Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005737 cytoplasm	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic inference of cytoplasmic localization, where TRIM5alpha acts in cytoplasmic bodies. Reason: TRIM5alpha is predominantly cytoplasmic and acts there (capsid recognition, signaling, autophagy); strongly supported experimentally. Supporting Evidence: file:human/TRIM5/TRIM5-uniprot.txt Predominantly localizes in cytoplasmic bodies
GO:0045087 innate immune response	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic inference of involvement in innate immunity; TRIM5alpha both restricts retroviruses and activates innate immune signaling. Reason: Core biological process; TRIM5alpha is an innate immune sensor of the retroviral capsid lattice that activates NF-kB/MAPK signaling. Supporting Evidence: PMID:21512573 TRIM5 is an innate immune sensor for the retrovirus capsid lattice
GO:0010468 regulation of gene expression	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Generic regulation-of-gene-expression term inherited phylogenetically; downstream consequence of TRIM5-driven NF-kB/MAPK activation. Reason: Correct but overly generic; the specific positive regulation of NF-kB signaling and MAPK cascade annotations better capture the mechanism. Supporting Evidence: file:human/TRIM5/TRIM5-uniprot.txt Activation of the MAP3K7/TAK1 complex by autophosphorylation
GO:0061630 ubiquitin protein ligase activity	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic inference of RING E3 ubiquitin ligase activity, consistent with the experimentally demonstrated RING-dependent ligase activity. Reason: Core molecular function; the RING domain confers E3 ligase activity essential for restriction, autoubiquitination and signaling. Supporting Evidence: file:human/TRIM5/TRIM5-uniprot.txt The RING-type zinc finger domain confers E3 ubiquitin ligase activity and is essential for retrovirus restriction activity, autoubiquitination
GO:0046596 regulation of viral entry into host cell	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Phylogenetic inference of regulation of viral entry; TRIM5alpha restricts retroviruses but acts after entry, before reverse transcription. 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. Supporting Evidence: file:human/TRIM5/TRIM5-uniprot.txt Blocks viral replication early in the life cycle, after viral entry but before reverse transcription
GO:0019901 protein kinase binding	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Phylogenetic inference of protein kinase binding; TRIM5alpha binds the TAK1 kinase complex and ULK1. Reason: Real and functionally relevant (TAK1/MAP3K7, ULK1) but the informative functions are the downstream signaling activation and autophagy regulation. Supporting Evidence: file:human/TRIM5/TRIM5-uniprot.txt MAP3K7/TAK1, TAB2 and TAB3
GO:0032880 regulation of protein localization	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Phylogenetic inference of regulation of protein localization, consistent with the IMP annotation from the autophagy study. Reason: Supported but a broad process term; reflects TRIM5's autophagy-platform role rather than a core dedicated function. Supporting Evidence: PMID:25127057 TRIM proteins regulate autophagy and can target autophagic substrates by direct recognition
GO:0042803 protein homodimerization activity	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic inference of homodimerization; TRIM5alpha forms homodimers and homotrimers essential for restriction activity. 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. Supporting Evidence: file:human/TRIM5/TRIM5-uniprot.txt Can form homodimers and homotrimers
GO:0043123 positive regulation of canonical NF-kappaB signal transduction	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic inference of positive regulation of NF-kB signaling, consistent with the experimental IMP/IDA evidence. Reason: Core biological process; capsid sensing triggers TRIM5-mediated K63-Ub/TAK1 activation that induces NF-kB. Supporting Evidence: file:human/TRIM5/TRIM5-uniprot.txt Activation of the MAP3K7/TAK1 complex by autophosphorylation
GO:0005634 nucleus	IEA GO_REF:0000044	MARK AS OVER ANNOTATED	Summary: Electronic transfer of a nuclear localization that is only "By similarity" in UniProt (partial nuclear pool seen with TRIM22/TRIM27 coexpression). Reason: Human TRIM5alpha is predominantly cytoplasmic; nuclear localization is only by similarity (UniProtKB:Q0PF16) and context-dependent, not a core or robustly supported localization. Supporting Evidence: file:human/TRIM5/TRIM5-uniprot.txt partial nuclear localization is observed in the presence of TRIM22 or TRIM27
GO:0005737 cytoplasm	IEA GO_REF:0000044	ACCEPT	Summary: Electronic transfer of cytoplasmic localization from the UniProt subcellular location; the core compartment. Reason: Correct core localization; redundant with experimental IDA cytoplasm annotations. Supporting Evidence: file:human/TRIM5/TRIM5-uniprot.txt Predominantly localizes in cytoplasmic bodies
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 and B-box zinc fingers. Reason: Correct (RING and B-box coordinate Zn2+) and underpins ligase/multimerization, but generic; the informative MF is ubiquitin ligase activity. Supporting Evidence: file:human/TRIM5/TRIM5-uniprot.txt /note="RING-type"
GO:0042802 identical protein binding	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: ARBA machine-learning assignment of identical protein binding, reflecting TRIM5 self-association. Reason: Correct (TRIM5 self-associates) but redundant with and less informative than the protein homodimerization activity annotation. Supporting Evidence: file:human/TRIM5/TRIM5-uniprot.txt Can form homodimers and homotrimers
