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.
| 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 |
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Download this section (compressed HTML)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?
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.
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