TRIM13

UniProt ID: O60858
Organism: Homo sapiens
Review Status: COMPLETE
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Gene Description

TRIM13 (RFP2/Leu5) is an endoplasmic reticulum (ER) membrane-anchored RING-type E3 ubiquitin ligase of the TRIM/RBCC family. Unlike cytosolic TRIMs it has an N-terminal RING-type zinc finger (conferring E3 ubiquitin ligase activity, EC 2.3.2.27, and required for its autopolyubiquitination), a B-box and a coiled-coil (the coiled-coil is required for induction of autophagy during ER stress), and a C-terminal transmembrane domain that anchors it as a single-pass protein in the ER membrane, concentrating at the perinuclear ER. Its best-defined role is in ER-associated degradation (ERAD): it participates in the retrotranslocation and turnover of misfolded membrane and secretory proteins (as well as regulated degradation of some correctly folded proteins) from the ER, working with the AAA-ATPase VCP/p97 (which it binds via its C-terminal domain) to deliver substrates for proteasomal degradation. TRIM13 also regulates ER-stress-induced autophagy/reticulophagy, colocalizing with SQSTM1/p62 and ZFYVE1/DFCP1 at the perinuclear ER and positively regulating macroautophagy, and has been proposed as a tumor suppressor (it lies in the minimal deletion region for B-cell chronic lymphocytic leukemia on chromosome 13). Additional reported activities include enhancing ionizing-radiation-induced p53 stabilization and apoptosis by ubiquitinating and degrading MDM2 and AKT1, and context-dependent modulation of NF-kappaB signaling: it can positively activate NF-kappaB through the TLR2 pathway (K29-linked ubiquitination of TRAF6) and in T-cell receptor signaling, but can also repress TNF-induced NF-kappaB by regulating ubiquitination and turnover of IKBKG/NEMO. It has further been implicated in antiviral responses affecting late stages of the retroviral life cycle.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0005737 cytoplasm
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: Phylogenetic inference of cytoplasmic activity; TRIM13 is more specifically an ER membrane-anchored protein facing the cytoplasm.
Reason: Correct but generic; the specific and core localization is the ER membrane (single-pass), captured by GO:0005789.
Supporting Evidence:
file:human/TRIM13/TRIM13-uniprot.txt
Endoplasmic reticulum membrane
GO:0045087 innate immune response
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: Phylogenetic inference of innate immune involvement; TRIM13 modulates NF-kB signaling (TLR2/TRAF6) and antiviral responses.
Reason: Supported (NF-kB/TLR2 modulation, antiviral effects) but a broad term and secondary to the core ERAD/autophagy ligase role.
Supporting Evidence:
file:human/TRIM13/TRIM13-uniprot.txt
Also plays a role in innate immune response by stimulating NF-kappa-B
GO:0061630 ubiquitin protein ligase activity
IBA
GO_REF:0000033 		ACCEPT
Summary: Phylogenetic inference of RING E3 ubiquitin ligase activity, consistent with the experimental RING-dependent ligase activity.
Reason: Core molecular function; TRIM13 is a RING-type E3 ubiquitin ligase.
Supporting Evidence:
file:human/TRIM13/TRIM13-uniprot.txt
The RING-type zinc finger is required for auto-
GO:0036503 ERAD pathway
IBA
GO_REF:0000033 		ACCEPT
Summary: Phylogenetic inference of involvement in ERAD, consistent with the experimental IDA evidence. Core process.
Reason: Core biological process; TRIM13 is an ER membrane E3 ligase that functions in ERAD.
Supporting Evidence:
file:human/TRIM13/TRIM13-uniprot.txt
associated degradation (ERAD). This process acts on misfolded proteins
GO:0016239 positive regulation of macroautophagy
IBA
GO_REF:0000033 		ACCEPT
Summary: Phylogenetic inference of positive regulation of macroautophagy, consistent with the IDA evidence from the ER-stress autophagy study. Core process.
Reason: Core biological process; TRIM13 positively regulates ER-stress-induced autophagy/reticulophagy.
Supporting Evidence:
PMID:22178386
TRIM13 regulates ER stress induced autophagy and clonogenic ability of the
GO:0043123 positive regulation of canonical NF-kappaB signal transduction
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: Phylogenetic inference of positive regulation of NF-kB signaling, consistent with TLR2/TRAF6 experimental evidence.
Reason: Supported (TLR2/TRAF6 K29-Ub activation) but context-dependent (TRIM13 also represses TNF-induced NF-kB via NEMO) and secondary to the core ERAD/autophagy role.
Supporting Evidence:
file:human/TRIM13/TRIM13-uniprot.txt
activity in the TLR2 signaling pathway. Ubiquitinates TRAF6 via the
GO:0005789 endoplasmic reticulum membrane
IEA
GO_REF:0000044 		ACCEPT
Summary: Electronic transfer of ER membrane localization from the UniProt subcellular location; the core compartment.
Reason: Core cellular component; TRIM13 is a single-pass ER membrane protein.
Supporting Evidence:
file:human/TRIM13/TRIM13-uniprot.txt
Endoplasmic reticulum membrane
GO:0008270 zinc ion binding
IEA
GO_REF:0000002 		KEEP AS NON CORE
Summary: InterPro-based electronic assignment of zinc ion binding by the RING/B-box zinc fingers.
Reason: Correct (RING/B-box coordinate Zn2+) and underpins ligase activity, but generic; the informative MF is ubiquitin ligase activity.
Supporting Evidence:
file:human/TRIM13/TRIM13-uniprot.txt
The RING-type zinc finger is required for auto-
GO:0044322 endoplasmic reticulum quality control compartment
IEA
GO_REF:0000108 		KEEP AS NON CORE
Summary: Inter-ontology electronic inference of ERQC localization, consistent with TRIM13's ERAD function at the ER.
Reason: Plausible and consistent with the ERAD role but electronically inferred; the experimentally supported localization is the ER/perinuclear ER membrane.
Supporting Evidence:
file:human/TRIM13/TRIM13-uniprot.txt
associated degradation (ERAD). This process acts on misfolded proteins
GO:0045893 positive regulation of DNA-templated transcription
IEA
GO_REF:0000108 		MARK AS OVER ANNOTATED
Summary: Inter-ontology electronic inference from a transcription coactivator activity annotation.
Reason: Derived from an over-interpreted transcription coactivator annotation (NF-kB activation phenotype); TRIM13 is an E3 ligase acting upstream in signaling, not a direct DNA-templated transcriptional activator.
Supporting Evidence:
file:human/TRIM13/TRIM13-uniprot.txt
Also plays a role in innate immune response by stimulating NF-kappa-B
GO:0061630 ubiquitin protein ligase activity
IEA
GO_REF:0000003 		ACCEPT
Summary: EC 2.3.2.27-based electronic assignment of ubiquitin protein ligase activity; core function.
Reason: Core molecular function corroborated by experimental RING-dependent ligase activity.
Supporting Evidence:
file:human/TRIM13/TRIM13-uniprot.txt
EC=2.3.2.27
GO:0005737 cytoplasm
IEA
GO_REF:0000107 		KEEP AS NON CORE
Summary: Ensembl-ortholog electronic transfer of cytoplasmic localization; generic relative to the ER membrane localization.
Reason: Correct but generic; the specific localization is the ER membrane.
Supporting Evidence:
file:human/TRIM13/TRIM13-uniprot.txt
Endoplasmic reticulum membrane
GO:0140374 antiviral innate immune response
IDA
PMID:18248090
TRIM E3 ligases interfere with early and late stages of the ... 		KEEP AS NON CORE
Summary: Direct evidence from the TRIM antiretroviral screen that TRIM13 functions in antiviral responses.
Reason: Experimentally supported but a secondary role relative to the core ERAD/autophagy ligase function. Defer to curator who read the full text.
Supporting Evidence:
PMID:18248090
Members of the TRIpartite interaction Motif (TRIM) family of E3 ligases have been shown to exhibit antiviral activities
GO:0016567 protein ubiquitination
IEA
GO_REF:0000041 		KEEP AS NON CORE
Summary: UniPathway-derived general protein ubiquitination process.
Reason: Correct but generic; the specific proteasome-mediated catabolism and autoubiquitination annotations better capture the activity.
Supporting Evidence:
file:human/TRIM13/TRIM13-uniprot.txt
PATHWAY: Protein modification; protein ubiquitination.
GO:0061630 ubiquitin protein ligase activity
TAS
Reactome:R-HSA-8867288 		ACCEPT
Summary: Reactome curation of TRIM13 ubiquitin ligase activity in the ERAD pathway. Core MF.
Reason: Core molecular function; consistent with experimental ERAD E3 ligase activity.
Supporting Evidence:
file:human/TRIM13/TRIM13-uniprot.txt
The RING-type zinc finger is required for auto-
GO:1904380 endoplasmic reticulum mannose trimming
TAS
Reactome:R-HSA-901032 		MARK AS OVER ANNOTATED
Summary: Reactome pathway-context placement of TRIM13 within ER quality control; mannose trimming itself is performed by ER mannosidases, not TRIM13.
Reason: TRIM13 is the ubiquitin ligase step of ERAD, not the glycan-trimming enzyme; this BP reflects pathway co-membership rather than a TRIM13 activity.
Supporting Evidence:
file:human/TRIM13/TRIM13-uniprot.txt
associated degradation (ERAD). This process acts on misfolded proteins
GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process
IDA
PMID:21333377
Ret finger protein 2 enhances ionizing radiation-induced apo... 		ACCEPT
Summary: Direct evidence that TRIM13 drives proteasomal degradation of substrates (MDM2, AKT1). Core process.
Reason: Core biological process; TRIM13 ubiquitinates substrates for proteasomal degradation.
Supporting Evidence:
file:human/TRIM13/TRIM13-uniprot.txt
and leads to its proteasomal degradation. Interacts with p62/SQSTM1.
GO:0061659 ubiquitin-like protein ligase activity
IDA
PMID:21333377
Ret finger protein 2 enhances ionizing radiation-induced apo... 		ACCEPT
Summary: Direct evidence of E3 ligase activity (ubiquitinating MDM2/AKT1). Core MF.
Reason: Core molecular function; TRIM13 RING-dependent ligase activity, demonstrated experimentally.
Supporting Evidence:
file:human/TRIM13/TRIM13-uniprot.txt
The RING-type zinc finger is required for auto-
GO:0005789 endoplasmic reticulum membrane
EXP
PMID:25152375
TRIM13 regulates ubiquitination and turnover of NEMO to supp... 		ACCEPT
Summary: Experimental evidence of ER membrane localization in the NEMO/NF-kB study. Core localization.
Reason: Core cellular component, experimentally demonstrated.
Supporting Evidence:
file:human/TRIM13/TRIM13-uniprot.txt
Endoplasmic reticulum membrane
GO:0003713 transcription coactivator activity
IDA
PMID:23077300
TRIM protein-mediated regulation of inflammatory and innate ... 		MARK AS OVER ANNOTATED
Summary: Assigned from a TRIM-family NF-kB/AP-1 activation screen; reflects TRIM13-driven NF-kB signaling rather than direct transcriptional coactivation.
Reason: TRIM13 acts upstream as an E3 ligase modulating NF-kB signaling, not as a DNA-associated transcription coactivator; this MF over-interprets the signaling phenotype.
Supporting Evidence:
file:human/TRIM13/TRIM13-uniprot.txt
Also plays a role in innate immune response by stimulating NF-kappa-B
GO:0044790 suppression of viral release by host
IDA
PMID:18248090
TRIM E3 ligases interfere with early and late stages of the ... 		KEEP AS NON CORE
Summary: Direct evidence from the TRIM screen that TRIM13 affects late stages of the retroviral life cycle (viral release).
Reason: Experimentally supported but a secondary antiviral role relative to the core ERAD/autophagy ligase function. Defer to curator.
Supporting Evidence:
PMID:18248090
many TRIM proteins affected late stages of the viral life cycle
GO:0005789 endoplasmic reticulum membrane
TAS
Reactome:R-HSA-8867288 		ACCEPT
Summary: Reactome curation of ER membrane localization in the ERAD pathway. Core localization.
Reason: Core cellular component; consistent with experimental ER membrane localization.
Supporting Evidence:
file:human/TRIM13/TRIM13-uniprot.txt
Endoplasmic reticulum membrane
GO:0043123 positive regulation of canonical NF-kappaB signal transduction
IDA
PMID:23077300
TRIM protein-mediated regulation of inflammatory and innate ... 		KEEP AS NON CORE
Summary: Direct evidence (TRIM-family NF-kB activation screen) that TRIM13 positively regulates NF-kB signaling.
Reason: Supported (TLR2/TRAF6 axis) but context-dependent and secondary to the core ERAD/autophagy function.
Supporting Evidence:
file:human/TRIM13/TRIM13-uniprot.txt
activity in the TLR2 signaling pathway. Ubiquitinates TRAF6 via the
GO:0005515 protein binding
IPI
PMID:22178386
TRIM13 regulates ER stress induced autophagy and clonogenic ... 		KEEP AS NON CORE
Summary: Interaction with SQSTM1/p62 (Q13501) in the ER-stress autophagy study. Bare protein binding is uninformative.
Reason: Records a real, functionally relevant SQSTM1 interaction but bare protein binding is uninformative.
Supporting Evidence:
file:human/TRIM13/TRIM13-uniprot.txt
and leads to its proteasomal degradation. Interacts with p62/SQSTM1.
GO:0016239 positive regulation of macroautophagy
IDA
PMID:22178386
TRIM13 regulates ER stress induced autophagy and clonogenic ... 		ACCEPT
Summary: Direct evidence that TRIM13 positively regulates ER-stress-induced autophagy. Core process.
Reason: Core biological process; TRIM13 (coiled-coil-dependent) induces autophagy during ER stress.
Supporting Evidence:
PMID:22178386
TRIM13 regulates ER stress induced autophagy and clonogenic ability of the
GO:0097038 perinuclear endoplasmic reticulum
IDA
PMID:22178386
TRIM13 regulates ER stress induced autophagy and clonogenic ... 		ACCEPT
Summary: Direct evidence of perinuclear ER localization (colocalizing with SQSTM1/ZFYVE1). Core localization sub-compartment.
Reason: Experimentally supported localization consistent with the ER-membrane/perinuclear ER site of action.
Supporting Evidence:
file:human/TRIM13/TRIM13-uniprot.txt
Concentrates and colocalizes with p62/SQSTM1 and ZFYVE1 at the
GO:0005515 protein binding
IPI
PMID:21333377
Ret finger protein 2 enhances ionizing radiation-induced apo... 		KEEP AS NON CORE
Summary: Interactions with substrates AKT1 (P31749) and MDM2 (Q00987) in the radiation/apoptosis study. Bare protein binding is uninformative.
Reason: Records real substrate interactions (AKT1, MDM2) but bare protein binding is uninformative.
Supporting Evidence:
file:human/TRIM13/TRIM13-uniprot.txt
and leads to its proteasomal degradation. Interacts with p62/SQSTM1.
GO:0097038 perinuclear endoplasmic reticulum
IDA
PMID:17314412
The RBCC gene RFP2 (Leu5) encodes a novel transmembrane E3 u... 		ACCEPT
Summary: Direct evidence of perinuclear ER localization in the founding ERAD study. Core localization sub-compartment.
Reason: Experimentally supported localization consistent with the ER membrane site of action.
Supporting Evidence:
file:human/TRIM13/TRIM13-uniprot.txt
Concentrates and colocalizes with p62/SQSTM1 and ZFYVE1 at the
GO:0005515 protein binding
IPI
PMID:17314412
The RBCC gene RFP2 (Leu5) encodes a novel transmembrane E3 u... 		KEEP AS NON CORE
Summary: Interaction with VCP/p97 (P55072) in the ERAD study. Bare protein binding is uninformative.
Reason: Records a real, functionally central ERAD partner interaction (VCP) but bare protein binding is uninformative.
Supporting Evidence:
file:human/TRIM13/TRIM13-uniprot.txt
Interacts (via C-terminal domain) with VCP. Interacts with
GO:0036503 ERAD pathway
IDA
PMID:17314412
The RBCC gene RFP2 (Leu5) encodes a novel transmembrane E3 u... 		ACCEPT
Summary: Direct evidence (founding study) that TRIM13 is a transmembrane E3 ligase functioning in ERAD. Core process.
Reason: Core biological process directly demonstrated; TRIM13 functions in ER-associated degradation.
Supporting Evidence:
PMID:17314412
The RBCC gene RFP2 (Leu5) encodes a novel transmembrane E3 ubiquitin ligase
GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process
IDA
PMID:17314412
The RBCC gene RFP2 (Leu5) encodes a novel transmembrane E3 u... 		ACCEPT
Summary: Direct evidence that TRIM13 mediates proteasomal degradation of ERAD substrates. Core process.
Reason: Core biological process; TRIM13 ubiquitinates ERAD substrates for proteasomal degradation.
Supporting Evidence:
file:human/TRIM13/TRIM13-uniprot.txt
associated degradation (ERAD). This process acts on misfolded proteins
GO:0051865 protein autoubiquitination
IDA
PMID:17314412
The RBCC gene RFP2 (Leu5) encodes a novel transmembrane E3 u... 		ACCEPT
Summary: Direct evidence that TRIM13 autopolyubiquitinates (RING-dependent), leading to its own proteasomal turnover. Core activity.
Reason: Core biological process; RING-dependent autoubiquitination is a hallmark of TRIM13 ligase activity.
Supporting Evidence:
file:human/TRIM13/TRIM13-uniprot.txt
The RING-type zinc finger is required for auto-
GO:0004842 ubiquitin-protein transferase activity
IDA
PMID:17314412
The RBCC gene RFP2 (Leu5) encodes a novel transmembrane E3 u... 		ACCEPT
Summary: Direct evidence of ubiquitin-protein transferase (E3 ligase) activity. Core MF.
Reason: Core molecular function; demonstrated RING E3 ligase activity.
Supporting Evidence:
PMID:17314412
The RBCC gene RFP2 (Leu5) encodes a novel transmembrane E3 ubiquitin ligase
GO:0005789 endoplasmic reticulum membrane
IDA
PMID:17314412
The RBCC gene RFP2 (Leu5) encodes a novel transmembrane E3 u... 		ACCEPT
Summary: Direct evidence (founding study) that TRIM13 localizes to the ER membrane. Core localization.
Reason: Core cellular component; TRIM13 is anchored in the ER membrane via its C-terminal transmembrane domain.
Supporting Evidence:
file:human/TRIM13/TRIM13-uniprot.txt
Endoplasmic reticulum membrane
GO:0043123 positive regulation of canonical NF-kappaB signal transduction
HMP
PMID:12761501
Large-scale identification and characterization of human gen... 		KEEP AS NON CORE
Summary: High-throughput functional screen identifying TRIM13/RFP2 among genes that activate NF-kB signaling.
Reason: Supported (NF-kB activation), but context-dependent and from a large-scale overexpression screen; secondary to the core ERAD/autophagy role.
Supporting Evidence:
file:human/TRIM13/TRIM13-uniprot.txt
Also plays a role in innate immune response by stimulating NF-kappa-B

