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-κB 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.