GO:0045893 positive regulation of DNA-templated transcription	IEA GO_REF:0000108	MARK AS OVER ANNOTATED	Summary: Inter-ontology electronic inference from the transcription coactivator activity annotation. 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. Supporting Evidence: PMID:23077300 to induce NF-κB and MAP kinase (MAPK) signaling
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/TRIM5/TRIM5-uniprot.txt EC=2.3.2.27
GO:0005515 protein binding	IPI PMID:22493164 Systematic analysis of dimeric E3-RING interactions reveals ...	KEEP AS NON CORE	Summary: Interaction from a systematic dimeric E3-RING interaction screen. Bare protein binding is uninformative. Reason: Records a real RING-RING interaction but bare protein binding is uninformative per curation guidelines. Supporting Evidence: PMID:22493164 Systematic analysis of dimeric E3-RING interactions
GO:0005515 protein binding	IPI PMID:25203322 PKD1 phosphorylation-dependent degradation of SNAIL by SCF-F...	KEEP AS NON CORE	Summary: Interaction reported in an SCF-FBXO11/SNAIL study (TRIM5 appears as an interactor). Bare protein binding is uninformative. Reason: Bare protein binding is uninformative; not a core TRIM5 function. Supporting Evidence: PMID:25203322 PKD1 phosphorylation-dependent degradation of SNAIL by SCF-FBXO11
GO:0005515 protein binding	IPI PMID:26618866 ∆F508 CFTR interactome remodelling promotes rescue of cystic...	KEEP AS NON CORE	Summary: Interaction from a CFTR interactome remodeling study (TRIM5 interacts with CFTR per IntAct). Bare protein binding is uninformative. Reason: High-throughput interactome interaction; bare protein binding is uninformative. Supporting Evidence: file:human/TRIM5/TRIM5-uniprot.txt Q9C035; P13569: CFTR; NbExp=3
GO:0005515 protein binding	IPI PMID:35156780 CFTR interactome mapping using the mammalian membrane two-hy...	KEEP AS NON CORE	Summary: Interaction from a CFTR mammalian-membrane-two-hybrid screen. Bare protein binding is uninformative. Reason: High-throughput interactome interaction; bare protein binding is uninformative. Supporting Evidence: file:human/TRIM5/TRIM5-uniprot.txt Q9C035; P13569: CFTR; NbExp=3
GO:0042802 identical protein binding	IPI PMID:22493164 Systematic analysis of dimeric E3-RING interactions reveals ...	KEEP AS NON CORE	Summary: TRIM5-TRIM5 self-interaction detected in the E3-RING dimer screen. Reason: Correct self-association but redundant with and less informative than protein homodimerization activity. Supporting Evidence: file:human/TRIM5/TRIM5-uniprot.txt Q9C035; Q9C035: TRIM5; NbExp=3
GO:0042802 identical protein binding	IPI PMID:22829933 TRIM27 negatively regulates NOD2 by ubiquitination and prote...	KEEP AS NON CORE	Summary: Self-interaction / TRIM-TRIM interaction reported in a TRIM27/NOD2 study. Reason: Correct self-association but redundant with the homodimerization annotation. Supporting Evidence: file:human/TRIM5/TRIM5-uniprot.txt Can form homodimers and homotrimers
GO:0140374 antiviral innate immune response	IDA PMID:18248090 TRIM E3 ligases interfere with early and late stages of the ...	ACCEPT	Summary: Direct evidence that TRIM5 functions in the antiviral innate immune response (retroviral restriction screen). Core process. Reason: Core biological process; TRIM5alpha is an antiviral restriction factor and innate immune effector. Supporting Evidence: PMID:18248090 Members of the TRIpartite interaction Motif (TRIM) family of E3 ligases have been shown to exhibit antiviral activities
GO:0036464 cytoplasmic ribonucleoprotein granule	IDA PMID:20357094 p62/sequestosome-1 associates with and sustains the expressi...	KEEP AS NON CORE	Summary: Localization to cytoplasmic RNP granules/P-bodies reported in the SQSTM1/p62 study. Reason: Experimentally observed but a specialized sub-compartment; the core localization is cytoplasmic bodies. Defer to curator who read the full text. Supporting Evidence: PMID:20357094 p62/sequestosome-1 associates with and sustains the expression of retroviral restriction factor TRIM5alpha
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 K63-linked ubiquitination annotation better captures the activity. Supporting Evidence: file:human/TRIM5/TRIM5-uniprot.txt PATHWAY: Protein modification; protein ubiquitination.
GO:0005829 cytosol	IDA GO_REF:0000052	ACCEPT	Summary: Immunofluorescence-based (HPA) cytosolic localization, consistent with the core cytoplasmic site of action. Reason: Correct cytosolic localization; consistent with cytoplasmic body localization. Supporting Evidence: file:human/TRIM5/TRIM5-uniprot.txt Predominantly localizes in cytoplasmic bodies
GO:0005634 nucleus	ISS GO_REF:0000024	MARK AS OVER ANNOTATED	Summary: Sequence-similarity transfer of nuclear localization, matching the "By similarity" nuclear note in UniProt. Reason: Nuclear localization for human TRIM5alpha is only by similarity and context-dependent (TRIM22/TRIM27 coexpression); the protein is predominantly cytoplasmic. Supporting Evidence: file:human/TRIM5/TRIM5-uniprot.txt partial nuclear localization is observed in the presence of TRIM22 or TRIM27
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/IFN activation screen; reflects TRIM5-driven TAK1/NF-kB signaling rather than direct transcriptional coactivation. 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. Supporting Evidence: PMID:23077300 to induce NF-κB and MAP kinase (MAPK) signaling
GO:0044790 suppression of viral release by host	IDA PMID:18248090 TRIM E3 ligases interfere with early and late stages of the ...	MARK AS OVER ANNOTATED	Summary: Late-stage (viral release) suppression assigned from a broad TRIM screen; for TRIM5alpha the validated dominant activity is early post-entry restriction. 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. Supporting Evidence: PMID:18248090 many TRIM proteins affected late stages of the viral life cycle