Core Functions

Functions as an ER membrane-anchored RING-type E3 ubiquitin ligase in ER-associated degradation (ERAD), ubiquitinating misfolded membrane and secretory proteins (and some regulated substrates such as AKT1 and MDM2) and cooperating with VCP/p97 to target them for proteasomal degradation.

Molecular Function:
ubiquitin protein ligase activity
Directly Involved In:
ERAD pathway proteasome-mediated ubiquitin-dependent protein catabolic process
Cellular Locations:
endoplasmic reticulum membrane
Supporting Evidence:
  • PMID:17314412
    The RBCC gene RFP2 (Leu5) encodes a novel transmembrane E3 ubiquitin ligase
  • file:human/TRIM13/TRIM13-uniprot.txt
    associated degradation (ERAD). This process acts on misfolded proteins

Positively regulates ER-stress-induced autophagy/reticulophagy via its coiled-coil domain, concentrating at the perinuclear ER with SQSTM1/p62 and ZFYVE1/DFCP1.

Molecular Function:
ubiquitin protein ligase activity
Directly Involved In:
positive regulation of macroautophagy
Cellular Locations:
perinuclear endoplasmic reticulum
Supporting Evidence:
  • PMID:22178386
    TRIM13 regulates ER stress induced autophagy and clonogenic ability of the

References

GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000003
Gene Ontology annotation based on Enzyme Commission mapping
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000041
Gene Ontology annotation based on UniPathway vocabulary mapping
GO_REF:0000044
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
GO_REF:0000107
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
GO_REF:0000108
Automatic assignment of GO terms using logical inference, based on on inter-ontology links
PMID:12761501
Large-scale identification and characterization of human genes that activate NF-kappaB and MAPK signaling pathways.
  • TRIM13/RFP2 was identified in a large-scale screen of human genes that activate NF-kappaB and MAPK signaling.
PMID:17314412
The RBCC gene RFP2 (Leu5) encodes a novel transmembrane E3 ubiquitin ligase involved in ERAD.
  • TRIM13/RFP2 is an ER membrane-anchored RING transmembrane E3 ubiquitin ligase that functions in ER-associated degradation (ERAD), undergoes RING-dependent autoubiquitination, and localizes to the perinuclear ER.
PMID:18248090
TRIM E3 ligases interfere with early and late stages of the retroviral life cycle.
  • Screen of TRIM E3 ligases for antiretroviral activity; several TRIMs (including TRIM13) affect late stages (viral release) of the retroviral life cycle.
PMID:21333377
Ret finger protein 2 enhances ionizing radiation-induced apoptosis via degradation of AKT and MDM2.
  • TRIM13/RFP2 ubiquitinates and degrades MDM2 and AKT1, enhancing ionizing-radiation-induced p53 stabilization and apoptosis.
PMID:22178386
TRIM13 regulates ER stress induced autophagy and clonogenic ability of the cells.
  • TRIM13 positively regulates ER-stress-induced autophagy (coiled-coil-dependent), colocalizes with SQSTM1/p62 and ZFYVE1 at the perinuclear ER, and influences clonogenic ability (tumor-suppressor-like).
PMID:23077300
TRIM protein-mediated regulation of inflammatory and innate immune signaling and its association with antiretroviral activity.
  • TRIM13 was among TRIMs that activate NF-kB/AP-1 signaling in a family-wide screen.
PMID:25152375
TRIM13 regulates ubiquitination and turnover of NEMO to suppress TNF induced NF-ฮบB activation.
  • In the presence of TNF, TRIM13 regulates IKBKG/NEMO ubiquitination and turnover to repress NF-kB activation, demonstrating a context-dependent negative role in NF-kB signaling.
Reactome:R-HSA-8867288
OS9:SEL1:ERAD E3 ligase:DERL2 ubiquitinates unfolded protein:(GlcNAc)2 (Man)9-5
Reactome:R-HSA-901032
ER Quality Control Compartment (ERQC)

Suggested Questions for Experts

Q: How is the direction of TRIM13's effect on NF-kB signaling (TLR2/TRAF6-mediated activation versus TNF/NEMO-mediated repression) determined by stimulus and cellular context?

Q: What are the endogenous ERAD substrates of TRIM13, and how does its ERAD ligase activity mechanistically connect to its role in inducing ER-stress autophagy/reticulophagy?

Suggested Experiments

Experiment: Perform substrate-trapping ubiquitinome/proteomics in TRIM13-knockout versus wild-type cells under ER stress to define the endogenous ERAD substrate repertoire and distinguish it from the regulated substrates (AKT1, MDM2, NEMO, TRAF6).

Experiment: Use coiled-coil and RING domain-specific TRIM13 mutants to separate its ERAD ligase activity from its ER-stress autophagy-inducing activity and test which is required for the proposed tumor-suppressor phenotype.

๐Ÿ“š Additional Documentation

Notes

(TRIM13-notes.md)

TRIM13 (RFP2 / Leu5) review notes

UniProt: O60858 (TRIM13_HUMAN). EC=2.3.2.27 (RING-type E3). TRIM/RBCC family.
ER membrane-anchored, single-pass membrane protein. Chromosome 13 (B-CLL minimal deletion region).

Domain architecture

  • RING-type zinc finger -> E3 ligase activity; required for autopolyubiquitination [UniProt DOMAIN]
  • B-box + coiled-coil (coiled-coil required for induction of autophagy during ER stress) [UniProt DOMAIN]
  • C-terminal transmembrane domain -> indispensable for ER localization [UniProt DOMAIN]
    (No PRYSPRY; differs from TRIM5.)

Core functions (UniProt FUNCTION + experimental)

  1. ER membrane-anchored E3 ubiquitin ligase in ERAD: retrotranslocation/turnover of membrane and secretory proteins from the ER; acts on misfolded and regulated correctly-folded proteins. Interacts (via C-terminal domain) with VCP/p97. [PMID:17314412 "novel transmembrane E3 ubiquitin ligase involved in ERAD"; UniProt]
  2. Supports GO:0036503 ERAD pathway (IDA, IBA), GO:0004842 ubiquitin-protein transferase (IDA), GO:0061659 ubiquitin-like protein ligase activity (IDA), GO:0043161 proteasome-mediated Ub-dependent catabolism (IDA), GO:0051865 protein autoubiquitination (IDA), GO:0005789 ER membrane (IDA/EXP).
  3. Regulates ER-stress-induced autophagy / reticulophagy; coiled-coil required; colocalizes with p62/SQSTM1 and ZFYVE1 (DFCP1) at perinuclear ER; may act as tumor suppressor. PMID:22178386
  4. Supports GO:0016239 positive regulation of macroautophagy (IDA, IBA), GO:0097038 perinuclear ER (IDA).
  5. Apoptosis/DNA-damage: enhances ionizing-radiation-induced p53 stability and apoptosis by ubiquitinating MDM2 and AKT1 -> their proteasomal degradation, decreasing AKT1 kinase activity. PMID:21333377
  6. NF-kB signaling - bidirectional:
  7. Positive: stimulates NF-kB in TLR2 pathway; ubiquitinates TRAF6 via K29 chains -> NF-kB activation (PMID:28087809); participates in TCR-mediated NF-kB activation (PMID:25088585). HMP screen (PMID:12761501) and IDA (PMID:23077300) report TRIM13 activates NF-kB.
  8. Negative: in presence of TNF, modulates IKK complex by regulating IKBKG/NEMO ubiquitination -> represses NF-kB (PMID:25152375 "TRIM13 regulates ubiquitination and turnover of NEMO to suppress TNF induced NF-kB activation").
  9. The existing positive-regulation-of-NF-kB annotations (GO:0043123) are supported (TLR2/TRAF6). Keep, with note that TRIM13 is context-dependent.
  10. Antiviral: in a broad TRIM screen (PMID:18248090), TRIM13 affected late stages of the retroviral life cycle (viral release). Also "negative regulation of viral transcription" (UniProt DR GO). The antiviral role is real but secondary/context.
  11. GO:0140374 antiviral innate immune response (IDA PMID:18248090), GO:0044790 suppression of viral release by host (IDA PMID:18248090).

