id: Q9C035
gene_symbol: TRIM5
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  TRIM5 (tripartite motif-containing protein 5; the antiviral isoform is
  TRIM5alpha) is a cytoplasmic RING-type E3 ubiquitin ligase of the TRIM/RBCC
  family that functions both as a capsid-specific retroviral restriction factor
  and as an innate immune pattern-recognition receptor. Its RBCC architecture
  comprises an N-terminal RING-type zinc finger that confers E3 ubiquitin ligase
  activity (EC 2.3.2.27), a B-box-type zinc finger and a coiled-coil that drive
  the higher- and lower-order self-multimerization required for activity, and a
  C-terminal B30.2/PRYSPRY (SPRY) domain that directly recognizes the assembled
  retroviral capsid lattice. Through the PRYSPRY domain TRIM5alpha binds the
  hexameric capsid lattice of incoming non-host-adapted retroviruses and blocks
  infection at an early post-entry step, before reverse transcription;
  polymorphisms in the PRYSPRY domain account for the species-specific spectrum
  of restriction (human TRIM5alpha restricts N-tropic MLV, EIAV, SIVmac, FIV and
  BIV but only weakly HIV-1). Capsid lattice binding also triggers TRIM5's RING
  E3 ligase activity: together with the UBE2V1-UBE2N (UBC13-UEV1A) E2 complex it
  synthesizes unanchored Lys63-linked polyubiquitin chains that activate the
  TAK1 (MAP3K7)-TAB2-TAB3 kinase complex by autophosphorylation, inducing
  NF-kappaB- and AP-1/MAPK-responsive inflammatory genes and thereby acting as a
  sensor that links capsid detection to innate immune signaling. TRIM5alpha is
  itself regulated by ubiquitination (RING/UBE2D2-dependent autoubiquitination,
  monoubiquitination by TRIM21) and undergoes rapid proteasome-dependent turnover
  upon engaging restriction-sensitive virus. It additionally functions in
  selective ("precision") autophagy: it acts as a platform that assembles and
  activates the autophagy regulators ULK1 and BECN1 (Beclin-1, by dissociating it
  from BCL2 and TAB2) and as a selective autophagy receptor that directly
  recognizes the HIV-1 capsid protein p24 and delivers it for autophagic
  degradation, interacting with SQSTM1/p62 and the ATG8 family proteins
  GABARAP/GABARAPL1/GABARAPL2 and MAP1LC3A/C. TRIM5alpha localizes predominantly
  to cytoplasmic bodies, where it can form homodimers and homotrimers and
  colocalizes with proteasomal subunits and SQSTM1.
alternative_products:
- name: Alpha
  id: Q9C035-1
- name: Beta
  id: Q9C035-2
  sequence_note: VSP_009010, VSP_009011
- name: Gamma
  id: Q9C035-3
  sequence_note: VSP_009012, VSP_009013
- name: Delta
  id: Q9C035-4
  sequence_note: VSP_009014, VSP_009015
- name: Epsilon (Kappa)
  id: Q9C035-5
  sequence_note: VSP_009016, VSP_009017
- name: Iota
  id: Q9C035-6
  sequence_note: VSP_044095, VSP_044096
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 localization, where TRIM5alpha acts in cytoplasmic bodies.
    action: ACCEPT
    reason: TRIM5alpha is predominantly cytoplasmic and acts there (capsid recognition, signaling, autophagy); strongly supported experimentally.
    supported_by:
    - reference_id: file:human/TRIM5/TRIM5-uniprot.txt
      supporting_text: Predominantly localizes in cytoplasmic bodies
- 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 involvement in innate immunity; TRIM5alpha both restricts retroviruses and activates innate immune signaling.
    action: ACCEPT
    reason: Core biological process; TRIM5alpha is an innate immune sensor of the retroviral capsid lattice that activates NF-kB/MAPK signaling.
    supported_by:
    - reference_id: PMID:21512573
      supporting_text: TRIM5 is an innate immune sensor for the retrovirus capsid lattice
- term:
    id: GO:0010468
    label: regulation of gene expression
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Generic regulation-of-gene-expression term inherited phylogenetically; downstream consequence of TRIM5-driven NF-kB/MAPK activation.
    action: KEEP_AS_NON_CORE
    reason: Correct but overly generic; the specific positive regulation of NF-kB signaling and MAPK cascade annotations better capture the mechanism.
    supported_by:
    - reference_id: file:human/TRIM5/TRIM5-uniprot.txt
      supporting_text: Activation of the MAP3K7/TAK1 complex by autophosphorylation
- 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 experimentally demonstrated RING-dependent ligase activity.
    action: ACCEPT
    reason: Core molecular function; the RING domain confers E3 ligase activity essential for restriction, autoubiquitination and signaling.