GO:0046597 host-mediated suppression of symbiont invasion	IDA PMID:18248090 TRIM E3 ligases interfere with early and late stages of the ...	ACCEPT	Summary: Direct evidence that TRIM5 suppresses retroviral invasion (early restriction). Core restriction process. Reason: Core biological process; captures the capsid-dependent post-entry restriction of incoming retroviruses. Supporting Evidence: file:human/TRIM5/TRIM5-uniprot.txt Capsid-specific restriction factor that prevents infection
GO:0005515 protein binding	IPI PMID:25127057 TRIM proteins regulate autophagy and can target autophagic s...	KEEP AS NON CORE	Summary: Autophagy-machinery interactions (ULK1, BECN1, SQSTM1, ATG8 proteins) from the precision-autophagy study. Bare protein binding is uninformative. Reason: Records real, functionally important autophagy interactions but bare protein binding is uninformative; better captured by the adaptor-activity and autophagy annotations. Supporting Evidence: file:human/TRIM5/TRIM5-uniprot.txt Interacts with ULK1 (phosphorylated form), GABARAP, GABARAPL1, GABARAPL2,
GO:0005737 cytoplasm	IDA PMID:25127057 TRIM proteins regulate autophagy and can target autophagic s...	ACCEPT	Summary: Direct evidence of cytoplasmic localization from the autophagy study. Core localization. Reason: Correct core localization, experimentally demonstrated. Supporting Evidence: file:human/TRIM5/TRIM5-uniprot.txt Predominantly localizes in cytoplasmic bodies
GO:0006914 autophagy	IDA PMID:25127057 TRIM proteins regulate autophagy and can target autophagic s...	ACCEPT	Summary: Direct evidence that TRIM5alpha functions in autophagy, as a selective autophagy receptor and as a platform activating ULK1/BECN1. Core process. Reason: Core biological process; TRIM5alpha regulates autophagy and acts as a selective autophagy receptor for the HIV-1 capsid. Supporting Evidence: PMID:25127057 TRIM5α acts as a selective autophagy receptor
GO:0098792 xenophagy	IDA PMID:25127057 TRIM proteins regulate autophagy and can target autophagic s...	NEW	Summary: TRIM5alpha delivers the HIV-1 capsid, a foreign cytosolic viral cargo, for selective autophagic degradation. 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. Supporting Evidence: PMID:25127057 TRIM5α delivered its cognate cytosolic target, a viral capsid protein, for autophagic degradation
GO:0019901 protein kinase binding	IPI PMID:25127057 TRIM proteins regulate autophagy and can target autophagic s...	KEEP AS NON CORE	Summary: Direct interaction with the kinase ULK1 (phosphorylated form) in the autophagy study. Reason: Real and functionally relevant (ULK1) but the informative function is the autophagy-platform/adaptor role. Supporting Evidence: file:human/TRIM5/TRIM5-uniprot.txt Interacts with ULK1 (phosphorylated form)
GO:0030674 protein-macromolecule adaptor activity	IPI PMID:25127057 TRIM proteins regulate autophagy and can target autophagic s...	ACCEPT	Summary: TRIM5alpha bridges autophagy machinery (ULK1, BECN1, ATG8s) and substrate, acting as a molecular adaptor/scaffold. Reason: Informative molecular function capturing TRIM5alpha's role as a selective-autophagy receptor/adaptor that links cargo to the autophagy apparatus. Supporting Evidence: PMID:25127057 act as platforms assembling ULK1 and Beclin 1 in their
GO:0160247 autophagy cargo adaptor activity	IPI PMID:25127057 TRIM proteins regulate autophagy and can target autophagic s...	NEW	Summary: TRIM5alpha acts as a selective-autophagy cargo adaptor/receptor that recognizes viral capsid cargo and couples it to autophagic degradation. 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. Supporting Evidence: PMID:25127057 TRIM5α acts as a selective autophagy receptor PMID:25127057 TRIM5α delivered its cognate cytosolic target, a viral capsid protein, for autophagic degradation
GO:0032880 regulation of protein localization	IMP PMID:25127057 TRIM proteins regulate autophagy and can target autophagic s...	KEEP AS NON CORE	Summary: Mutant-phenotype evidence that TRIM5alpha regulates localization of autophagy components/cargo. Reason: Supported but a broad process term reflecting the autophagy-platform role. Supporting Evidence: PMID:25127057 TRIM proteins regulate autophagy and can target autophagic substrates by direct recognition
GO:1990462 omegasome	IDA PMID:25127057 TRIM proteins regulate autophagy and can target autophagic s...	ACCEPT	Summary: Colocalization with the omegasome (autophagosome-formation site), consistent with TRIM5alpha's autophagy-platform role. Reason: Experimentally supported colocalization at autophagosome biogenesis sites, consistent with the autophagy function. Supporting Evidence: PMID:25127057 act as platforms assembling ULK1 and Beclin 1 in their
GO:0005829 cytosol	TAS Reactome:R-HSA-1031716	ACCEPT	Summary: Reactome curation of cytosolic localization in the interferon-gamma-stimulated gene context. Reason: Correct cytosolic localization, consistent with the core cytoplasmic site of action. Supporting Evidence: file:human/TRIM5/TRIM5-uniprot.txt Predominantly localizes in cytoplasmic bodies
GO:0043123 positive regulation of canonical NF-kappaB signal transduction	IDA PMID:23077300 TRIM protein-mediated regulation of inflammatory and innate ...	ACCEPT	Summary: Direct evidence (TRIM-family NF-kB activation screen) that TRIM5 positively regulates NF-kB signaling via TAK1. Reason: Core biological process; TRIM5-driven TAK1 activation induces NF-kB. Supporting Evidence: PMID:23077300 to induce NF-κB and MAP kinase (MAPK) signaling
GO:0005737 cytoplasm	IDA PMID:18248090 TRIM E3 ligases interfere with early and late stages of the ...	ACCEPT	Summary: Direct evidence of cytoplasmic localization in the retroviral restriction screen. Core localization. Reason: Correct core localization, experimentally demonstrated. Supporting Evidence: file:human/TRIM5/TRIM5-uniprot.txt Predominantly localizes in cytoplasmic bodies