Localization

  • ER membrane (single-pass TM), perinuclear ER; concentrates with SQSTM1 and ZFYVE1. [UniProt; PMID:17314412; PMID:22178386]
  • GO:0005737 cytoplasm (IBA/IEA) - generic; the specific localization is ER membrane.
  • GO:0044322 ER quality control compartment (IEA GOC, inter-ontology from ERAD) - reasonable for an ERAD ligase.

Notes on specific annotations

  • GO:0003713 transcription coactivator activity (IDA PMID:23077300, ARUK-UCL): same caveat as TRIM5 - reflects NF-kB activation in a TRIM screen, not direct transcriptional coactivation. MARK_AS_OVER_ANNOTATED. NOTE: the YAML stub does NOT include this annotation in existing_annotations (it's in UniProt DR but not GOA stub), so only review what's present.
  • GO:1904380 ER mannose trimming (TAS Reactome R-HSA-901032): TRIM13 placed in ERAD/ERQC Reactome pathway; mannose trimming itself is done by mannosidases, not TRIM13. This is a pathway-context over-annotation. MARK_AS_OVER_ANNOTATED.
  • GO:0061630 ubiquitin protein ligase activity (multiple: IBA, IEA EC, TAS Reactome): core. ACCEPT representative; others ACCEPT/KEEP redundant.
  • GO:0045893 positive regulation of DNA-templated transcription (IEA GO_REF:0000108): inter-ontology inference from transcription coactivator activity; over-annotation (TRIM13 not a direct transcriptional activator). MARK_AS_OVER_ANNOTATED.
  • protein binding (GO:0005515) IPI: AKT1 (P31749), MDM2 (Q00987), VCP (P55072 - actually P55072 is VCP), Bcl2/Q13501? (PMID:22178386 with UniProtKB:Q13501 = SQSTM1? no, Q13501 = SQSTM1/p62). Bare protein binding -> KEEP_AS_NON_CORE.
  • PMID:21333377 IPI with P31749 (AKT1) and Q00987 (MDM2): substrate interactions.
  • PMID:17314412 IPI with P55072 (VCP/p97): ERAD partner.
  • PMID:22178386 IPI with Q13501 (SQSTM1/p62): autophagy partner.

GO IDs verified relevant

  • GO:0036503 ERAD pathway (core BP)
  • GO:0061630 / GO:0004842 / GO:0061659 ubiquitin ligase/transferase (core MF)
  • GO:0016239 positive regulation of macroautophagy
  • GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process
  • GO:0051865 protein autoubiquitination
  • GO:0005789 endoplasmic reticulum membrane (core CC)
  • GO:0097038 perinuclear endoplasmic reticulum
  • GO:0043123 positive regulation of canonical NF-kappaB signal transduction (supported, context-dependent)

Pn Notes

(TRIM13-pn-notes.md)

TRIM13 PN Consistency Notes

  • Generated: 2026-06-18
  • Project: PROTEOSTASIS
  • Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
  • UniProt: O60858
  • AIGR review status: COMPLETE
  • Review batch: proteostasis-batch-2026-06-14
  • Batch change status: added

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AIGR Review Snapshot

  • Description: TRIM13 (RFP2/Leu5) is an endoplasmic reticulum (ER) membrane-anchored RING-type E3 ubiquitin ligase of the TRIM/RBCC family. Unlike cytosolic TRIMs it has an N-terminal RING-type zinc finger (conferring E3 ubiquitin ligase activity, EC 2.3.2.27, and required for its autopolyubiquitination), a B-box and a coiled-coil (the coiled-coil is required for induction of autophagy during ER stress), and a C-terminal transmembrane domain that anchors it as a single-pass protein in the ER membrane, concentrating at the perinuclear ER. Its best-defined role is in ER-associated degradation (ERAD): it participates in the retrotranslocation and turnover of misfolded membrane and secretory proteins (as well as regulated degradation of some correctly folded proteins) from the ER, working with the AAA-ATPase VCP/p97 (which it binds via its C-terminal domain) to deliver substrates for proteasomal degradation. TRIM13 also regulates ER-stress-induced autophagy/reticulophagy, colocalizing with SQSTM1/p62 and ZFYVE1/DFCP1 at the perinuclear ER and positively regulating macroautophagy, and has been proposed as a tumor suppressor (it lies in the minimal deletion region for B-cell chronic lymphocytic leukemia on chromosome 13). Additional reported activities include enhancing ionizing-radiation-induced p53 stabilization and apoptosis by ubiquitinating and degrading MDM2 and AKT1, and context-dependent modulation of NF-kappaB signaling: it can positively activate NF-kappaB through the TLR2 pathway (K29-linked ubiquitination of TRAF6) and in T-cell receptor signaling, but can also repress TNF-induced NF-kappaB by regulating ubiquitination and turnover of IKBKG/NEMO. It has further been implicated in antiviral responses affecting late stages of the retroviral life cycle.
  • Existing/core annotation action counts: ACCEPT: 18; KEEP_AS_NON_CORE: 14; MARK_AS_OVER_ANNOTATED: 3

PN Consistency Summary

  • Consistency: Strongly consistent. PN (ER-membrane RING E3 ligase in ERAD + ERphagy marker), review, and notes all agree: TRIM13 is a single-pass ER-membrane RING E3 (functional RING, PMID:17314412) working with VCP/p97 in ERAD, and a positive regulator of ER-stress-induced autophagy/reticulophagy colocalizing with SQSTM1/ZFYVE1 (PMID:22178386). Genuine catalytic RING โ†’ catalytic ligase MF is correct. No contradictions.
  • PN story / NEW pressure: Two stories: (1) ERAD/RING-ligase โ€” already_in_goa_exact (GOA has GO:0036503 ERAD IDA+IBA and GO:0061630/0004842 ligase) โ†’ already captured. (2) ERphagy/reticulophagy โ€” GO:0061709 reticulophagy verified real and confirmed NOT in GOA (GOA has only ERAD). The review captures this as GO:0016239 positive regulation of macroautophagy (ACCEPT, IDA PMID:22178386), so the autophagy role is partly captured but at a less specific altitude than reticulophagy. Defensible ADD: GO:0061709 reticulophagy (or regulation thereof, GO:0140500). Note TRIM13's reticulophagy evidence is "positively regulates ER-stress autophagy" โ†’ regulation of reticulophagy (GO:0140500, verified real) may fit better than the bare process.
  • Evidence alignment: Strong overlap. PN ERphagy titles (Regulatory events controlling ER-phagy; N-Degron Pathway Mediates ER-phagy) are reviews; the review's reticulophagy anchor is the experimental PMID:22178386. RING-node refs 33791238/19489725 are TRIM/E3 reviews. Review refs (PMID:17314412, 22178386, 21333377, 25152375) cover ERAD + autophagy + substrate + NF-kB arms.
  • Verdict: Consistent; ERAD/RING already captured; reticulophagy ADD warranted (regulatory framing preferable). Recommended edits: [YAML] add GO:0061709 reticulophagy (or GO:0140500 regulation of reticulophagy, matching the regulatory evidence) involved_in, supported by PMID:22178386 โ€” currently new_to_goa and more specific than the existing GO:0016239.