    supported_by:
    - reference_id: file:human/TRIM5/TRIM5-uniprot.txt
      supporting_text: The RING-type zinc finger domain confers E3 ubiquitin ligase activity and is essential for retrovirus restriction activity, autoubiquitination
- term:
    id: GO:0046596
    label: regulation of viral entry into host cell
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic inference of regulation of viral entry; TRIM5alpha restricts retroviruses but acts after entry, before reverse transcription.
    action: KEEP_AS_NON_CORE
    reason: TRIM5alpha blocks an early post-entry (uncoating/pre-reverse-transcription) step rather than viral entry itself; the restriction role is better captured by host-mediated suppression of symbiont invasion and defense response to virus.
    supported_by:
    - reference_id: file:human/TRIM5/TRIM5-uniprot.txt
      supporting_text: Blocks viral replication early in the life cycle, after viral entry but before reverse transcription
- term:
    id: GO:0019901
    label: protein kinase binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetic inference of protein kinase binding; TRIM5alpha binds the TAK1 kinase complex and ULK1.
    action: KEEP_AS_NON_CORE
    reason: Real and functionally relevant (TAK1/MAP3K7, ULK1) but the informative functions are the downstream signaling activation and autophagy regulation.
    supported_by:
    - reference_id: file:human/TRIM5/TRIM5-uniprot.txt
      supporting_text: MAP3K7/TAK1, TAB2 and TAB3
- term:
    id: GO:0032880
    label: regulation of protein localization
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic inference of regulation of protein localization, consistent with the IMP annotation from the autophagy study.
    action: KEEP_AS_NON_CORE
    reason: Supported but a broad process term; reflects TRIM5's autophagy-platform role rather than a core dedicated function.
    supported_by:
    - reference_id: PMID:25127057
      supporting_text: TRIM proteins regulate autophagy and can target autophagic substrates by direct recognition
- term:
    id: GO:0042803
    label: protein homodimerization activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetic inference of homodimerization; TRIM5alpha forms homodimers and homotrimers essential for restriction activity.
    action: ACCEPT
    reason: Core molecular function; self-association (coiled-coil-mediated dimerization plus B-box-driven higher-order multimerization) is essential for capsid-lattice recognition and restriction.
    supported_by:
    - reference_id: file:human/TRIM5/TRIM5-uniprot.txt
      supporting_text: Can form homodimers and homotrimers
- 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 the experimental IMP/IDA evidence.
    action: ACCEPT
    reason: Core biological process; capsid sensing triggers TRIM5-mediated K63-Ub/TAK1 activation that induces NF-kB.
    supported_by:
    - reference_id: file:human/TRIM5/TRIM5-uniprot.txt
      supporting_text: Activation of the MAP3K7/TAK1 complex by autophosphorylation
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic transfer of a nuclear localization that is only "By similarity" in UniProt (partial nuclear pool seen with TRIM22/TRIM27 coexpression).
    action: MARK_AS_OVER_ANNOTATED
    reason: Human TRIM5alpha is predominantly cytoplasmic; nuclear localization is only by similarity (UniProtKB:Q0PF16) and context-dependent, not a core or robustly supported localization.
    supported_by:
    - reference_id: file:human/TRIM5/TRIM5-uniprot.txt
      supporting_text: partial nuclear localization is observed in the presence of TRIM22 or TRIM27
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic transfer of cytoplasmic localization from the UniProt subcellular location; the core compartment.
    action: ACCEPT
    reason: Correct core localization; redundant with experimental IDA cytoplasm annotations.
    supported_by:
    - reference_id: file:human/TRIM5/TRIM5-uniprot.txt
      supporting_text: Predominantly localizes in cytoplasmic bodies
- 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 and B-box zinc fingers.
    action: KEEP_AS_NON_CORE
    reason: Correct (RING and B-box coordinate Zn2+) and underpins ligase/multimerization, but generic; the informative MF is ubiquitin ligase activity.
    supported_by:
    - reference_id: file:human/TRIM5/TRIM5-uniprot.txt
      supporting_text: /note="RING-type"
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: enables
  review:
    summary: ARBA machine-learning assignment of identical protein binding, reflecting TRIM5 self-association.
    action: KEEP_AS_NON_CORE
    reason: Correct (TRIM5 self-associates) but redundant with and less informative than the protein homodimerization activity annotation.
    supported_by:
    - reference_id: file:human/TRIM5/TRIM5-uniprot.txt
      supporting_text: Can form homodimers and homotrimers
- 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 the transcription coactivator activity annotation.
    action: MARK_AS_OVER_ANNOTATED
    reason: Derived from the over-interpreted transcription coactivator annotation; TRIM5 acts upstream in NF-kB/MAPK signaling rather than as a direct DNA-templated transcriptional activator.