GO:0005515 protein binding	IPI PMID:20357094 p62/sequestosome-1 associates with and sustains the expressi...	KEEP AS NON CORE	Summary: Interaction with SQSTM1/p62 that sustains TRIM5alpha expression. Bare protein binding is uninformative. Reason: Records a real, functionally relevant SQSTM1 interaction but bare protein binding is uninformative. Supporting Evidence: file:human/TRIM5/TRIM5-uniprot.txt Interacts with SQSTM1
GO:0005515 protein binding	IPI PMID:22078707 TRIM5alpha associates with proteasomal subunits in cells whi...	KEEP AS NON CORE	Summary: Interaction with proteasome subunit PSMC2 (and other proteasome subunits) in cytoplasmic bodies. Bare protein binding is uninformative. Reason: Records a real proteasome-subunit interaction relevant to TRIM5 turnover/restriction but bare protein binding is uninformative. Supporting Evidence: file:human/TRIM5/TRIM5-uniprot.txt Interacts with PSMC2
GO:0051607 defense response to virus	TAS PMID:22291694 TRIM5alpha and Species Tropism of HIV/SIV.	ACCEPT	Summary: Author-statement (review) that TRIM5alpha defends against retroviruses. Core process. Reason: Core biological process; TRIM5alpha is a retroviral restriction factor. Supporting Evidence: PMID:22291694 TRIM5α recognizes the multimerized capsid proteins (viral core) of an incoming virus by its PRYSPRY domain
GO:0002218 activation of innate immune response	IDA PMID:21512573 TRIM5 is an innate immune sensor for the retrovirus capsid l...	ACCEPT	Summary: Direct evidence that capsid-lattice sensing by TRIM5 activates the innate immune response. Core process. Reason: Core biological process; capsid recognition triggers TRIM5 ligase activity and innate immune signaling. Supporting Evidence: PMID:21512573 TRIM5 is an innate immune sensor for the retrovirus capsid lattice
GO:0004842 ubiquitin-protein transferase activity	IDA PMID:21512573 TRIM5 is an innate immune sensor for the retrovirus capsid l...	ACCEPT	Summary: Direct evidence that capsid binding triggers TRIM5 E3 ubiquitin transferase activity (with UBE2V1-UBE2N). Core MF. Reason: Core molecular function; TRIM5 catalyzes ubiquitin transfer to generate K63-linked chains upon capsid sensing. Supporting Evidence: file:human/TRIM5/TRIM5-uniprot.txt Binding to the viral capsid triggers its E3 ubiquitin ligase activity
GO:0005515 protein binding	IPI PMID:21512573 TRIM5 is an innate immune sensor for the retrovirus capsid l...	KEEP AS NON CORE	Summary: Interactions with the TAK1 complex (MAP3K7, TAB2, TAB3) from the innate-sensor study. Bare protein binding is uninformative. Reason: Records real, functionally central interactions (TAK1 complex) but bare protein binding is uninformative. Supporting Evidence: file:human/TRIM5/TRIM5-uniprot.txt MAP3K7/TAK1, TAB2 and TAB3
GO:0031664 regulation of lipopolysaccharide-mediated signaling pathway	IMP PMID:21512573 TRIM5 is an innate immune sensor for the retrovirus capsid l...	KEEP AS NON CORE	Summary: Mutant-phenotype evidence linking TRIM5-mediated TAK1 activation to LPS/innate signaling pathways. Reason: Supported but a specific signaling-context process; the core mechanism is capsid-triggered TAK1/NF-kB activation. Defer to curator. Supporting Evidence: file:human/TRIM5/TRIM5-uniprot.txt autophosphorylation of the MAP3K7/TAK1 complex
GO:0038187 pattern recognition receptor activity	IDA PMID:21512573 TRIM5 is an innate immune sensor for the retrovirus capsid l...	ACCEPT	Summary: Direct evidence that TRIM5 acts as a pattern recognition receptor for the retroviral capsid lattice. Core molecular function. Reason: Core molecular function; TRIM5 is a cytosolic PRR sensing the capsid lattice PAMP. Supporting Evidence: PMID:21512573 TRIM5 is an innate immune sensor for the retrovirus capsid lattice
GO:0043123 positive regulation of canonical NF-kappaB signal transduction	IMP PMID:21512573 TRIM5 is an innate immune sensor for the retrovirus capsid l...	ACCEPT	Summary: Mutant-phenotype evidence that TRIM5 positively regulates NF-kB signaling. Core process. Reason: Core biological process; redundant with the IDA/IBA NF-kB annotations. Supporting Evidence: file:human/TRIM5/TRIM5-uniprot.txt Activation of the MAP3K7/TAK1 complex by autophosphorylation
GO:0043410 positive regulation of MAPK cascade	IMP PMID:21512573 TRIM5 is an innate immune sensor for the retrovirus capsid l...	ACCEPT	Summary: Mutant-phenotype evidence that TRIM5-mediated TAK1 activation positively regulates the MAPK cascade. Core process. Reason: Core biological process; capsid-triggered TAK1 activation induces MAPK-responsive genes. Supporting Evidence: file:human/TRIM5/TRIM5-uniprot.txt autophosphorylation of the MAP3K7/TAK1 complex
GO:0051607 defense response to virus	TAS PMID:21512573 TRIM5 is an innate immune sensor for the retrovirus capsid l...	ACCEPT	Summary: Author-statement that TRIM5 defends against retroviruses. Core process. Reason: Core biological process; redundant with the antiviral/restriction annotations. Supporting Evidence: PMID:21512573 TRIM5 is an innate immune sensor for the retrovirus capsid lattice
GO:0070534 protein K63-linked ubiquitination	IDA PMID:21512573 TRIM5 is an innate immune sensor for the retrovirus capsid l...	ACCEPT	Summary: Direct evidence that TRIM5, with UBE2V1-UBE2N, generates K63-linked polyubiquitin chains. Core activity. Reason: Core biological process; the K63-chain synthesis is the mechanistic link between capsid sensing and TAK1/NF-kB activation. Supporting Evidence: file:human/TRIM5/TRIM5-uniprot.txt generates 'Lys-63'-linked
GO:0042803 protein homodimerization activity	IPI PMID:11331580 The tripartite motif family identifies cell compartments.	ACCEPT	Summary: Self-association reported in the foundational TRIM-family paper; homodimerization/multimerization essential for restriction. Core MF. Reason: Core molecular function; self-multimerization underlies capsid-lattice avidity and restriction. Supporting Evidence: file:human/TRIM5/TRIM5-uniprot.txt Can form homodimers and homotrimers

