble cytosolic protein that is recruited transiently to membrane- and organelle-proximal complexes. The many duplicate Reactome TAS rows all report the same, correct fact. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9013990 | ACCEPT | Summary: Cytosolic localisation, asserted by Reactome across the TLR, RLR, CD40 and non-canonical NF-kappaB reactions in which TRAF3 participates. Reason: TRAF3 has no transmembrane segment or targeting signal and is a soluble cytosolic protein that is recruited transiently to membrane- and organelle-proximal complexes. The many duplicate Reactome TAS rows all report the same, correct fact. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-918225 | ACCEPT | Summary: Cytosolic localisation, asserted by Reactome across the TLR, RLR, CD40 and non-canonical NF-kappaB reactions in which TRAF3 participates. Reason: TRAF3 has no transmembrane segment or targeting signal and is a soluble cytosolic protein that is recruited transiently to membrane- and organelle-proximal complexes. The many duplicate Reactome TAS rows all report the same, correct fact. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-918227 | ACCEPT | Summary: Cytosolic localisation, asserted by Reactome across the TLR, RLR, CD40 and non-canonical NF-kappaB reactions in which TRAF3 participates. Reason: TRAF3 has no transmembrane segment or targeting signal and is a soluble cytosolic protein that is recruited transiently to membrane- and organelle-proximal complexes. The many duplicate Reactome TAS rows all report the same, correct fact. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-918229 | ACCEPT | Summary: Cytosolic localisation, asserted by Reactome across the TLR, RLR, CD40 and non-canonical NF-kappaB reactions in which TRAF3 participates. Reason: TRAF3 has no transmembrane segment or targeting signal and is a soluble cytosolic protein that is recruited transiently to membrane- and organelle-proximal complexes. The many duplicate Reactome TAS rows all report the same, correct fact. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-918232 | ACCEPT | Summary: Cytosolic localisation, asserted by Reactome across the TLR, RLR, CD40 and non-canonical NF-kappaB reactions in which TRAF3 participates. Reason: TRAF3 has no transmembrane segment or targeting signal and is a soluble cytosolic protein that is recruited transiently to membrane- and organelle-proximal complexes. The many duplicate Reactome TAS rows all report the same, correct fact. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-936381 | ACCEPT | Summary: Cytosolic localisation, asserted by Reactome across the TLR, RLR, CD40 and non-canonical NF-kappaB reactions in which TRAF3 participates. Reason: TRAF3 has no transmembrane segment or targeting signal and is a soluble cytosolic protein that is recruited transiently to membrane- and organelle-proximal complexes. The many duplicate Reactome TAS rows all report the same, correct fact. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9685162 | ACCEPT | Summary: Cytosolic localisation, asserted by Reactome across the TLR, RLR, CD40 and non-canonical NF-kappaB reactions in which TRAF3 participates. Reason: TRAF3 has no transmembrane segment or targeting signal and is a soluble cytosolic protein that is recruited transiently to membrane- and organelle-proximal complexes. The many duplicate Reactome TAS rows all report the same, correct fact. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9705137 | ACCEPT | Summary: Cytosolic localisation, asserted by Reactome across the TLR, RLR, CD40 and non-canonical NF-kappaB reactions in which TRAF3 participates. Reason: TRAF3 has no transmembrane segment or targeting signal and is a soluble cytosolic protein that is recruited transiently to membrane- and organelle-proximal complexes. The many duplicate Reactome TAS rows all report the same, correct fact. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9705320 | ACCEPT | Summary: Cytosolic localisation, asserted by Reactome across the TLR, RLR, CD40 and non-canonical NF-kappaB reactions in which TRAF3 participates. Reason: TRAF3 has no transmembrane segment or targeting signal and is a soluble cytosolic protein that is recruited transiently to membrane- and organelle-proximal complexes. The many duplicate Reactome TAS rows all report the same, correct fact. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9823904 | ACCEPT | Summary: Cytosolic localisation, asserted by Reactome across the TLR, RLR, CD40 and non-canonical NF-kappaB reactions in which TRAF3 participates. Reason: TRAF3 has no transmembrane segment or targeting signal and is a soluble cytosolic protein that is recruited transiently to membrane- and organelle-proximal complexes. The many duplicate Reactome TAS rows all report the same, correct fact. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9823906 | ACCEPT | Summary: Cytosolic localisation, asserted by Reactome across the TLR, RLR, CD40 and non-canonical NF-kappaB reactions in which TRAF3 participates. Reason: TRAF3 has no transmembrane segment or targeting signal and is a soluble cytosolic protein that is recruited transiently to membrane- and organelle-proximal complexes. The many duplicate Reactome TAS rows all report the same, correct fact. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9823910 | ACCEPT | Summary: Cytosolic localisation, asserted by Reactome across the TLR, RLR, CD40 and non-canonical NF-kappaB reactions in which TRAF3 participates. Reason: TRAF3 has no transmembrane segment or targeting signal and is a soluble cytosolic protein that is recruited transiently to membrane- and organelle-proximal complexes. The many duplicate Reactome TAS rows all report the same, correct fact. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9823932 | ACCEPT | Summary: Cytosolic localisation, asserted by Reactome across the TLR, RLR, CD40 and non-canonical NF-kappaB reactions in which TRAF3 participates. Reason: TRAF3 has no transmembrane segment or targeting signal and is a soluble cytosolic protein that is recruited transiently to membrane- and organelle-proximal complexes. The many duplicate Reactome TAS rows all report the same, correct fact. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9823934 | ACCEPT | Summary: Cytosolic localisation, asserted by Reactome across the TLR, RLR, CD40 and non-canonical NF-kappaB reactions in which TRAF3 participates. Reason: TRAF3 has no transmembrane segment or targeting signal and is a soluble cytosolic protein that is recruited transiently to membrane- and organelle-proximal complexes. The many duplicate Reactome TAS rows all report the same, correct fact. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9823939 | ACCEPT | Summary: Cytosolic localisation, asserted by Reactome across the TLR, RLR, CD40 and non-canonical NF-kappaB reactions in which TRAF3 participates. Reason: TRAF3 has no transmembrane segment or targeting signal and is a soluble cytosolic protein that is recruited transiently to membrane- and organelle-proximal complexes. The many duplicate Reactome TAS rows all report the same, correct fact. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9824882 | ACCEPT | Summary: Cytosolic localisation, asserted by Reactome across the TLR, RLR, CD40 and non-canonical NF-kappaB reactions in which TRAF3 participates. Reason: TRAF3 has no transmembrane segment or targeting signal and is a soluble cytosolic protein that is recruited transiently to membrane- and organelle-proximal complexes. The many duplicate Reactome TAS rows all report the same, correct fact. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9828196 | ACCEPT | Summary: Cytosolic localisation, asserted by Reactome across the TLR, RLR, CD40 and non-canonical NF-kappaB reactions in which TRAF3 participates. Reason: TRAF3 has no transmembrane segment or targeting signal and is a soluble cytosolic protein that is recruited transiently to membrane- and organelle-proximal complexes. The many duplicate Reactome TAS rows all report the same, correct fact. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9828200 | ACCEPT | Summary: Cytosolic localisation, asserted by Reactome across the TLR, RLR, CD40 and non-canonical NF-kappaB reactions in which TRAF3 participates. Reason: TRAF3 has no transmembrane segment or targeting signal and is a soluble cytosolic protein that is recruited transiently to membrane- and organelle-proximal complexes. The many duplicate Reactome TAS rows all report the same, correct fact. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9828204 | ACCEPT | Summary: Cytosolic localisation, asserted by Reactome across the TLR, RLR, CD40 and non-canonical NF-kappaB reactions in which TRAF3 participates. Reason: TRAF3 has no transmembrane segment or targeting signal and is a soluble cytosolic protein that is recruited transiently to membrane- and organelle-proximal complexes. The many duplicate Reactome TAS rows all report the same, correct fact. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9828205 | ACCEPT | Summary: Cytosolic localisation, asserted by Reactome across the TLR, RLR, CD40 and non-canonical NF-kappaB reactions in which TRAF3 participates. Reason: TRAF3 has no transmembrane segment or targeting signal and is a soluble cytosolic protein that is recruited transiently to membrane- and organelle-proximal complexes. The many duplicate Reactome TAS rows all report the same, correct fact. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9828209 | ACCEPT | Summary: Cytosolic localisation, asserted by Reactome across the TLR, RLR, CD40 and non-canonical NF-kappaB reactions in which TRAF3 participates. Reason: TRAF3 has no transmembrane segment or targeting signal and is a soluble cytosolic protein that is recruited transiently to membrane- and organelle-proximal complexes. The many duplicate Reactome TAS rows all report the same, correct fact. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9830706 | ACCEPT | Summary: Cytosolic localisation, asserted by Reactome across the TLR, RLR, CD40 and non-canonical NF-kappaB reactions in which TRAF3 participates. Reason: TRAF3 has no transmembrane segment or targeting signal and is a soluble cytosolic protein that is recruited transiently to membrane- and organelle-proximal complexes. The many duplicate Reactome TAS rows all report the same, correct fact. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9830710 | ACCEPT | Summary: Cytosolic localisation, asserted by Reactome across the TLR, RLR, CD40 and non-canonical NF-kappaB reactions in which TRAF3 participates. Reason: TRAF3 has no transmembrane segment or targeting signal and is a soluble cytosolic protein that is recruited transiently to membrane- and organelle-proximal complexes. The many duplicate Reactome TAS rows all report the same, correct fact. |
| GO:0019903 protein phosphatase binding | IPI PMID:23871208 The autoimmunity-associated gene PTPN22 potentiates toll-lik... | KEEP AS NON CORE | Summary: TRAF3 associates with the phosphatase PTPN22, which promotes TRAF3 K63 ubiquitination. Reason: Supported by the cited study, but this is TRAF3 acting as the regulated partner rather than exercising a function of its own; 'protein phosphatase binding' is not informative about TRAF3's activity. Retain as non-core. Supporting Evidence: PMID:23871208 PTPN22 directly associated with TNF receptor-associated factor 3 (TRAF3) and promotes TRAF3 lysine 63-linked ubiquitination |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5602624 | ACCEPT | Summary: Cytosolic localisation, asserted by Reactome across the TLR, RLR, CD40 and non-canonical NF-kappaB reactions in which TRAF3 participates. Reason: TRAF3 has no transmembrane segment or targeting signal and is a soluble cytosolic protein that is recruited transiently to membrane- and organelle-proximal complexes. The many duplicate Reactome TAS rows all report the same, correct fact. |
| GO:0005164 tumor necrosis factor receptor binding | IPI PMID:11728344 A novel TNF receptor family member binds TWEAK and is implic... | ACCEPT | Summary: TRAF3 binds the cytoplasmic tails of TNF receptor superfamily members through its MATH/TRAF-C domain - the interaction that defines the TRAF family. Reason: Established for CD40 by two independent two-hybrid screens, and extended to LTBR, BAFF-R, BCMA, CD30, OX40, EDAR and Fn14/TweakR. This is an informative molecular function that captures receptor-proximal recruitment. Supporting Evidence: PMID:11728344 The TweakR cytoplasmic domain binds TRAFs 1, 2, and 3. PMID:7527023 we have utilized the yeast two-hybrid system to clone cDNAs encoding proteins that bind the CD40 cytoplasmic domain |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5668454 | ACCEPT | Summary: Cytosolic localisation, asserted by Reactome across the TLR, RLR, CD40 and non-canonical NF-kappaB reactions in which TRAF3 participates. Reason: TRAF3 has no transmembrane segment or targeting signal and is a soluble cytosolic protein that is recruited transiently to membrane- and organelle-proximal complexes. The many duplicate Reactome TAS rows all report the same, correct fact. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5668481 | ACCEPT | Summary: Cytosolic localisation, asserted by Reactome across the TLR, RLR, CD40 and non-canonical NF-kappaB reactions in which TRAF3 participates. Reason: TRAF3 has no transmembrane segment or targeting signal and is a soluble cytosolic protein that is recruited transiently to membrane- and organelle-proximal complexes. The many duplicate Reactome TAS rows all report the same, correct fact. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-936475 | ACCEPT | Summary: Cytosolic localisation, asserted by Reactome across the TLR, RLR, CD40 and non-canonical NF-kappaB reactions in which TRAF3 participates. Reason: TRAF3 has no transmembrane segment or targeting signal and is a soluble cytosolic protein that is recruited transiently to membrane- and organelle-proximal complexes. The many duplicate Reactome TAS rows all report the same, correct fact. |