    supported_by:
    - reference_id: PMID:23077300
      supporting_text: to induce NF-κB and MAP kinase (MAPK) signaling
- 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/TRIM5/TRIM5-uniprot.txt
      supporting_text: EC=2.3.2.27
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22493164
  qualifier: enables
  review:
    summary: Interaction from a systematic dimeric E3-RING interaction screen. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records a real RING-RING interaction but bare protein binding is uninformative per curation guidelines.
    supported_by:
    - reference_id: PMID:22493164
      supporting_text: Systematic analysis of dimeric E3-RING interactions
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25203322
  qualifier: enables
  review:
    summary: Interaction reported in an SCF-FBXO11/SNAIL study (TRIM5 appears as an interactor). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Bare protein binding is uninformative; not a core TRIM5 function.
    supported_by:
    - reference_id: PMID:25203322
      supporting_text: PKD1 phosphorylation-dependent degradation of SNAIL by SCF-FBXO11
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26618866
  qualifier: enables
  review:
    summary: Interaction from a CFTR interactome remodeling study (TRIM5 interacts with CFTR per IntAct). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome interaction; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/TRIM5/TRIM5-uniprot.txt
      supporting_text: 'Q9C035; P13569: CFTR; NbExp=3'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35156780
  qualifier: enables
  review:
    summary: Interaction from a CFTR mammalian-membrane-two-hybrid screen. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactome interaction; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/TRIM5/TRIM5-uniprot.txt
      supporting_text: 'Q9C035; P13569: CFTR; NbExp=3'
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:22493164
  qualifier: enables
  review:
    summary: TRIM5-TRIM5 self-interaction detected in the E3-RING dimer screen.
    action: KEEP_AS_NON_CORE
    reason: Correct self-association but redundant with and less informative than protein homodimerization activity.
    supported_by:
    - reference_id: file:human/TRIM5/TRIM5-uniprot.txt
      supporting_text: 'Q9C035; Q9C035: TRIM5; NbExp=3'
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:22829933
  qualifier: enables
  review:
    summary: Self-interaction / TRIM-TRIM interaction reported in a TRIM27/NOD2 study.
    action: KEEP_AS_NON_CORE
    reason: Correct self-association but redundant with the homodimerization annotation.
    supported_by:
    - reference_id: file:human/TRIM5/TRIM5-uniprot.txt
      supporting_text: Can form homodimers and homotrimers
- term:
    id: GO:0140374
    label: antiviral innate immune response
  evidence_type: IDA
  original_reference_id: PMID:18248090
  qualifier: involved_in
  review:
    summary: Direct evidence that TRIM5 functions in the antiviral innate immune response (retroviral restriction screen). Core process.
    action: ACCEPT
    reason: Core biological process; TRIM5alpha is an antiviral restriction factor and innate immune effector.
    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:0036464
    label: cytoplasmic ribonucleoprotein granule
  evidence_type: IDA
  original_reference_id: PMID:20357094
  qualifier: located_in
  review:
    summary: Localization to cytoplasmic RNP granules/P-bodies reported in the SQSTM1/p62 study.
    action: KEEP_AS_NON_CORE
    reason: Experimentally observed but a specialized sub-compartment; the core localization is cytoplasmic bodies. Defer to curator who read the full text.
    supported_by:
    - reference_id: PMID:20357094
      supporting_text: p62/sequestosome-1 associates with and sustains the expression of retroviral restriction factor TRIM5alpha
- 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 K63-linked ubiquitination annotation better captures the activity.
    supported_by:
    - reference_id: file:human/TRIM5/TRIM5-uniprot.txt
      supporting_text: 'PATHWAY: Protein modification; protein ubiquitination.'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Immunofluorescence-based (HPA) cytosolic localization, consistent with the core cytoplasmic site of action.
    action: ACCEPT
    reason: Correct cytosolic localization; consistent with cytoplasmic body localization.
    supported_by:
    - reference_id: file:human/TRIM5/TRIM5-uniprot.txt
      supporting_text: Predominantly localizes in cytoplasmic bodies
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: Sequence-similarity transfer of nuclear localization, matching the "By similarity" nuclear note in UniProt.
    action: MARK_AS_OVER_ANNOTATED
    reason: Nuclear localization for human TRIM5alpha is only by similarity and context-dependent (TRIM22/TRIM27 coexpression); the protein is predominantly cytoplasmic.
    supported_by:
    - reference_id: file:human/TRIM5/TRIM5-uniprot.txt
      supporting_text: partial nuclear localization is observed in the presence of TRIM22 or TRIM27
- 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/IFN activation screen; reflects TRIM5-driven TAK1/NF-kB signaling rather than direct transcriptional coactivation.