Core Functions

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:

pattern recognition receptor activity

Directly Involved In:

host-mediated suppression of symbiont invasion defense response to virus

Cellular Locations:

cytoplasm

Supporting Evidence:

PMID:21512573
TRIM5 is an innate immune sensor for the retrovirus capsid lattice
PMID:22291694
TRIM5α recognizes the multimerized capsid proteins (viral core) of an incoming virus by its PRYSPRY domain

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:

ubiquitin protein ligase activity

Directly Involved In:

protein K63-linked ubiquitination activation of innate immune response positive regulation of canonical NF-kappaB signal transduction

Cellular Locations:

cytoplasm

Supporting Evidence:

file:human/TRIM5/TRIM5-uniprot.txt
Binding to the viral capsid triggers its E3 ubiquitin ligase activity
PMID:21512573
TRIM5 is an innate immune sensor for the retrovirus capsid lattice

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:

autophagy cargo adaptor activity

Directly Involved In:

xenophagy

Cellular Locations:

cytoplasm

Supporting Evidence:

PMID:25127057
TRIM5α acts as a selective autophagy receptor

Self-multimerizes (homodimers/homotrimers via the coiled-coil and B-box) to achieve the avidity required for capsid-lattice recognition and restriction.

Molecular Function:

protein homodimerization activity

Cellular Locations:

cytoplasm

Supporting Evidence:

file:human/TRIM5/TRIM5-uniprot.txt
Can form homodimers and homotrimers

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000003

Gene Ontology annotation based on Enzyme Commission mapping

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000041

Gene Ontology annotation based on UniPathway vocabulary mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000108

Automatic assignment of GO terms using logical inference, based on on inter-ontology links

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

PMID:11331580

The tripartite motif family identifies cell compartments.

TRIM5 belongs to the TRIM/RBCC family and can self-associate and localize to cytoplasmic bodies.

PMID:18248090

TRIM E3 ligases interfere with early and late stages of the retroviral life cycle.

Screen of 55 TRIM E3 ligases for antiretroviral activity; TRIM proteins affect early and late stages of HIV/MLV/ALV replication.

PMID:20357094

p62/sequestosome-1 associates with and sustains the expression of retroviral restriction factor TRIM5alpha.

SQSTM1/p62 associates with TRIM5alpha in cytoplasmic bodies and sustains its expression.

PMID:21512573

TRIM5 is an innate immune sensor for the retrovirus capsid lattice.

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.

PMID:22078707

TRIM5alpha associates with proteasomal subunits in cells while in complex with HIV-1 virions.

TRIM5alpha interacts with the proteasome subunit PSMC2 and other proteasomal subunits.

PMID:22291694

TRIM5alpha and Species Tropism of HIV/SIV.

TRIM5alpha recognizes the multimerized capsid (viral core) via its PRYSPRY/B30.2 domain; PRYSPRY polymorphisms determine species-specific restriction.

PMID:22493164

Systematic analysis of dimeric E3-RING interactions reveals increased combinatorial complexity in human ubiquitination networks.

PMID:22829933

TRIM27 negatively regulates NOD2 by ubiquitination and proteasomal degradation.

PMID:23077300

TRIM protein-mediated regulation of inflammatory and innate immune signaling and its association with antiretroviral activity.

TRIM5 (with TRIM8) activates TAK1, a downstream kinase that induces NF-kB and MAPK signaling.

PMID:25127057

TRIM proteins regulate autophagy and can target autophagic substrates by direct recognition.

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.