Full Consistency Review

  • UniProt: O60858 (RFP2/Leu5) ยท batch: proteostasis-batch-2026-06-14 ยท review status: COMPLETE (thorough)
  • PN placement: 3 rows โ€” ER proteostasis|Organelle-specific protein degradation|ER associated degradation|Cytosolic handling of ERAD substrates|ERAD-associated RING E3 ligase; ALP|...|Marking substrates for selective autophagy|ERphagy|Ubiquitination of ER proteins; UPS|E3 ubiquitin and UBL ligases|RING|TRIM / class XI|transmembrane. PN-node mapping: ERAD group โ†’ mapped/exact GO:0036503 ERAD pathway (already_in_goa_exact); ERAD subtype RING โ†’ mapped GO:0061630 (already_in_goa_exact); ERphagy type+subtype โ†’ mapped/ok GO:0061709 reticulophagy (new_to_goa, x2); RING group โ†’ GO:0061630 (already_in_goa_exact).
  • Consistency: Strongly consistent. PN (ER-membrane RING E3 ligase in ERAD + ERphagy marker), review, and notes all agree: TRIM13 is a single-pass ER-membrane RING E3 (functional RING, PMID:17314412) working with VCP/p97 in ERAD, and a positive regulator of ER-stress-induced autophagy/reticulophagy colocalizing with SQSTM1/ZFYVE1 (PMID:22178386). Genuine catalytic RING โ†’ catalytic ligase MF is correct. No contradictions.
  • PN story / NEW pressure: Two stories: (1) ERAD/RING-ligase โ€” already_in_goa_exact (GOA has GO:0036503 ERAD IDA+IBA and GO:0061630/0004842 ligase) โ†’ already captured. (2) ERphagy/reticulophagy โ€” GO:0061709 reticulophagy verified real and confirmed NOT in GOA (GOA has only ERAD). The review captures this as GO:0016239 positive regulation of macroautophagy (ACCEPT, IDA PMID:22178386), so the autophagy role is partly captured but at a less specific altitude than reticulophagy. Defensible ADD: GO:0061709 reticulophagy (or regulation thereof, GO:0140500). Note TRIM13's reticulophagy evidence is "positively regulates ER-stress autophagy" โ†’ regulation of reticulophagy (GO:0140500, verified real) may fit better than the bare process.
  • Mapping strategy: No node change needed. ERAD=exact and RING=exact are correct (catalytic RING, genuinely ERAD). The reticulophagy projection is appropriately new_to_goa; consider whether the PN should project regulation of reticulophagy given the evidence is regulatory rather than TRIM13-as-receptor.
  • Evidence alignment: Strong overlap. PN ERphagy titles (Regulatory events controlling ER-phagy; N-Degron Pathway Mediates ER-phagy) are reviews; the review's reticulophagy anchor is the experimental PMID:22178386. RING-node refs 33791238/19489725 are TRIM/E3 reviews. Review refs (PMID:17314412, 22178386, 21333377, 25152375) cover ERAD + autophagy + substrate + NF-kB arms.
  • Verdict: Consistent; ERAD/RING already captured; reticulophagy ADD warranted (regulatory framing preferable). Recommended edits: [YAML] add GO:0061709 reticulophagy (or GO:0140500 regulation of reticulophagy, matching the regulatory evidence) involved_in, supported by PMID:22178386 โ€” currently new_to_goa and more specific than the existing GO:0016239.

PN Dossier Context

  • review_batch: proteostasis-batch-2026-06-14
  • review_yaml: genes/human/TRIM13/TRIM13-ai-review.yaml
  • PN workbook rows: 3

PN row 1: ER proteostasis | Organelle-specific protein degradation | ER associated degradation | Cytosolic handling of ERAD substrates | ERAD-associated RING E3 ligase

  • UniProt: O60858
  • In branches: ER, ALP, UPS
  • PN-node mapping records (path + ancestors):
    • [subtype] ER proteostasis|Organelle-specific protein degradation|ER associated degradation|Cytosolic handling of ERAD substrates|ERAD-associated RING E3 ligase
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0061630 ubiquitin protein ligase activity]
      rationale: This PN subtype denotes ERAD-associated RING E3 ligases. Ubiquitin protein ligase activity is the appropriate shared catalytic target.
    • [type] ER proteostasis|Organelle-specific protein degradation|ER associated degradation|Cytosolic handling of ERAD substrates
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0036503 ERAD pathway]
      rationale: This PN type covers the cytosolic processing steps that receive ERAD substrates after retrotranslocation. These activities remain part of the ERAD pathway, but the source category is a specific mechanistic slice.
    • [group] ER proteostasis|Organelle-specific protein degradation|ER associated degradation
      status=mapped scope=exact GO=[GO:0036503 ERAD pathway]
      rationale: The PN group "ER associated degradation" is a direct lexical and biological match to the GO ERAD pathway term. The additional branch and class context disambiguates the source string from any broader degradation language.
    • [class] ER proteostasis|Organelle-specific protein degradation
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a broad PN category rather than a single GO class. The member genes span multiple activities, complexes, or contexts, so direct propagation from this node would overstate the shared biology.
    • [branch] ER proteostasis
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a top-level PN branch. This is a systems/taxonomy umbrella, not a direct GO assertion; narrower child curations carry any propagating GO mappings.

PN row 2: Autophagy-Lysosome Pathway | Autophagy substrate selection | Marking substrates for selective autophagy | ERphagy | Ubiquitination of ER proteins

  • UniProt: O60858
  • In branches: ER, ALP, UPS
  • Notes: ER-membrane E3-ligase that self-ubiquitinates and recruits SQSTM1 to damaged ER for ERphagy
  • PN references (titles):
    • Regulatory events controlling ER-phagy - ScienceDirect
    • The N-Degron Pathway Mediates ER-phagy - ScienceDirect
  • PN-node mapping records (path + ancestors):
    • [subtype] Autophagy-Lysosome Pathway|Autophagy substrate selection|Marking substrates for selective autophagy|ERphagy|Ubiquitination of ER proteins
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0061709 reticulophagy]
      rationale: This PN subtype denotes ubiquitin-based marking of ER cargo within the ERphagy pathway. The subtype is one mechanistic route into reticulophagy rather than a separate GO process.
    • [type] Autophagy-Lysosome Pathway|Autophagy substrate selection|Marking substrates for selective autophagy|ERphagy
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0061709 reticulophagy]
      rationale: The PN ERphagy marking category captures factors that mark ER cargo for selective autophagic turnover. GO uses reticulophagy for this pathway, so propagation to reticulophagy is appropriate.
    • [group] Autophagy-Lysosome Pathway|Autophagy substrate selection|Marking substrates for selective autophagy
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a broad PN taxonomy container. The descendants mix components, regulators, context labels, and mechanistic leaves, so propagation should come only from narrower curated nodes.
    • [class] Autophagy-Lysosome Pathway|Autophagy substrate selection
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a broad substrate-selection container. GO has useful targets for specific receptor, cargo-adaptor, and selective-autophagy leaves, but this class mixes marking, recognition, receptor regulation, and unknown roles and should not propagate as one term.
    • [branch] Autophagy-Lysosome Pathway
      status=no_mapping scope= GO=[]
      rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

PN row 3: Ubiquitin Proteasome System | E3 ubiquitin and UBL ligases | RING | TRIM / class XI | transmembrane

  • UniProt: O60858
  • In branches: ER, ALP, UPS
  • Signature domains: IPR001841
  • Auxiliary domains: (none)
  • PN references (titles):
    • 33791238 / rev
    • 19489725 / rev
  • PN-node mapping records (path + ancestors):
    • [subtype] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|RING|TRIM / class XI|transmembrane
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a narrower E3-ligase architecture, component, or domain subdivision already covered by the curated parent E3 mapping. No additional direct GO mapping is needed at this node.
    • [type] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|RING|TRIM / class XI
      status=no_mapping scope= GO=[]
      rationale: Reviewed as a narrower E3-ligase architecture, component, or domain subdivision already covered by the curated parent E3 mapping. No additional direct GO mapping is needed at this node.
    • [group] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|RING
      status=mapped scope=ok_for_propagation_to_go GO=[GO:0061630 ubiquitin protein ligase activity]
      rationale: This PN group is a catalytic ubiquitin E3 ligase bucket. The shared GO molecular-function target is ubiquitin protein ligase activity.
    • [class] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases
      status=context_only scope=too_broad_to_propagate GO=[GO:0061630 ubiquitin protein ligase activity]
      rationale: This class is a genuine E3-ligase context, but its descendants include catalytic ligases, cullin scaffolds, substrate receptors, adaptors, cofactors, regulators, and UBL modifier systems. A class-level propagation would over-annotate.
    • [branch] Ubiquitin Proteasome System
      status=no_mapping scope= GO=[]
      rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.