    action: MARK_AS_OVER_ANNOTATED
    reason: TRIM5 acts upstream as a signaling activator (TAK1->NF-kB/MAPK), not as a DNA-associated transcription coactivator; this MF over-interprets the signaling phenotype.
    supported_by:
    - reference_id: PMID:23077300
      supporting_text: to induce NF-κB and MAP kinase (MAPK) signaling
- term:
    id: GO:0044790
    label: suppression of viral release by host
  evidence_type: IDA
  original_reference_id: PMID:18248090
  qualifier: involved_in
  review:
    summary: Late-stage (viral release) suppression assigned from a broad TRIM screen; for TRIM5alpha the validated dominant activity is early post-entry restriction.
    action: MARK_AS_OVER_ANNOTATED
    reason: The screen found late-stage effects for several TRIMs (e.g. TRIM25/31/62); TRIM5alpha's well-established mechanism is early post-entry capsid restriction, so a "viral release" role is weakly supported for TRIM5.
    supported_by:
    - reference_id: PMID:18248090
      supporting_text: many TRIM proteins affected late stages of the viral life cycle
- term:
    id: GO:0046597
    label: host-mediated suppression of symbiont invasion
  evidence_type: IDA
  original_reference_id: PMID:18248090
  qualifier: involved_in
  review:
    summary: Direct evidence that TRIM5 suppresses retroviral invasion (early restriction). Core restriction process.
    action: ACCEPT
    reason: Core biological process; captures the capsid-dependent post-entry restriction of incoming retroviruses.
    supported_by:
    - reference_id: file:human/TRIM5/TRIM5-uniprot.txt
      supporting_text: Capsid-specific restriction factor that prevents infection
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25127057
  qualifier: enables
  review:
    summary: Autophagy-machinery interactions (ULK1, BECN1, SQSTM1, ATG8 proteins) from the precision-autophagy study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records real, functionally important autophagy interactions but bare protein binding is uninformative; better captured by the adaptor-activity and autophagy annotations.
    supported_by:
    - reference_id: file:human/TRIM5/TRIM5-uniprot.txt
      supporting_text: Interacts with ULK1 (phosphorylated form), GABARAP, GABARAPL1, GABARAPL2,
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:25127057
  qualifier: located_in
  review:
    summary: Direct evidence of cytoplasmic localization from the autophagy study. Core localization.
    action: ACCEPT
    reason: Correct core localization, experimentally demonstrated.
    supported_by:
    - reference_id: file:human/TRIM5/TRIM5-uniprot.txt
      supporting_text: Predominantly localizes in cytoplasmic bodies
- term:
    id: GO:0006914
    label: autophagy
  evidence_type: IDA
  original_reference_id: PMID:25127057
  qualifier: involved_in
  review:
    summary: Direct evidence that TRIM5alpha functions in autophagy, as a selective autophagy receptor and as a platform activating ULK1/BECN1. Core process.
    action: ACCEPT
    reason: Core biological process; TRIM5alpha regulates autophagy and acts as a selective autophagy receptor for the HIV-1 capsid.
    supported_by:
    - reference_id: PMID:25127057
      supporting_text: TRIM5α acts as a selective autophagy receptor
- term:
    id: GO:0098792
    label: xenophagy
  evidence_type: IDA
  original_reference_id: PMID:25127057
  qualifier: involved_in
  review:
    summary: TRIM5alpha delivers the HIV-1 capsid, a foreign cytosolic viral cargo, for selective autophagic degradation.
    action: NEW
    reason: PN correctly flagged that the existing autophagy annotation is generic for this role. Xenophagy is the more specific process term for autophagic degradation of a cytosolic viral capsid.
    supported_by:
    - reference_id: PMID:25127057
      supporting_text: TRIM5α delivered its cognate cytosolic target, a viral capsid protein, for autophagic degradation
      reference_section_type: ABSTRACT
- term:
    id: GO:0019901
    label: protein kinase binding
  evidence_type: IPI
  original_reference_id: PMID:25127057
  qualifier: enables
  review:
    summary: Direct interaction with the kinase ULK1 (phosphorylated form) in the autophagy study.
    action: KEEP_AS_NON_CORE
    reason: Real and functionally relevant (ULK1) but the informative function is the autophagy-platform/adaptor role.
    supported_by:
    - reference_id: file:human/TRIM5/TRIM5-uniprot.txt
      supporting_text: Interacts with ULK1 (phosphorylated form)
- term:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  evidence_type: IPI
  original_reference_id: PMID:25127057
  qualifier: enables
  review:
    summary: TRIM5alpha bridges autophagy machinery (ULK1, BECN1, ATG8s) and substrate, acting as a molecular adaptor/scaffold.