PMID:25203322

PKD1 phosphorylation-dependent degradation of SNAIL by SCF-FBXO11 regulates epithelial-mesenchymal transition and metastasis.

PMID:26618866

∆F508 CFTR interactome remodelling promotes rescue of cystic fibrosis.

PMID:35156780

CFTR interactome mapping using the mammalian membrane two-hybrid high-throughput screening system.

Reactome:R-HSA-1031716

Expression of IFNG-stimulated genes

Suggested Experiments

Experiment: 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.

Experiment: 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.

📚 Additional Documentation

Notes

(TRIM5-notes.md)

TRIM5 (TRIM5alpha) review notes

UniProt: Q9C035 (TRIM5_HUMAN), 493 aa. EC=2.3.2.27 (RING-type E3 ubiquitin transferase).
HGNC:16276. Chromosome 11.

Domain architecture (RBCC/TRIM)

RING-type zinc finger (15-59) -> E3 ubiquitin ligase activity [UniProt FT; PMID:21734049 RING NMR structure]
B box-type zinc finger (90-132) -> higher-order multimerization
Coiled-coil (130-241) -> dimerization/low-order multimerization
B30.2/PRYSPRY (281-493) -> capsid recognition domain (species-specific restriction)
TRIM5alpha (isoform Alpha, Q9C035-1) is the full-length antiviral isoform; other splice isoforms lack the PRYSPRY domain and are non-restrictive (e.g. Iota is dominant-negative).

Core functions (from UniProt FUNCTION + experimental papers)

Capsid-specific retroviral restriction factor. Blocks infection after entry, before reverse transcription. Recognizes the assembled retroviral capsid lattice via the B30.2/PRYSPRY domain. Restricts N-MLV, EIAV, SIVmac, FIV, BIV (human TRIM5a restricts these; weak vs HIV-1). [UniProt; PMID:17156811; PMID:22291694]
Pattern recognition receptor / innate immune sensor of the retroviral capsid lattice. Binding to capsid lattice triggers its RING E3 ligase activity; with UBE2V1-UBE2N (UBC13-UEV1A) it synthesizes unanchored K63-linked polyubiquitin chains that activate the TAK1 (MAP3K7)/TAB2/TAB3 kinase complex by autophosphorylation -> NF-kB and AP-1/MAPK inflammatory gene induction. PMID:21512573
PMID:21512573 supports: GO:0038187 PRR activity (IDA), GO:0002218 activation of innate immune response (IDA), GO:0004842 ubiquitin-protein transferase activity (IDA), GO:0070534 protein K63-linked ubiquitination (IDA), GO:0043123 positive reg canonical NF-kB (IMP), GO:0043410 positive reg MAPK cascade (IMP), GO:0031664 regulation of LPS-mediated signaling (IMP).
E3 ubiquitin ligase: RING-dependent. Autoubiquitinated (RING/UBE2D2-dependent); monoubiquitinated by TRIM21. Generates K63 chains. EC 2.3.2.27. [UniProt; PMID:18312418]
Precision/selective autophagy. TRIM5a is a selective autophagy receptor: directly recognizes HIV-1 capsid protein p24 and delivers it for autophagic degradation; also acts as a platform/regulator assembling ULK1 and Beclin-1 (BECN1) in activated states, activating BECN1 by dissociating it from inhibitors BCL2 and TAB2. Interacts with ULK1, GABARAP/GABARAPL1/GABARAPL2, MAP1LC3A/C, BECN1, SQSTM1. PMID:25127057
Supports GO:0006914 autophagy (IDA), GO:1990462 omegasome (colocalizes), GO:0030674 protein-macromolecule adaptor activity (IPI), GO:0019901 protein kinase binding (IPI ULK1), GO:0032880 regulation of protein localization (IMP).

Localization

Cytoplasm; predominantly in cytoplasmic bodies. [UniProt; PMID:12878161; PMID:20357094; PMID:25127057]
Colocalizes with proteasomal subunits and SQSTM1/p62 in cytoplasmic bodies. PSMC2 interaction. [PMID:22078707; PMID:20357094]
Cytoplasmic ribonucleoprotein granule / P-body (GO:0036464 / GO:0000932) reported via SQSTM1 study. PMID:20357094
Nucleus: only "By similarity" (UniProtKB:Q0PF16) - partial nuclear localization when coexpressed with TRIM22/TRIM27. Not a core localization for human TRIM5a.