Projected GO annotations (6)

  • GO:0036503 ERAD pathway | scope=exact | goa_status=already_in_goa_exact | from=ER proteostasis|Organelle-specific protein degradation|ER associated degradation
  • GO:0036503 ERAD pathway | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=ER proteostasis|Organelle-specific protein degradation|ER associated degradation|Cytosolic handling of ERAD substrates
  • GO:0061630 ubiquitin protein ligase activity | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=ER proteostasis|Organelle-specific protein degradation|ER associated degradation|Cytosolic handling of ERAD substrates|ERAD-associated RING E3 ligase
  • GO:0061709 reticulophagy | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Autophagy-Lysosome Pathway|Autophagy substrate selection|Marking substrates for selective autophagy|ERphagy
  • GO:0061709 reticulophagy | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Autophagy-Lysosome Pathway|Autophagy substrate selection|Marking substrates for selective autophagy|ERphagy|Ubiquitination of ER proteins
  • GO:0061630 ubiquitin protein ligase activity | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|RING

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

๐Ÿ“„ View Raw YAML

 
id: O60858
gene_symbol: TRIM13
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  TRIM13 (RFP2/Leu5) is an endoplasmic reticulum (ER) membrane-anchored RING-type
  E3 ubiquitin ligase of the TRIM/RBCC family. Unlike cytosolic TRIMs it has an
  N-terminal RING-type zinc finger (conferring E3 ubiquitin ligase activity,
  EC 2.3.2.27, and required for its autopolyubiquitination), a B-box and a
  coiled-coil (the coiled-coil is required for induction of autophagy during ER
  stress), and a C-terminal transmembrane domain that anchors it as a single-pass
  protein in the ER membrane, concentrating at the perinuclear ER. Its best-defined
  role is in ER-associated degradation (ERAD): it participates in the
  retrotranslocation and turnover of misfolded membrane and secretory proteins
  (as well as regulated degradation of some correctly folded proteins) from the
  ER, working with the AAA-ATPase VCP/p97 (which it binds via its C-terminal
  domain) to deliver substrates for proteasomal degradation. TRIM13 also regulates
  ER-stress-induced autophagy/reticulophagy, colocalizing with SQSTM1/p62 and
  ZFYVE1/DFCP1 at the perinuclear ER and positively regulating macroautophagy, and
  has been proposed as a tumor suppressor (it lies in the minimal deletion region
  for B-cell chronic lymphocytic leukemia on chromosome 13). Additional reported
  activities include enhancing ionizing-radiation-induced p53 stabilization and
  apoptosis by ubiquitinating and degrading MDM2 and AKT1, and context-dependent
  modulation of NF-kappaB signaling: it can positively activate NF-kappaB through
  the TLR2 pathway (K29-linked ubiquitination of TRAF6) and in T-cell receptor
  signaling, but can also repress TNF-induced NF-kappaB by regulating
  ubiquitination and turnover of IKBKG/NEMO. It has further been implicated in
  antiviral responses affecting late stages of the retroviral life cycle.
alternative_products:
- name: 1 (Alpha)
  id: O60858-1
- name: 2 (Beta)
  id: O60858-2
  sequence_note: VSP_005746, VSP_005747
- name: '3'
  id: O60858-3
  sequence_note: VSP_038142
existing_annotations:
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic inference of cytoplasmic activity; TRIM13 is more specifically an ER membrane-anchored protein facing the cytoplasm.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the specific and core localization is the ER membrane (single-pass), captured by GO:0005789.
    supported_by:
    - reference_id: file:human/TRIM13/TRIM13-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
- term:
    id: GO:0045087
    label: innate immune response
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic inference of innate immune involvement; TRIM13 modulates NF-kB signaling (TLR2/TRAF6) and antiviral responses.
    action: KEEP_AS_NON_CORE
    reason: Supported (NF-kB/TLR2 modulation, antiviral effects) but a broad term and secondary to the core ERAD/autophagy ligase role.
    supported_by:
    - reference_id: file:human/TRIM13/TRIM13-uniprot.txt
      supporting_text: Also plays a role in innate immune response by stimulating NF-kappa-B
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetic inference of RING E3 ubiquitin ligase activity, consistent with the experimental RING-dependent ligase activity.
    action: ACCEPT
    reason: Core molecular function; TRIM13 is a RING-type E3 ubiquitin ligase.
    supported_by:
    - reference_id: file:human/TRIM13/TRIM13-uniprot.txt
      supporting_text: The RING-type zinc finger is required for auto-
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic inference of involvement in ERAD, consistent with the experimental IDA evidence. Core process.
    action: ACCEPT
    reason: Core biological process; TRIM13 is an ER membrane E3 ligase that functions in ERAD.
    supported_by:
    - reference_id: file:human/TRIM13/TRIM13-uniprot.txt
      supporting_text: associated degradation (ERAD). This process acts on misfolded proteins
- term:
    id: GO:0016239
    label: positive regulation of macroautophagy
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic inference of positive regulation of macroautophagy, consistent with the IDA evidence from the ER-stress autophagy study. Core process.
    action: ACCEPT
    reason: Core biological process; TRIM13 positively regulates ER-stress-induced autophagy/reticulophagy.
    supported_by:
    - reference_id: PMID:22178386
      supporting_text: TRIM13 regulates ER stress induced autophagy and clonogenic ability of the
- term:
    id: GO:0043123
    label: positive regulation of canonical NF-kappaB signal transduction
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic inference of positive regulation of NF-kB signaling, consistent with TLR2/TRAF6 experimental evidence.
    action: KEEP_AS_NON_CORE
    reason: Supported (TLR2/TRAF6 K29-Ub activation) but context-dependent (TRIM13 also represses TNF-induced NF-kB via NEMO) and secondary to the core ERAD/autophagy role.
    supported_by:
    - reference_id: file:human/TRIM13/TRIM13-uniprot.txt
      supporting_text: activity in the TLR2 signaling pathway. Ubiquitinates TRAF6 via the
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic transfer of ER membrane localization from the UniProt subcellular location; the core compartment.
    action: ACCEPT
    reason: Core cellular component; TRIM13 is a single-pass ER membrane protein.
    supported_by:
    - reference_id: file:human/TRIM13/TRIM13-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
- term:
    id: GO:0008270
    label: zinc ion binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro-based electronic assignment of zinc ion binding by the RING/B-box zinc fingers.
    action: KEEP_AS_NON_CORE
    reason: Correct (RING/B-box coordinate Zn2+) and underpins ligase activity, but generic; the informative MF is ubiquitin ligase activity.
    supported_by:
    - reference_id: file:human/TRIM13/TRIM13-uniprot.txt
      supporting_text: The RING-type zinc finger is required for auto-
- term:
    id: GO:0044322
    label: endoplasmic reticulum quality control compartment
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  qualifier: located_in
  review:
    summary: Inter-ontology electronic inference of ERQC localization, consistent with TRIM13's ERAD function at the ER.
    action: KEEP_AS_NON_CORE
    reason: Plausible and consistent with the ERAD role but electronically inferred; the experimentally supported localization is the ER/perinuclear ER membrane.
    supported_by:
    - reference_id: file:human/TRIM13/TRIM13-uniprot.txt
      supporting_text: associated degradation (ERAD). This process acts on misfolded proteins
- term:
    id: GO:0045893
    label: positive regulation of DNA-templated transcription
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  qualifier: involved_in
  review:
    summary: Inter-ontology electronic inference from a transcription coactivator activity annotation.
    action: MARK_AS_OVER_ANNOTATED
    reason: Derived from an over-interpreted transcription coactivator annotation (NF-kB activation phenotype); TRIM13 is an E3 ligase acting upstream in signaling, not a direct DNA-templated transcriptional activator.
    supported_by:
    - reference_id: file:human/TRIM13/TRIM13-uniprot.txt
      supporting_text: Also plays a role in innate immune response by stimulating NF-kappa-B
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000003
  qualifier: enables
  review:
    summary: EC 2.3.2.27-based electronic assignment of ubiquitin protein ligase activity; core function.
    action: ACCEPT
    reason: Core molecular function corroborated by experimental RING-dependent ligase activity.
    supported_by:
    - reference_id: file:human/TRIM13/TRIM13-uniprot.txt
      supporting_text: EC=2.3.2.27
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Ensembl-ortholog electronic transfer of cytoplasmic localization; generic relative to the ER membrane localization.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the specific localization is the ER membrane.
    supported_by:
    - reference_id: file:human/TRIM13/TRIM13-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
- term:
    id: GO:0140374
    label: antiviral innate immune response
  evidence_type: IDA
  original_reference_id: PMID:18248090
  qualifier: involved_in