    action: ACCEPT
    reason: Informative molecular function capturing TRIM5alpha's role as a selective-autophagy receptor/adaptor that links cargo to the autophagy apparatus.
    supported_by:
    - reference_id: PMID:25127057
      supporting_text: act as platforms assembling ULK1 and Beclin 1 in their
- term:
    id: GO:0160247
    label: autophagy cargo adaptor activity
  evidence_type: IPI
  original_reference_id: PMID:25127057
  qualifier: enables
  review:
    summary: TRIM5alpha acts as a selective-autophagy cargo adaptor/receptor that recognizes viral capsid cargo and couples it to autophagic degradation.
    action: NEW
    reason: PN showed that the accepted GO:0030674 adaptor annotation can be made more precise with existing GO:0160247. This is an upgrade to an existing GO term, not a new term request.
    supported_by:
    - reference_id: PMID:25127057
      supporting_text: TRIM5α acts as a selective autophagy receptor
      reference_section_type: ABSTRACT
    - reference_id: PMID:25127057
      supporting_text: TRIM5α delivered its cognate cytosolic target, a viral capsid protein, for autophagic degradation
      reference_section_type: ABSTRACT
- term:
    id: GO:0032880
    label: regulation of protein localization
  evidence_type: IMP
  original_reference_id: PMID:25127057
  qualifier: involved_in
  review:
    summary: Mutant-phenotype evidence that TRIM5alpha regulates localization of autophagy components/cargo.
    action: KEEP_AS_NON_CORE
    reason: Supported but a broad process term reflecting the autophagy-platform role.
    supported_by:
    - reference_id: PMID:25127057
      supporting_text: TRIM proteins regulate autophagy and can target autophagic substrates by direct recognition
- term:
    id: GO:1990462
    label: omegasome
  evidence_type: IDA
  original_reference_id: PMID:25127057
  qualifier: colocalizes_with
  review:
    summary: Colocalization with the omegasome (autophagosome-formation site), consistent with TRIM5alpha's autophagy-platform role.
    action: ACCEPT
    reason: Experimentally supported colocalization at autophagosome biogenesis sites, consistent with the autophagy function.
    supported_by:
    - reference_id: PMID:25127057
      supporting_text: act as platforms assembling ULK1 and Beclin 1 in their
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-1031716
  qualifier: located_in
  review:
    summary: Reactome curation of cytosolic localization in the interferon-gamma-stimulated gene context.
    action: ACCEPT
    reason: Correct cytosolic localization, consistent with the core cytoplasmic site of action.
    supported_by:
    - reference_id: file:human/TRIM5/TRIM5-uniprot.txt
      supporting_text: Predominantly localizes in cytoplasmic bodies
- 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 TRIM5 positively regulates NF-kB signaling via TAK1.
    action: ACCEPT
    reason: Core biological process; TRIM5-driven TAK1 activation induces NF-kB.
    supported_by:
    - reference_id: PMID:23077300
      supporting_text: to induce NF-κB and MAP kinase (MAPK) signaling
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:18248090
  qualifier: located_in
  review:
    summary: Direct evidence of cytoplasmic localization in the retroviral restriction screen. Core localization.
    action: ACCEPT
    reason: Correct core localization, experimentally demonstrated.
    supported_by:
    - reference_id: file:human/TRIM5/TRIM5-uniprot.txt
      supporting_text: Predominantly localizes in cytoplasmic bodies
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:20357094
  qualifier: enables
  review:
    summary: Interaction with SQSTM1/p62 that sustains TRIM5alpha expression. 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/TRIM5/TRIM5-uniprot.txt
      supporting_text: Interacts with SQSTM1
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22078707
  qualifier: enables
  review:
    summary: Interaction with proteasome subunit PSMC2 (and other proteasome subunits) in cytoplasmic bodies. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records a real proteasome-subunit interaction relevant to TRIM5 turnover/restriction but bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/TRIM5/TRIM5-uniprot.txt
      supporting_text: Interacts with PSMC2
- term:
    id: GO:0051607
    label: defense response to virus
  evidence_type: TAS
  original_reference_id: PMID:22291694
  qualifier: involved_in
  review:
    summary: Author-statement (review) that TRIM5alpha defends against retroviruses. Core process.
    action: ACCEPT
    reason: Core biological process; TRIM5alpha is a retroviral restriction factor.
    supported_by:
    - reference_id: PMID:22291694
      supporting_text: TRIM5α recognizes the multimerized capsid proteins (viral core) of an incoming virus by its PRYSPRY domain
- term:
    id: GO:0002218
    label: activation of innate immune response
  evidence_type: IDA
  original_reference_id: PMID:21512573
  qualifier: involved_in
  review:
    summary: Direct evidence that capsid-lattice sensing by TRIM5 activates the innate immune response. Core process.