Notes on specific annotations

GO:0003713 transcription coactivator activity (IDA, PMID:23077300, ARUK-UCL): PMID:23077300 is a TRIM-family screen for NF-kB/AP-1/IFN activation; TRIM5 activates TAK1 -> NF-kB. The "transcription coactivator activity" framing is an over-interpretation; TRIM5 acts upstream in signaling, not as a DNA-associated coactivator. MARK_AS_OVER_ANNOTATED.
GO:0045893 positive regulation of DNA-templated transcription (IEA GO_REF:0000108, inter-ontology from coactivator): inherits from the coactivator over-annotation. MARK_AS_OVER_ANNOTATED.
GO:0010468 regulation of gene expression (IBA): generic; downstream of NF-kB activation. KEEP_AS_NON_CORE.
GO:0046596 regulation of viral entry into host cell (IBA): TRIM5 blocks post-entry (uncoating/RT), not entry per se; but family-level IBA. Restriction is better captured by host-mediated suppression of symbiont invasion / defense response to virus. KEEP_AS_NON_CORE / acceptable as restriction-related.
GO:0044790 suppression of viral release by host (IDA, PMID:18248090): PMID:18248090 screened TRIM late-stage effects; for TRIM5 the dominant validated activity is early (post-entry) restriction. This late-stage "viral release" assignment is weak for TRIM5a. MARK_AS_OVER_ANNOTATED.
GO:0046597 host-mediated suppression of symbiont invasion (IDA, PMID:18248090): captures the early restriction block. ACCEPT (core restriction).
GO:0140374 antiviral innate immune response (IDA, PMID:18248090): core. ACCEPT.
protein binding (GO:0005515) IPI: many are from CFTR interactome screens (PMID:26618866, PMID:35156780), SNAIL/FBXO11 study (PMID:25203322 - this is about SCF-FBXO11/SNAIL, TRIM5 appears as interactor in IntAct), E3-RING dimer screen (PMID:22493164), NOD2/TRIM27 (PMID:22829933). Bare protein binding -> KEEP_AS_NON_CORE (uninformative per guidelines).
GO:0042802 identical protein binding / GO:0042803 homodimerization: TRIM5 forms homodimers/trimers; multimerization essential for restriction. ACCEPT homodimerization as it is functionally core; identical protein binding redundant -> KEEP_AS_NON_CORE / ACCEPT.
GO:0008270 zinc ion binding (IEA): correct (RING + B-box coordinate Zn). KEEP_AS_NON_CORE (supports but generic).
GO:0019901 protein kinase binding: TRIM5 binds TAK1/MAP3K7 and ULK1 (phosphorylated). Functionally meaningful but the informative function is the signaling activation. KEEP_AS_NON_CORE.

GO IDs verified relevant

GO:0038187 pattern recognition receptor activity (core MF)
GO:0061630 ubiquitin protein ligase activity / GO:0004842 ubiquitin-protein transferase activity (core MF)
GO:0070534 protein K63-linked ubiquitination
GO:0002218 activation of innate immune response
GO:0140374 antiviral innate immune response
GO:0043123 positive regulation of canonical NF-kappaB signal transduction
GO:0043410 positive regulation of MAPK cascade
GO:0006914 autophagy
GO:0042803 protein homodimerization activity

Pn Notes

(TRIM5-pn-notes.md)

TRIM5 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q9C035
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-14
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/TRIM5/TRIM5-ai-review.yaml
AIGR review HTML: missing - genes/human/TRIM5/TRIM5-ai-review.html
Gene notes: present - genes/human/TRIM5/TRIM5-notes.md
GOA TSV: present - genes/human/TRIM5/TRIM5-goa.tsv
UniProt record: present - genes/human/TRIM5/TRIM5-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/TRIM5.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/TRIM5.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

No *-deep-research*.md file found in this gene directory.

AIGR Review Snapshot

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.
Existing/core annotation action counts: ACCEPT: 26; KEEP_AS_NON_CORE: 21; MARK_AS_OVER_ANNOTATED: 5; NEW: 2

PN Consistency Summary

Consistency: Strongly consistent. PN (selective-autophagy receptor for virophagy + catalytic RING E3 ligase), review YAML, and notes all agree: TRIM5alpha is a genuine RING E3 (capsid-triggered K63 chains via UBE2V1-UBE2N → TAK1/NF-kB; PMID:21512573) AND a selective autophagy receptor that delivers HIV-1 capsid for degradation and scaffolds ULK1/BECN1 (PMID:25127057). Both the RING-ligase and the receptor arms are real and confirmed by the review's experimental annotations. TRIM5 has a functional RING (per the critical-distinction guideline) — catalytic ligase MF is correct here.
PN story / NEW pressure: PN xenophagy is genuinely more specific than GOA: GOA carries GO:0006914 autophagy (IDA, PMID:25127057) but NOT GO:0098792 xenophagy (verified real). Virophagy of the HIV-1 capsid is textbook xenophagy → defensible ADD. The RING/ligase node is already_in_goa_exact (GO:0061630 present, IBA+IEA) — already captured. The selective-autophagy-receptor MF (cargo adaptor) is captured in the review as GO:0030674 protein-macromolecule adaptor activity (ACCEPT); the more specific GO:0160247 autophagy cargo adaptor activity (verified real, child of GO:0030674) would be a precise upgrade.
Evidence alignment: Strong overlap. PN cites the selective-autophagy/LIR review and the TRIM5-virophagy paper (= PMID:25127057, in review HIGH) plus 33791238/19489725/21490953 (TRIM/E3 reviews). Review's core refs (PMID:21512573, 25127057, 22291694, 18248090) cover both arms.
Verdict: Consistent; xenophagy ADD warranted; RING ligase already captured. Recommended edits: [YAML] add GO:0098792 xenophagy (involved_in, supported by PMID:25127057) as a more-specific child of the existing autophagy annotation. [YAML] optionally upgrade the GO:0030674 adaptor MF to the more specific GO:0160247 autophagy cargo adaptor activity for the capsid-receptor role.