  review:
    summary: Direct evidence from the TRIM antiretroviral screen that TRIM13 functions in antiviral responses.
    action: KEEP_AS_NON_CORE
    reason: Experimentally supported but a secondary role relative to the core ERAD/autophagy ligase function. Defer to curator who read the full text.
    supported_by:
    - reference_id: PMID:18248090
      supporting_text: Members of the TRIpartite interaction Motif (TRIM) family of E3 ligases have been shown to exhibit antiviral activities
- term:
    id: GO:0016567
    label: protein ubiquitination
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    summary: UniPathway-derived general protein ubiquitination process.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the specific proteasome-mediated catabolism and autoubiquitination annotations better capture the activity.
    supported_by:
    - reference_id: file:human/TRIM13/TRIM13-uniprot.txt
      supporting_text: 'PATHWAY: Protein modification; protein ubiquitination.'
- term:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8867288
  qualifier: enables
  review:
    summary: Reactome curation of TRIM13 ubiquitin ligase activity in the ERAD pathway. Core MF.
    action: ACCEPT
    reason: Core molecular function; consistent with experimental ERAD E3 ligase activity.
    supported_by:
    - reference_id: file:human/TRIM13/TRIM13-uniprot.txt
      supporting_text: The RING-type zinc finger is required for auto-
- term:
    id: GO:1904380
    label: endoplasmic reticulum mannose trimming
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-901032
  qualifier: involved_in
  review:
    summary: Reactome pathway-context placement of TRIM13 within ER quality control; mannose trimming itself is performed by ER mannosidases, not TRIM13.
    action: MARK_AS_OVER_ANNOTATED
    reason: TRIM13 is the ubiquitin ligase step of ERAD, not the glycan-trimming enzyme; this BP reflects pathway co-membership rather than a TRIM13 activity.
    supported_by:
    - reference_id: file:human/TRIM13/TRIM13-uniprot.txt
      supporting_text: associated degradation (ERAD). This process acts on misfolded proteins
- term:
    id: GO:0043161
    label: proteasome-mediated ubiquitin-dependent protein catabolic process
  evidence_type: IDA
  original_reference_id: PMID:21333377
  qualifier: involved_in
  review:
    summary: Direct evidence that TRIM13 drives proteasomal degradation of substrates (MDM2, AKT1). Core process.
    action: ACCEPT
    reason: Core biological process; TRIM13 ubiquitinates substrates for proteasomal degradation.
    supported_by:
    - reference_id: file:human/TRIM13/TRIM13-uniprot.txt
      supporting_text: and leads to its proteasomal degradation. Interacts with p62/SQSTM1.
- term:
    id: GO:0061659
    label: ubiquitin-like protein ligase activity
  evidence_type: IDA
  original_reference_id: PMID:21333377
  qualifier: enables
  review:
    summary: Direct evidence of E3 ligase activity (ubiquitinating MDM2/AKT1). Core MF.
    action: ACCEPT
    reason: Core molecular function; TRIM13 RING-dependent ligase activity, demonstrated experimentally.
    supported_by:
    - reference_id: file:human/TRIM13/TRIM13-uniprot.txt
      supporting_text: The RING-type zinc finger is required for auto-
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: EXP
  original_reference_id: PMID:25152375
  qualifier: located_in
  review:
    summary: Experimental evidence of ER membrane localization in the NEMO/NF-kB study. Core localization.
    action: ACCEPT
    reason: Core cellular component, experimentally demonstrated.
    supported_by:
    - reference_id: file:human/TRIM13/TRIM13-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
- term:
    id: GO:0003713
    label: transcription coactivator activity
  evidence_type: IDA
  original_reference_id: PMID:23077300
  qualifier: enables
  review:
    summary: Assigned from a TRIM-family NF-kB/AP-1 activation screen; reflects TRIM13-driven NF-kB signaling rather than direct transcriptional coactivation.
    action: MARK_AS_OVER_ANNOTATED
    reason: TRIM13 acts upstream as an E3 ligase modulating NF-kB signaling, not as a DNA-associated transcription coactivator; this MF over-interprets the signaling phenotype.
    supported_by:
    - reference_id: file:human/TRIM13/TRIM13-uniprot.txt
      supporting_text: Also plays a role in innate immune response by stimulating NF-kappa-B
- term:
    id: GO:0044790
    label: suppression of viral release by host
  evidence_type: IDA
  original_reference_id: PMID:18248090
  qualifier: involved_in
  review:
    summary: Direct evidence from the TRIM screen that TRIM13 affects late stages of the retroviral life cycle (viral release).
    action: KEEP_AS_NON_CORE
    reason: Experimentally supported but a secondary antiviral role relative to the core ERAD/autophagy ligase function. Defer to curator.
    supported_by:
    - reference_id: PMID:18248090
      supporting_text: many TRIM proteins affected late stages of the viral life cycle
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8867288
  qualifier: located_in
  review:
    summary: Reactome curation of ER membrane localization in the ERAD pathway. Core localization.
    action: ACCEPT
    reason: Core cellular component; consistent with experimental ER membrane localization.
    supported_by:
    - reference_id: file:human/TRIM13/TRIM13-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
- term:
    id: GO:0043123
    label: positive regulation of canonical NF-kappaB signal transduction
  evidence_type: IDA
  original_reference_id: PMID:23077300
  qualifier: involved_in
  review:
    summary: Direct evidence (TRIM-family NF-kB activation screen) that TRIM13 positively regulates NF-kB signaling.
    action: KEEP_AS_NON_CORE
    reason: Supported (TLR2/TRAF6 axis) but context-dependent and secondary to the core ERAD/autophagy function.
    supported_by:
    - reference_id: file:human/TRIM13/TRIM13-uniprot.txt
      supporting_text: activity in the TLR2 signaling pathway. Ubiquitinates TRAF6 via the
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22178386
  qualifier: enables
  review:
    summary: Interaction with SQSTM1/p62 (Q13501) in the ER-stress autophagy study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records a real, functionally relevant SQSTM1 interaction but bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/TRIM13/TRIM13-uniprot.txt
      supporting_text: and leads to its proteasomal degradation. Interacts with p62/SQSTM1.
- term:
    id: GO:0016239
    label: positive regulation of macroautophagy
  evidence_type: IDA
  original_reference_id: PMID:22178386
  qualifier: involved_in
  review:
    summary: Direct evidence that TRIM13 positively regulates ER-stress-induced autophagy. Core process.
    action: ACCEPT
    reason: Core biological process; TRIM13 (coiled-coil-dependent) induces autophagy during ER stress.
    supported_by:
    - reference_id: PMID:22178386
      supporting_text: TRIM13 regulates ER stress induced autophagy and clonogenic ability of the
- term:
    id: GO:0097038
    label: perinuclear endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:22178386
  qualifier: located_in
  review:
    summary: Direct evidence of perinuclear ER localization (colocalizing with SQSTM1/ZFYVE1). Core localization sub-compartment.
    action: ACCEPT
    reason: Experimentally supported localization consistent with the ER-membrane/perinuclear ER site of action.
    supported_by:
    - reference_id: file:human/TRIM13/TRIM13-uniprot.txt
      supporting_text: Concentrates and colocalizes with p62/SQSTM1 and ZFYVE1 at the
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21333377
  qualifier: enables
  review:
    summary: Interactions with substrates AKT1 (P31749) and MDM2 (Q00987) in the radiation/apoptosis study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records real substrate interactions (AKT1, MDM2) but bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/TRIM13/TRIM13-uniprot.txt
      supporting_text: and leads to its proteasomal degradation. Interacts with p62/SQSTM1.
- term:
    id: GO:0097038
    label: perinuclear endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:17314412
  qualifier: located_in
  review:
    summary: Direct evidence of perinuclear ER localization in the founding ERAD study. Core localization sub-compartment.
    action: ACCEPT
    reason: Experimentally supported localization consistent with the ER membrane site of action.
    supported_by:
    - reference_id: file:human/TRIM13/TRIM13-uniprot.txt
      supporting_text: Concentrates and colocalizes with p62/SQSTM1 and ZFYVE1 at the
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17314412
  qualifier: enables
  review:
    summary: Interaction with VCP/p97 (P55072) in the ERAD study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records a real, functionally central ERAD partner interaction (VCP) but bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/TRIM13/TRIM13-uniprot.txt
      supporting_text: Interacts (via C-terminal domain) with VCP. Interacts with
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IDA
  original_reference_id: PMID:17314412
  qualifier: involved_in
  review:
    summary: Direct evidence (founding study) that TRIM13 is a transmembrane E3 ligase functioning in ERAD. Core process.
    action: ACCEPT
    reason: Core biological process directly demonstrated; TRIM13 functions in ER-associated degradation.
    supported_by:
    - reference_id: PMID:17314412