    action: ACCEPT
    reason: Core biological process; capsid recognition triggers TRIM5 ligase activity and innate immune signaling.
    supported_by:
    - reference_id: PMID:21512573
      supporting_text: TRIM5 is an innate immune sensor for the retrovirus capsid lattice
- term:
    id: GO:0004842
    label: ubiquitin-protein transferase activity
  evidence_type: IDA
  original_reference_id: PMID:21512573
  qualifier: enables
  review:
    summary: Direct evidence that capsid binding triggers TRIM5 E3 ubiquitin transferase activity (with UBE2V1-UBE2N). Core MF.
    action: ACCEPT
    reason: Core molecular function; TRIM5 catalyzes ubiquitin transfer to generate K63-linked chains upon capsid sensing.
    supported_by:
    - reference_id: file:human/TRIM5/TRIM5-uniprot.txt
      supporting_text: Binding to the viral capsid triggers its E3 ubiquitin ligase activity
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:21512573
  qualifier: enables
  review:
    summary: Interactions with the TAK1 complex (MAP3K7, TAB2, TAB3) from the innate-sensor study. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Records real, functionally central interactions (TAK1 complex) but bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/TRIM5/TRIM5-uniprot.txt
      supporting_text: MAP3K7/TAK1, TAB2 and TAB3
- term:
    id: GO:0031664
    label: regulation of lipopolysaccharide-mediated signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:21512573
  qualifier: involved_in
  review:
    summary: Mutant-phenotype evidence linking TRIM5-mediated TAK1 activation to LPS/innate signaling pathways.
    action: KEEP_AS_NON_CORE
    reason: Supported but a specific signaling-context process; the core mechanism is capsid-triggered TAK1/NF-kB activation. Defer to curator.
    supported_by:
    - reference_id: file:human/TRIM5/TRIM5-uniprot.txt
      supporting_text: autophosphorylation of the MAP3K7/TAK1 complex
- term:
    id: GO:0038187
    label: pattern recognition receptor activity
  evidence_type: IDA
  original_reference_id: PMID:21512573
  qualifier: enables
  review:
    summary: Direct evidence that TRIM5 acts as a pattern recognition receptor for the retroviral capsid lattice. Core molecular function.
    action: ACCEPT
    reason: Core molecular function; TRIM5 is a cytosolic PRR sensing the capsid lattice PAMP.
    supported_by:
    - reference_id: PMID:21512573
      supporting_text: TRIM5 is an innate immune sensor for the retrovirus capsid lattice
- term:
    id: GO:0043123
    label: positive regulation of canonical NF-kappaB signal transduction
  evidence_type: IMP
  original_reference_id: PMID:21512573
  qualifier: involved_in
  review:
    summary: Mutant-phenotype evidence that TRIM5 positively regulates NF-kB signaling. Core process.
    action: ACCEPT
    reason: Core biological process; redundant with the IDA/IBA NF-kB annotations.
    supported_by:
    - reference_id: file:human/TRIM5/TRIM5-uniprot.txt
      supporting_text: Activation of the MAP3K7/TAK1 complex by autophosphorylation
- term:
    id: GO:0043410
    label: positive regulation of MAPK cascade
  evidence_type: IMP
  original_reference_id: PMID:21512573
  qualifier: involved_in
  review:
    summary: Mutant-phenotype evidence that TRIM5-mediated TAK1 activation positively regulates the MAPK cascade. Core process.
    action: ACCEPT
    reason: Core biological process; capsid-triggered TAK1 activation induces MAPK-responsive genes.
    supported_by:
    - reference_id: file:human/TRIM5/TRIM5-uniprot.txt
      supporting_text: autophosphorylation of the MAP3K7/TAK1 complex
- term:
    id: GO:0051607
    label: defense response to virus
  evidence_type: TAS
  original_reference_id: PMID:21512573
  qualifier: involved_in
  review:
    summary: Author-statement that TRIM5 defends against retroviruses. Core process.
    action: ACCEPT
    reason: Core biological process; redundant with the antiviral/restriction annotations.
    supported_by:
    - reference_id: PMID:21512573
      supporting_text: TRIM5 is an innate immune sensor for the retrovirus capsid lattice
- term:
    id: GO:0070534
    label: protein K63-linked ubiquitination
  evidence_type: IDA
  original_reference_id: PMID:21512573
  qualifier: involved_in
  review:
    summary: Direct evidence that TRIM5, with UBE2V1-UBE2N, generates K63-linked polyubiquitin chains. Core activity.