| GO:0031625 ubiquitin protein ligase binding | IPI PMID:11279055 A diverse family of proteins containing tumor necrosis facto... | KEEP AS NON CORE | Summary: Binding to ubiquitin protein ligases, from an in vitro TRAF-domain survey (MUL/TRIM37) and family-level rules. Reason: TRAF3 does associate with E3s in vivo (cIAP1/2 within the NIK-degrading complex, TRIM35, NEDD4L, FBXO11), so the term is not wrong. However the IPI evidence comes from isolated TRAF domains binding all six TRAFs indiscriminately in vitro, and the term describes a partner class rather than a TRAF3 activity. Retain as non-core. Supporting Evidence: PMID:11279055 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) |
| GO:0031996 thioesterase binding | IPI PMID:11279055 A diverse family of proteins containing tumor necrosis facto... | KEEP AS NON CORE | Summary: Binding to thioesterases, i.e. to ubiquitin thioesterases/deubiquitinases. Reason: TRAF3 is a well-documented substrate of the deubiquitinases OTUB1, OTUB2, OTUD5/DUBA and MYSM1, so binding ubiquitin thioesterases is real. As with the other partner-class binding terms, it describes what acts on TRAF3 rather than what TRAF3 does. Retain as non-core. Supporting Evidence: PMID:17991829 DUBA selectively cleaved the lysine-63-linked polyubiquitin chains on TRAF3, resulting in its dissociation from the downstream signaling complex containing TANK-binding kinase 1 |
| GO:0005515 protein binding | IPI PMID:19419966 The tyrosine kinase c-Src enhances RIG-I (retinoic acid-indu... | REMOVE | Summary: Uninformative generic protein binding annotation from an interaction dataset. Reason: GO:0005515 conveys nothing about TRAF3's molecular function. TRAF3 is a well-characterised adaptor whose informative interactions are already captured by GO:0005164 (TNF receptor binding), GO:0035591 (signalling adaptor activity), GO:0019901 (protein kinase binding), GO:0019903 (protein phosphatase binding) and GO:0042802 (homotrimerisation). Per project curation guidance the bare term should be replaced by informative molecular function terms. |
| GO:0035631 CD40 receptor complex | ISS GO_REF:0000024 | ACCEPT | Summary: TRAF3 was discovered as a CD40 cytoplasmic-tail binding protein and is a component of the ligand-engaged CD40 receptor complex. Reason: Two independent yeast two-hybrid screens against the CD40 cytoplasmic domain identified TRAF3 (as CD40BP and as CAP-1), and CD40 ligation reorganises the TRAF2/TRAF3 content of the complex. Supporting Evidence: PMID:7530216 cDNAs were obtained that encode a novel protein, CD40-associated protein-1 (CAP-1), which binds specifically to the cytosolic domain of CD40 PMID:15383523 Ligation of CD40 on Ramos B cells by recombinant CD154 caused TRAF2 and TRAF3 to dissociate |
| GO:0009898 cytoplasmic side of plasma membrane | ISS GO_REF:0000024 | ACCEPT | Summary: TRAF3 is recruited to the cytoplasmic tails of plasma-membrane TNF receptor superfamily members (CD40, LTBR, BAFF-R, CD30, OX40, EDAR), so it acts at the cytoplasmic face of the plasma membrane. Reason: Supported by the founding CD40 cytoplasmic-domain two-hybrid work and by LTBR signalling-complex recruitment; the MATH/TRAF domain is the receptor-tail binding module. Supporting Evidence: PMID:7527023 One such interacting protein, designated CD40-binding protein, has a N-terminal RING finger motif PMID:20185819 Increased expression of TRAF3 correlated with its increased recruitment to LTBR-induced signaling complexes |
| GO:0001817 regulation of cytokine production | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Regulation of cytokine production - TRAF3 controls the balance between type I interferons, IL-10 and pro-inflammatory cytokines. Reason: Correct: TRAF3 is required for IFN and IL-10 induction while restraining pro-inflammatory cytokines. However the term is a broad parent and the informative, signed children (GO:0032481, GO:0032728) are annotated separately. Retain as non-core. Supporting Evidence: PMID:16306937 TRAF3-deficient cells overproduce pro-inflammatory cytokines owing to defective IL-10 production |
| GO:0002224 toll-like receptor signaling pathway | ISS GO_REF:0000024 | ACCEPT | Summary: TRAF3 is a component of TLR signalling complexes, recruited via MyD88 and TRIF, and is required for their interferon output. Reason: Core process. TRAF3 is recruited to TIR-adaptor signalling complexes and is directly observed in the internalised TLR4/TRAM endosomal complex. Supporting Evidence: PMID:16306937 we identified TNF receptor-associated factor 3 (TRAF3) as a new component of TIR signalling complexes that is recruited along with TRAF6 PMID:18222170 The internalized signaling complex consisting of TLR4 and TRAM colocalizes with TRAF3, a signaling molecule downstream of TRIF, in endosome/lysosome |