      supporting_text: The RBCC gene RFP2 (Leu5) encodes a novel transmembrane E3 ubiquitin ligase
- term:
    id: GO:0043161
    label: proteasome-mediated ubiquitin-dependent protein catabolic process
  evidence_type: IDA
  original_reference_id: PMID:17314412
  qualifier: involved_in
  review:
    summary: Direct evidence that TRIM13 mediates proteasomal degradation of ERAD substrates. Core process.
    action: ACCEPT
    reason: Core biological process; TRIM13 ubiquitinates ERAD substrates for proteasomal degradation.
    supported_by:
    - reference_id: file:human/TRIM13/TRIM13-uniprot.txt
      supporting_text: associated degradation (ERAD). This process acts on misfolded proteins
- term:
    id: GO:0051865
    label: protein autoubiquitination
  evidence_type: IDA
  original_reference_id: PMID:17314412
  qualifier: involved_in
  review:
    summary: Direct evidence that TRIM13 autopolyubiquitinates (RING-dependent), leading to its own proteasomal turnover. Core activity.
    action: ACCEPT
    reason: Core biological process; RING-dependent autoubiquitination is a hallmark of TRIM13 ligase activity.
    supported_by:
    - reference_id: file:human/TRIM13/TRIM13-uniprot.txt
      supporting_text: The RING-type zinc finger is required for auto-
- term:
    id: GO:0004842
    label: ubiquitin-protein transferase activity
  evidence_type: IDA
  original_reference_id: PMID:17314412
  qualifier: enables
  review:
    summary: Direct evidence of ubiquitin-protein transferase (E3 ligase) activity. Core MF.
    action: ACCEPT
    reason: Core molecular function; demonstrated RING E3 ligase activity.
    supported_by:
    - reference_id: PMID:17314412
      supporting_text: The RBCC gene RFP2 (Leu5) encodes a novel transmembrane E3 ubiquitin ligase
- term:
    id: GO:0005789
    label: endoplasmic reticulum membrane
  evidence_type: IDA
  original_reference_id: PMID:17314412
  qualifier: located_in
  review:
    summary: Direct evidence (founding study) that TRIM13 localizes to the ER membrane. Core localization.
    action: ACCEPT
    reason: Core cellular component; TRIM13 is anchored in the ER membrane via its C-terminal transmembrane domain.
    supported_by:
    - reference_id: file:human/TRIM13/TRIM13-uniprot.txt
      supporting_text: Endoplasmic reticulum membrane
- term:
    id: GO:0043123
    label: positive regulation of canonical NF-kappaB signal transduction
  evidence_type: HMP
  original_reference_id: PMID:12761501
  qualifier: involved_in
  review:
    summary: High-throughput functional screen identifying TRIM13/RFP2 among genes that activate NF-kB signaling.
    action: KEEP_AS_NON_CORE
    reason: Supported (NF-kB activation), but context-dependent and from a large-scale overexpression screen; secondary to the core ERAD/autophagy role.
    supported_by:
    - reference_id: file:human/TRIM13/TRIM13-uniprot.txt
      supporting_text: Also plays a role in innate immune response by stimulating NF-kappa-B
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000003
  title: Gene Ontology annotation based on Enzyme Commission mapping
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000041
  title: Gene Ontology annotation based on UniPathway vocabulary mapping
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000108
  title: Automatic assignment of GO terms using logical inference, based on on inter-ontology links
  findings: []
- id: PMID:12761501
  title: Large-scale identification and characterization of human genes that activate NF-kappaB and MAPK signaling pathways.
  findings:
  - statement: TRIM13/RFP2 was identified in a large-scale screen of human genes that activate NF-kappaB and MAPK signaling.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Large-scale overexpression screen; supports NF-kB activation but TRIM13's NF-kB role is context-dependent (also represses TNF-induced NF-kB via NEMO).
- id: PMID:17314412
  title: The RBCC gene RFP2 (Leu5) encodes a novel transmembrane E3 ubiquitin ligase involved in ERAD.
  findings:
  - statement: TRIM13/RFP2 is an ER membrane-anchored RING transmembrane E3 ubiquitin ligase that functions in ER-associated degradation (ERAD), undergoes RING-dependent autoubiquitination, and localizes to the perinuclear ER.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available. Founding study establishing TRIM13 as a transmembrane ERAD E3 ligase; source of ERAD, ER membrane localization, autoubiquitination and VCP interaction.
- id: PMID:18248090
  title: TRIM E3 ligases interfere with early and late stages of the retroviral life cycle.
  findings:
  - statement: Screen of TRIM E3 ligases for antiretroviral activity; several TRIMs (including TRIM13) affect late stages (viral release) of the retroviral life cycle.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Full text available. Supports a secondary antiviral role for TRIM13 at late (release) stages.
- id: PMID:21333377
  title: Ret finger protein 2 enhances ionizing radiation-induced apoptosis via degradation of AKT and MDM2.
  findings:
  - statement: TRIM13/RFP2 ubiquitinates and degrades MDM2 and AKT1, enhancing ionizing-radiation-induced p53 stabilization and apoptosis.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available. Source of substrate (AKT1, MDM2) ubiquitination/proteasomal degradation and ubiquitin-like ligase activity annotations.
- id: PMID:22178386
  title: TRIM13 regulates ER stress induced autophagy and clonogenic ability of the cells.
  findings:
  - statement: TRIM13 positively regulates ER-stress-induced autophagy (coiled-coil-dependent), colocalizes with SQSTM1/p62 and ZFYVE1 at the perinuclear ER, and influences clonogenic ability (tumor-suppressor-like).
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available. Source of positive regulation of macroautophagy, perinuclear ER localization, and SQSTM1 interaction.
- id: PMID:23077300
  title: TRIM protein-mediated regulation of inflammatory and innate immune signaling and its association with antiretroviral activity.
  findings:
  - statement: TRIM13 was among TRIMs that activate NF-kB/AP-1 signaling in a family-wide screen.
    reference_section_type: RESULTS
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Full text available. Supports NF-kB activation; the derived transcription coactivator activity annotation over-interprets this upstream signaling role.
- id: PMID:25152375
  title: "TRIM13 regulates ubiquitination and turnover of NEMO to suppress TNF induced NF-ฮบB activation."
  findings:
  - statement: In the presence of TNF, TRIM13 regulates IKBKG/NEMO ubiquitination and turnover to repress NF-kB activation, demonstrating a context-dependent negative role in NF-kB signaling.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached abstract-only (full_text_available false). Establishes the context-dependent (negative, TNF/NEMO) arm of TRIM13's NF-kB regulation and confirms ER membrane localization.
- id: Reactome:R-HSA-8867288
  title: 'OS9:SEL1:ERAD E3 ligase:DERL2 ubiquitinates unfolded protein:(GlcNAc)2 (Man)9-5'
  findings: []
- id: Reactome:R-HSA-901032
  title: ER Quality Control Compartment (ERQC)
  findings: []
core_functions:
- description: Functions as an ER membrane-anchored RING-type E3 ubiquitin ligase in ER-associated degradation (ERAD), ubiquitinating misfolded membrane and secretory proteins (and some regulated substrates such as AKT1 and MDM2) and cooperating with VCP/p97 to target them for proteasomal degradation.
  molecular_function:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  locations:
  - id: GO:0005789
    label: endoplasmic reticulum membrane
  supported_by:
  - reference_id: PMID:17314412
    supporting_text: The RBCC gene RFP2 (Leu5) encodes a novel transmembrane E3 ubiquitin ligase
  - reference_id: file:human/TRIM13/TRIM13-uniprot.txt
    supporting_text: associated degradation (ERAD). This process acts on misfolded proteins
  directly_involved_in:
  - id: GO:0036503
    label: ERAD pathway
  - id: GO:0043161
    label: proteasome-mediated ubiquitin-dependent protein catabolic process
- description: Positively regulates ER-stress-induced autophagy/reticulophagy via its coiled-coil domain, concentrating at the perinuclear ER with SQSTM1/p62 and ZFYVE1/DFCP1.
  molecular_function:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  locations:
  - id: GO:0097038
    label: perinuclear endoplasmic reticulum
  supported_by:
  - reference_id: PMID:22178386
    supporting_text: TRIM13 regulates ER stress induced autophagy and clonogenic ability of the
  directly_involved_in:
  - id: GO:0016239
    label: positive regulation of macroautophagy
proposed_new_terms: []
suggested_questions:
- question: How is the direction of TRIM13's effect on NF-kB signaling (TLR2/TRAF6-mediated activation versus TNF/NEMO-mediated repression) determined by stimulus and cellular context?
- question: What are the endogenous ERAD substrates of TRIM13, and how does its ERAD ligase activity mechanistically connect to its role in inducing ER-stress autophagy/reticulophagy?
suggested_experiments:
- description: Perform substrate-trapping ubiquitinome/proteomics in TRIM13-knockout versus wild-type cells under ER stress to define the endogenous ERAD substrate repertoire and distinguish it from the regulated substrates (AKT1, MDM2, NEMO, TRAF6).
- description: Use coiled-coil and RING domain-specific TRIM13 mutants to separate its ERAD ligase activity from its ER-stress autophagy-inducing activity and test which is required for the proposed tumor-suppressor phenotype.