    action: ACCEPT
    reason: Core biological process; the K63-chain synthesis is the mechanistic link between capsid sensing and TAK1/NF-kB activation.
    supported_by:
    - reference_id: file:human/TRIM5/TRIM5-uniprot.txt
      supporting_text: generates 'Lys-63'-linked
- term:
    id: GO:0042803
    label: protein homodimerization activity
  evidence_type: IPI
  original_reference_id: PMID:11331580
  qualifier: enables
  review:
    summary: Self-association reported in the foundational TRIM-family paper; homodimerization/multimerization essential for restriction. Core MF.
    action: ACCEPT
    reason: Core molecular function; self-multimerization underlies capsid-lattice avidity and restriction.
    supported_by:
    - reference_id: file:human/TRIM5/TRIM5-uniprot.txt
      supporting_text: Can form homodimers and homotrimers
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:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
  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:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000108
  title: Automatic assignment of GO terms using logical inference, based on on inter-ontology links
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: PMID:11331580
  title: The tripartite motif family identifies cell compartments.
  findings:
  - statement: TRIM5 belongs to the TRIM/RBCC family and can self-associate and localize to cytoplasmic bodies.
    reference_section_type: RESULTS
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Foundational TRIM-family paper; source of the homodimerization (self-association) annotation and cytoplasmic body localization.
- id: PMID:18248090
  title: TRIM E3 ligases interfere with early and late stages of the retroviral life cycle.
  findings:
  - statement: Screen of 55 TRIM E3 ligases for antiretroviral activity; TRIM proteins affect early and late stages of HIV/MLV/ALV replication.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available. Supports TRIM5 antiviral innate immune response and early restriction; the "suppression of viral release" (late-stage) assignment is weak for TRIM5alpha specifically (screen highlighted TRIM25/31/62 for release).
- id: PMID:20357094
  title: p62/sequestosome-1 associates with and sustains the expression of retroviral restriction factor TRIM5alpha.
  findings:
  - statement: SQSTM1/p62 associates with TRIM5alpha in cytoplasmic bodies and sustains its expression.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Full text available. Source of SQSTM1 interaction and cytoplasmic RNP granule localization.
- id: PMID:21512573
  title: TRIM5 is an innate immune sensor for the retrovirus capsid lattice.
  findings:
  - statement: TRIM5 senses the retroviral capsid lattice as a pattern-recognition receptor; capsid binding activates its RING E3 ligase to generate, with UBE2V1-UBE2N, K63-linked polyubiquitin chains that activate the TAK1/TAB2/TAB3 complex, inducing NF-kB and MAPK/AP-1 inflammatory signaling.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available. Foundational study for TRIM5 PRR activity, K63 ubiquitination, TAK1/NF-kB/MAPK activation.
- id: PMID:22078707
  title: TRIM5alpha associates with proteasomal subunits in cells while in complex with HIV-1 virions.
  findings:
  - statement: TRIM5alpha interacts with the proteasome subunit PSMC2 and other proteasomal subunits.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Full text available. Source of PSMC2/proteasome interaction.
- id: PMID:22291694
  title: TRIM5alpha and Species Tropism of HIV/SIV.
  findings:
  - statement: TRIM5alpha recognizes the multimerized capsid (viral core) via its PRYSPRY/B30.2 domain; PRYSPRY polymorphisms determine species-specific restriction.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available. Review establishing capsid recognition, PRYSPRY species specificity, and proteasome-dependent turnover.
- id: PMID:22493164
  title: Systematic analysis of dimeric E3-RING interactions reveals increased combinatorial complexity in human ubiquitination networks.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput E3-RING dimer screen; source of bare protein binding and identical protein binding annotations.
- id: PMID:22829933
  title: TRIM27 negatively regulates NOD2 by ubiquitination and proteasomal degradation.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: TRIM27/NOD2 study; source of an identical protein binding annotation for TRIM5 (TRIM self-association).
- id: PMID:23077300
  title: TRIM protein-mediated regulation of inflammatory and innate immune signaling and its association with antiretroviral activity.
  findings:
  - statement: TRIM5 (with TRIM8) activates TAK1, a downstream kinase that induces NF-kB and MAPK signaling.
    reference_section_type: RESULTS
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Full text available. Supports NF-kB activation via TAK1; the derived transcription coactivator activity annotation over-interprets this upstream signaling role.
- id: PMID:25127057
  title: TRIM proteins regulate autophagy and can target autophagic substrates by direct recognition.
  findings:
  - statement: TRIM5alpha regulates autophagy by acting as a platform assembling/activating ULK1 and Beclin-1, and functions as a selective autophagy receptor that directly recognizes the HIV-1 capsid protein and delivers it for autophagic degradation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Cached abstract-only (full_text_available false). Abstract explicitly states TRIM5alpha is a selective autophagy receptor and ULK1/Beclin-1 platform; supports autophagy, adaptor activity, omegasome colocalization.