| GO:0032648 regulation of interferon-beta production | ISS GO_REF:0000024 | MODIFY | Summary: Unsigned parent term for regulation of interferon-beta production. Reason: TRAF3 is required for IFN-beta induction downstream of TRIF and MAVS; the direction is established, so the signed child GO:0032728 is the appropriate term. Proposed replacements: positive regulation of interferon-beta production Supporting Evidence: PMID:16306937 TRAF3 is essential for the induction of type I interferons (IFN) and the anti-inflammatory cytokine interleukin-10 (IL-10) |
| GO:0050688 regulation of defense response to virus | ISS GO_REF:0000024 | MODIFY | Summary: Unsigned 'regulation of defense response to virus'. Reason: TRAF3's contribution to antiviral defence is positive and well established, so the signed child GO:0002230 should be used rather than the unsigned parent. Proposed replacements: positive regulation of defense response to virus by host Supporting Evidence: PMID:16306936 Our data demonstrate that TRAF3 is a major regulator of type I IFN production and the innate antiviral response |
| GO:0005515 protein binding | IPI PMID:19893624 The E3 ubiquitin ligase Triad3A negatively regulates the RIG... | REMOVE | Summary: Uninformative generic protein binding annotation from an interaction dataset. Reason: GO:0005515 conveys nothing about TRAF3's molecular function. TRAF3 is a well-characterised adaptor whose informative interactions are already captured by GO:0005164 (TNF receptor binding), GO:0035591 (signalling adaptor activity), GO:0019901 (protein kinase binding), GO:0019903 (protein phosphatase binding) and GO:0042802 (homotrimerisation). Per project curation guidance the bare term should be replaced by informative molecular function terms. |
| GO:0030162 regulation of proteolysis | IMP PMID:20185819 TRAF3 controls activation of the canonical and alternative N... | ACCEPT | Summary: TRAF3 controls proteolysis of key NF-kappaB pathway components: it drives constitutive proteasomal degradation of NIK/MAP3K14 and thereby limits processing of NFKB2/p100 to p52. Reason: Core process, directly demonstrated - TRAF3 knockdown raises NIK protein and triggers p100 processing without any receptor stimulus. The term is general; the specific mechanism is proposed as new annotations (GO:0043161 and GO:1901223). Supporting Evidence: PMID:20185819 TRAF3 knock-down also increased mRNA and protein expression of several non-canonical NFkappaB components, including NFkappaB2/p100, RelB, and NIK, accompanied by processing of NFkappaB2/p100 into p52 PMID:15084608 this molecular interaction appears to target NIK for degradation by the proteasome |
| GO:0033209 tumor necrosis factor-mediated signaling pathway | IMP PMID:20185819 TRAF3 controls activation of the canonical and alternative N... | KEEP AS NON CORE | Summary: Involvement in TNF-superfamily receptor signalling; the IMP evidence is from lymphotoxin-beta receptor rather than TNF/TNFR1. Reason: TRAF3 does not bind TNFR1 and is not a component of the TNF/TNFR1 signalling complex; the supporting experiment concerns LTBR, and TRAF3 acts across several TNFRSF members (CD40, LTBR, BAFF-R, BCMA, CD30, OX40). The term is therefore only loosely correct, and this is not TRAF3's core process. Retained as non-core because no specific LTBR-signalling term is available in GO. Supporting Evidence: PMID:20185819 we report that TRAF3 functions as a negative regulator of LTBR signaling via both canonical and non-canonical NFkappaB pathways by two distinct mechanisms |
| GO:0005515 protein binding | IPI PMID:20174559 Optineurin negatively regulates the induction of IFNbeta in ... | REMOVE | Summary: Uninformative generic protein binding annotation from an interaction dataset. Reason: GO:0005515 conveys nothing about TRAF3's molecular function. TRAF3 is a well-characterised adaptor whose informative interactions are already captured by GO:0005164 (TNF receptor binding), GO:0035591 (signalling adaptor activity), GO:0019901 (protein kinase binding), GO:0019903 (protein phosphatase binding) and GO:0042802 (homotrimerisation). Per project curation guidance the bare term should be replaced by informative molecular function terms. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-2201338 | ACCEPT | Summary: Cytosolic localisation, asserted by Reactome across the TLR, RLR, CD40 and non-canonical NF-kappaB reactions in which TRAF3 participates. Reason: TRAF3 has no transmembrane segment or targeting signal and is a soluble cytosolic protein that is recruited transiently to membrane- and organelle-proximal complexes. The many duplicate Reactome TAS rows all report the same, correct fact. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5668414 | ACCEPT | Summary: Cytosolic localisation, asserted by Reactome across the TLR, RLR, CD40 and non-canonical NF-kappaB reactions in which TRAF3 participates. Reason: TRAF3 has no transmembrane segment or targeting signal and is a soluble cytosolic protein that is recruited transiently to membrane- and organelle-proximal complexes. The many duplicate Reactome TAS rows all report the same, correct fact. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5668417 | ACCEPT | Summary: Cytosolic localisation, asserted by Reactome across the TLR, RLR, CD40 and non-canonical NF-kappaB reactions in which TRAF3 participates. Reason: TRAF3 has no transmembrane segment or targeting signal and is a soluble cytosolic protein that is recruited transiently to membrane- and organelle-proximal complexes. The many duplicate Reactome TAS rows all report the same, correct fact. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5668534 | ACCEPT | Summary: Cytosolic localisation, asserted by Reactome across the TLR, RLR, CD40 and non-canonical NF-kappaB reactions in which TRAF3 participates. Reason: TRAF3 has no transmembrane segment or targeting signal and is a soluble cytosolic protein that is recruited transiently to membrane- and organelle-proximal complexes. The many duplicate Reactome TAS rows all report the same, correct fact. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5668543 | ACCEPT | Summary: Cytosolic localisation, asserted by Reactome across the TLR, RLR, CD40 and non-canonical NF-kappaB reactions in which TRAF3 participates. Reason: TRAF3 has no transmembrane segment or targeting signal and is a soluble cytosolic protein that is recruited transiently to membrane- and organelle-proximal complexes. The many duplicate Reactome TAS rows all report the same, correct fact. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5676593 | ACCEPT | Summary: Cytosolic localisation, asserted by Reactome across the TLR, RLR, CD40 and non-canonical NF-kappaB reactions in which TRAF3 participates. Reason: TRAF3 has no transmembrane segment or targeting signal and is a soluble cytosolic protein that is recruited transiently to membrane- and organelle-proximal complexes. The many duplicate Reactome TAS rows all report the same, correct fact. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5676595 | ACCEPT | Summary: Cytosolic localisation, asserted by Reactome across the TLR, RLR, CD40 and non-canonical NF-kappaB reactions in which TRAF3 participates. Reason: TRAF3 has no transmembrane segment or targeting signal and is a soluble cytosolic protein that is recruited transiently to membrane- and organelle-proximal complexes. The many duplicate Reactome TAS rows all report the same, correct fact. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5676596 | ACCEPT | Summary: Cytosolic localisation, asserted by Reactome across the TLR, RLR, CD40 and non-canonical NF-kappaB reactions in which TRAF3 participates. Reason: TRAF3 has no transmembrane segment or targeting signal and is a soluble cytosolic protein that is recruited transiently to membrane- and organelle-proximal complexes. The many duplicate Reactome TAS rows all report the same, correct fact. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5676597 | ACCEPT | Summary: Cytosolic localisation, asserted by Reactome across the TLR, RLR, CD40 and non-canonical NF-kappaB reactions in which TRAF3 participates. Reason: TRAF3 has no transmembrane segment or targeting signal and is a soluble cytosolic protein that is recruited transiently to membrane- and organelle-proximal complexes. The many duplicate Reactome TAS rows all report the same, correct fact. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5676598 | ACCEPT | Summary: Cytosolic localisation, asserted by Reactome across the TLR, RLR, CD40 and non-canonical NF-kappaB reactions in which TRAF3 participates. Reason: TRAF3 has no transmembrane segment or targeting signal and is a soluble cytosolic protein that is recruited transiently to membrane- and organelle-proximal complexes. The many duplicate Reactome TAS rows all report the same, correct fact. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5690843 | ACCEPT | Summary: Cytosolic localisation, asserted by Reactome across the TLR, RLR, CD40 and non-canonical NF-kappaB reactions in which TRAF3 participates. Reason: TRAF3 has no transmembrane segment or targeting signal and is a soluble cytosolic protein that is recruited transiently to membrane- and organelle-proximal complexes. The many duplicate Reactome TAS rows all report the same, correct fact. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9013992 | ACCEPT | Summary: Cytosolic localisation, asserted by Reactome across the TLR, RLR, CD40 and non-canonical NF-kappaB reactions in which TRAF3 participates. Reason: TRAF3 has no transmembrane segment or targeting signal and is a soluble cytosolic protein that is recruited transiently to membrane- and organelle-proximal complexes. The many duplicate Reactome TAS rows all report the same, correct fact. |