- id: PMID:25203322
  title: PKD1 phosphorylation-dependent degradation of SNAIL by SCF-FBXO11 regulates epithelial-mesenchymal transition and metastasis.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: SNAIL/SCF-FBXO11 study; source of a bare protein binding annotation (IntAct interactor), not core to TRIM5.
- id: PMID:26618866
  title: "∆F508 CFTR interactome remodelling promotes rescue of cystic fibrosis."
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: CFTR interactome screen; source of a bare protein binding (CFTR) annotation.
- id: PMID:35156780
  title: CFTR interactome mapping using the mammalian membrane two-hybrid high-throughput screening system.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: CFTR two-hybrid interactome screen; source of a bare protein binding (CFTR) annotation.
- id: Reactome:R-HSA-1031716
  title: Expression of IFNG-stimulated genes
  findings: []
core_functions:
- description: Acts as a capsid-specific retroviral restriction factor and pattern-recognition receptor; the C-terminal B30.2/PRYSPRY domain directly recognizes the assembled retroviral capsid lattice, blocking infection at an early post-entry step and triggering downstream signaling.
  molecular_function:
    id: GO:0038187
    label: pattern recognition receptor activity
  locations:
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: PMID:21512573
    supporting_text: TRIM5 is an innate immune sensor for the retrovirus capsid lattice
  - reference_id: PMID:22291694
    supporting_text: TRIM5α recognizes the multimerized capsid proteins (viral core) of an incoming virus by its PRYSPRY domain
  directly_involved_in:
  - id: GO:0046597
    label: host-mediated suppression of symbiont invasion
  - id: GO:0051607
    label: defense response to virus
- description: Functions as a RING-type E3 ubiquitin ligase that, upon capsid sensing and together with UBE2V1-UBE2N, synthesizes Lys63-linked polyubiquitin chains to activate the TAK1 (MAP3K7)-TAB2-TAB3 kinase complex and drive NF-kB and MAPK/AP-1 innate immune signaling.
  molecular_function:
    id: GO:0061630
    label: ubiquitin protein ligase activity
  locations:
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: file:human/TRIM5/TRIM5-uniprot.txt
    supporting_text: Binding to the viral capsid triggers its E3 ubiquitin ligase activity
  - reference_id: PMID:21512573
    supporting_text: TRIM5 is an innate immune sensor for the retrovirus capsid lattice
  directly_involved_in:
  - id: GO:0070534
    label: protein K63-linked ubiquitination
  - id: GO:0002218
    label: activation of innate immune response
  - id: GO:0043123
    label: positive regulation of canonical NF-kappaB signal transduction
- description: Acts in selective ("precision") autophagy as a receptor/adaptor that directly recognizes the HIV-1 capsid protein and delivers it for autophagic degradation, and as a platform that assembles and activates ULK1 and Beclin-1.
  molecular_function:
    id: GO:0160247
    label: autophagy cargo adaptor activity
  locations:
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: PMID:25127057
    supporting_text: TRIM5α acts as a selective autophagy receptor
  directly_involved_in:
  - id: GO:0098792
    label: xenophagy
- description: Self-multimerizes (homodimers/homotrimers via the coiled-coil and B-box) to achieve the avidity required for capsid-lattice recognition and restriction.
  molecular_function:
    id: GO:0042803
    label: protein homodimerization activity
  locations:
  - id: GO:0005737
    label: cytoplasm
  supported_by:
  - reference_id: file:human/TRIM5/TRIM5-uniprot.txt
    supporting_text: Can form homodimers and homotrimers
proposed_new_terms: []
suggested_questions:
- question: How is the balance between TRIM5alpha's two effector outcomes after capsid recognition - proteasome-dependent restriction versus selective autophagic delivery of the capsid - controlled in a given cell type?
- question: To what extent does the innate immune signaling (PRR/TAK1/NF-kB) function of TRIM5alpha contribute to antiviral protection in vivo independently of direct capsid restriction?
suggested_experiments:
- description: Reconstitute capsid-triggered TRIM5alpha E3 ligase activity in vitro with purified TRIM5alpha (wild-type vs RING C15A and PRYSPRY mutants), UBE2V1-UBE2N, ubiquitin and assembled capsid tubes, to map how lattice binding stimulates unanchored K63-chain synthesis and TAK1 activation.
- description: Use separation-of-function TRIM5alpha mutants (restriction-competent/signaling-dead and signaling-competent/restriction-dead) in primary human cells to dissect the relative contributions of capsid restriction, NF-kB/MAPK signaling, and selective autophagy to antiretroviral defense.