| GO:0005515 protein binding | IPI PMID:12270937 Role of TRAF3 and -6 in the activation of the NF-kappa B and... | REMOVE | Summary: Uninformative generic protein binding annotation from an interaction dataset. Reason: GO:0005515 conveys nothing about TRAF3's molecular function. TRAF3 is a well-characterised adaptor whose informative interactions are already captured by GO:0005164 (TNF receptor binding), GO:0035591 (signalling adaptor activity), GO:0019901 (protein kinase binding), GO:0019903 (protein phosphatase binding) and GO:0042802 (homotrimerisation). Per project curation guidance the bare term should be replaced by informative molecular function terms. |
| GO:0006915 apoptotic process | TAS PMID:10799510 The lymphotoxin-beta receptor is necessary and sufficient fo... | MARK AS OVER ANNOTATED | Summary: Direct involvement in the apoptotic process, from a study of LIGHT/LTBR-induced death. Reason: The evidence is that overexpressed dominant-negative TRAF3 blocks LIGHT-induced killing - an indirect, upstream signalling effect. TRAF3 is not part of the apoptotic execution machinery and has no caspase-pathway activity; annotating it to the apoptotic process itself over-states the relationship. The regulatory term GO:0042981 covers what is actually supported. Supporting Evidence: PMID:10799510 LTbetaR, not HveA, recruits TNF receptor-associated factor-3 (TRAF3), and LIGHT-induced death is blocked by a dominant negative TRAF3 mutant |
| GO:0007165 signal transduction | TAS PMID:7530216 A novel member of the TRAF family of putative signal transdu... | MODIFY | Summary: Root-level 'signal transduction', from an InterPro rule and from the original CD40-binding paper. Reason: Uninformative at this level. The anchoring publication is the discovery of TRAF3 as a CD40 cytoplasmic-tail binding protein, so GO:0023035 (CD40 signaling pathway) is the specific term that this evidence actually supports. Proposed replacements: CD40 signaling pathway Supporting Evidence: PMID:7530216 CD40 is a member of the tumor necrosis factor receptor (TNF-R) family that regulates B-lymphocyte proliferation, immunoglobulin class-switching, and apoptosis |
| GO:1901223 negative regulation of non-canonical NF-kappaB signal transduction | IMP PMID:20185819 TRAF3 controls activation of the canonical and alternative N... | NEW | Summary: TRAF3 is the constitutive brake on the non-canonical NF-kappaB pathway: by recruiting NIK/MAP3K14 into a TRAF2-cIAP1/2 complex it keeps NIK levels low and p100 unprocessed until receptor engagement destroys TRAF3. Reason: This is TRAF3's best-established and most distinctive function and it is entirely missing from the current GOA set, which represents it only as the vague GO:0030162 (regulation of proteolysis). It is supported by direct biochemistry, by loss-of-function in cells, by mouse genetics (TRAF3-null lethality is rescued by deleting one Nik allele) and by recurrent TRAF3 inactivation in multiple myeloma. Supporting Evidence: PMID:18997794 the degradation of NIK occurs upon assembly of a regulatory complex through TRAF3 recruitment of NIK and TRAF2 recruitment of cIAP1 and cIAP2 PMID:20185819 These effects of TRAF3 depletion did not require LTBR signaling and were consistent with autonomous activation of the non-canonical NFkappaB pathway PMID:15084608 Interestingly, induction of noncanonical NF-kappaB signaling by extracellular signals involves degradation of TRAF3 and the concomitant enhancement of NIK expression |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | IDA PMID:15084608 Regulation of the NF-kappaB-inducing kinase by tumor necrosi... | NEW | Summary: TRAF3 targets NIK/MAP3K14 for ubiquitin-dependent proteasomal degradation, the mechanism by which it restrains non-canonical NF-kappaB signalling. Reason: The mechanism underlying the proposed GO:1901223 annotation and the specific form of the existing GO:0030162 (regulation of proteolysis) IMP. Directly demonstrated: TRAF3 binds a defined motif in the NIK N-terminus and this association targets NIK to the proteasome. Supporting Evidence: PMID:15084608 TRAF3 physically associates with NIK via a specific sequence motif located in the N-terminal region of NIK; this molecular interaction appears to target NIK for degradation by the proteasome PMID:18997794 cIAP1 and cIAP2 seem to play redundant roles in the degradation of NIK |
| GO:0070534 protein K63-linked ubiquitination | IDA PMID:25847972 MAVS Promotes Inflammasome Activation by Targeting ASC for K... | NEW | Summary: As a RING E3, TRAF3 assembles K63-linked polyubiquitin chains - on ASC to license inflammasome speck formation, and on itself downstream of TRIF to activate the interferon response. Reason: The existing GO:0061630 annotation records that TRAF3 is an E3 but not which chain type it builds, which is the functionally decisive detail: K63 chains are the signalling output, whereas the K48 chains on TRAF3 are placed by other ligases (cIAP1/2, Triad3A). Directly supported by biochemistry on ASC and by the TRIF-driven self-ubiquitination experiments. Supporting Evidence: PMID:25847972 Ubiquitination of ASC at Lys(174) was critical for speck formation and inflammasome activation PMID:17991829 TRAF3 is an E3 ubiquitin ligase that preferentially assembled lysine-63-linked polyubiquitin chains PMID:19898473 TRIF-dependent signaling triggered noncanonical TRAF3 self-ubiquitination that activated the interferon response |
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Download this section (compressed HTML)Q: Is TRAF3's suppression of canonical NF-kappaB and MAPK signalling a direct adaptor activity - competitive exclusion of TRAF2/IKK1 from the receptor complex - or is it entirely downstream of the NIK and cIAP effects? The answer determines whether a separate 'negative regulation of canonical NF-kappaB signal transduction' annotation is warranted alongside GO:1901223.
Suggested experts: Michael Karin, Genhong Cheng, Shao-Cong Sun
Q: Beyond ASC, which proteins are direct TRAF3 ubiquitination substrates? Almost all published 'TRAF3 ubiquitination' work concerns TRAF3 as the substrate of other ligases, leaving TRAF3's own substrate repertoire - and therefore the scope of its GO:0061630 annotation - largely undefined.
Suggested experts: Vishva M. Dixit, Michael Karin
Q: Does isoform 2 (Q13114-2) have any distinct function, tissue distribution or dominant-negative behaviour? No functional data were found for it, so all current annotations implicitly refer to the canonical isoform.
Q: How should the K33-linked ubiquitination/exocyst route (PMID:27438768) be represented? It is a genuine TRAF3-dependent process but was demonstrated in a single cell type; is a 'bacterial expulsion' or exocyst-recruitment annotation justified, and does TRAF3 act there as adaptor rather than ligase?
Suggested experts: Soman N. Abraham, Yuxuan Miao
Experiment: In NIK-null (MAP3K14 knockout) cells, reconstitute with wild-type TRAF3 or with a receptor-binding-deficient MATH-domain mutant, then stimulate LTBR and measure IkappaB-alpha/RelA phosphorylation and the TRAF2/IKK1 content of the receptor-associated complex by immunoprecipitation. If TRAF3 still suppresses canonical signalling on a NIK-null background, the adaptor mechanism is direct.
Hypothesis: TRAF3 restrains canonical NF-kappaB at LTBR by directly competing with TRAF2 for the receptor tail, independently of its effect on NIK levels.
Type: Genetic complementation with structure-guided separation-of-function mutants, plus receptor-complex immunoprecipitation
Experiment: Perform ubiquitin-remnant (diGly) proteomics in TRAF3-knockout versus reconstituted cells, with and without RING-mutant TRAF3, after TLR3/TLR4 and Sendai virus stimulation. Validate candidates by in vitro reconstitution with recombinant TRAF3, E1, UBE2N/UBE2V1 and ubiquitin chain-linkage mutants (K63R, K48R) to confirm both directness and chain type.
Hypothesis: TRAF3 has direct ubiquitination substrates beyond ASC that account for its signalling output.
Type: Quantitative diGly ubiquitinome mass spectrometry with in vitro ubiquitination reconstitution
Experiment: Reconstitute TRAF3-null cells with TRAF3 fused to a mitochondrial outer-membrane anchor, to a plasma-membrane anchor, or untargeted, and compare IFN-beta induction after Sendai virus infection versus poly(I:C) endosomal stimulation. Pair with proximity labelling (TurboID) from mitochondrial TRAF3 to define the compartment-specific interactome. This would also settle whether the disputed GO:0005739 IDA row reflects a real, reproducible localisation.
Hypothesis: The mitochondrial TRAF3 pool is functionally required for RLR-driven interferon induction rather than being a passive consequence of MAVS binding.
Type: Compartment-restricted rescue with proximity-dependent biotinylation proteomics
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