Full Consistency Review

UniProt: Q9C035 (TRIM5alpha) · batch: proteostasis-batch-2026-06-14 · review status: COMPLETE (very thorough, 40+ annotations)
PN placement: 3 rows — ALP|Autophagy substrate selection|Selective autophagy receptor|Xenophagy; UPS|E3 ubiquitin and UBL ligases|RING|TRIM / class IV|SPRY; UPS|Ubiquitin and UBL binding|E3 ligase|RING / TRIM class IV|SIM. PN-node mapping: Xenophagy type → mapped/ok GO:0098792 xenophagy (more_specific_than_existing_goa); RING group → mapped/ok GO:0061630 ubiquitin protein ligase activity (already_in_goa_exact, x2); E3-ligase ancestors = context_only/too_broad or no_mapping.
Consistency: Strongly consistent. PN (selective-autophagy receptor for virophagy + catalytic RING E3 ligase), review YAML, and notes all agree: TRIM5alpha is a genuine RING E3 (capsid-triggered K63 chains via UBE2V1-UBE2N → TAK1/NF-kB; PMID:21512573) AND a selective autophagy receptor that delivers HIV-1 capsid for degradation and scaffolds ULK1/BECN1 (PMID:25127057). Both the RING-ligase and the receptor arms are real and confirmed by the review's experimental annotations. TRIM5 has a functional RING (per the critical-distinction guideline) — catalytic ligase MF is correct here.
PN story / NEW pressure: PN xenophagy is genuinely more specific than GOA: GOA carries GO:0006914 autophagy (IDA, PMID:25127057) but NOT GO:0098792 xenophagy (verified real). Virophagy of the HIV-1 capsid is textbook xenophagy → defensible ADD. The RING/ligase node is already_in_goa_exact (GO:0061630 present, IBA+IEA) — already captured. The selective-autophagy-receptor MF (cargo adaptor) is captured in the review as GO:0030674 protein-macromolecule adaptor activity (ACCEPT); the more specific GO:0160247 autophagy cargo adaptor activity (verified real, child of GO:0030674) would be a precise upgrade.
Mapping strategy: No node change needed. Xenophagy projection is correct and appropriately narrower than GOA's bare autophagy. Pattern alert (selective-autophagy receptor → elevate cargo-adaptor MF): review uses GO:0030674; GO:0160247 is the more specific cargo-adaptor term and matches the receptor role.
Evidence alignment: Strong overlap. PN cites the selective-autophagy/LIR review and the TRIM5-virophagy paper (= PMID:25127057, in review HIGH) plus 33791238/19489725/21490953 (TRIM/E3 reviews). Review's core refs (PMID:21512573, 25127057, 22291694, 18248090) cover both arms.
Verdict: Consistent; xenophagy ADD warranted; RING ligase already captured. Recommended edits: [YAML] add GO:0098792 xenophagy (involved_in, supported by PMID:25127057) as a more-specific child of the existing autophagy annotation. [YAML] optionally upgrade the GO:0030674 adaptor MF to the more specific GO:0160247 autophagy cargo adaptor activity for the capsid-receptor role.
2026-06-18 follow-up: Implemented both YAML edits: added GO:0098792 xenophagy and GO:0160247 autophagy cargo adaptor activity as NEW recommendations, and updated the core capsid-autophagy function to the more specific MF/process pair.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-14
review_yaml: genes/human/TRIM5/TRIM5-ai-review.yaml
PN workbook rows: 3

PN row 1: Autophagy-Lysosome Pathway | Autophagy substrate selection | Selective autophagy receptor | Xenophagy

UniProt: Q9C035
In branches: ALP, UPS
Notes: Adapter for selective autophagy. Binds to ATG8 and ubiquitinated or degron-contaning substrates. Active in virophagy
PN references (titles):
- Selective Autophagy: ATG8 Family Proteins, LIR Motifs and Cargo Receptors - ScienceDirect
- Full article: TRIM proteins regulate autophagy: TRIM5 is a selective autophagy receptor mediating HIV-1 restriction (tandfonline.com)
PN-node mapping records (path + ancestors):
- [type] Autophagy-Lysosome Pathway|Autophagy substrate selection|Selective autophagy receptor|Xenophagy
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0098792 xenophagy]
  rationale: This PN category captures receptors for selective autophagy of pathogens or pathogen-derived material. The receptor class is narrower than the GO xenophagy process, so this is a propagation mapping.
- [group] Autophagy-Lysosome Pathway|Autophagy substrate selection|Selective autophagy receptor
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad PN taxonomy container. The descendants mix components, regulators, context labels, and mechanistic leaves, so propagation should come only from narrower curated nodes.
- [class] Autophagy-Lysosome Pathway|Autophagy substrate selection
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad substrate-selection container. GO has useful targets for specific receptor, cargo-adaptor, and selective-autophagy leaves, but this class mixes marking, recognition, receptor regulation, and unknown roles and should not propagate as one term.
- [branch] Autophagy-Lysosome Pathway
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level PN branch. It is a project taxonomy umbrella rather than a direct GO assertion; all propagation must come from manually curated child nodes.

PN row 2: Ubiquitin Proteasome System | E3 ubiquitin and UBL ligases | RING | TRIM / class IV | SPRY

UniProt: Q9C035
In branches: ALP, UPS
Signature domains: IPR001841
Auxiliary domains: IPR003877, IPR001870
PN references (titles):
- 33791238 / rev
- 19489725 / rev
PN-node mapping records (path + ancestors):
- [subtype] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|RING|TRIM / class IV|SPRY
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a narrower E3-ligase architecture, component, or domain subdivision already covered by the curated parent E3 mapping. No additional direct GO mapping is needed at this node.
- [type] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|RING|TRIM / class IV
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a narrower E3-ligase architecture, component, or domain subdivision already covered by the curated parent E3 mapping. No additional direct GO mapping is needed at this node.
- [group] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|RING
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0061630 ubiquitin protein ligase activity]
  rationale: This PN group is a catalytic ubiquitin E3 ligase bucket. The shared GO molecular-function target is ubiquitin protein ligase activity.
- [class] Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases
  status=context_only scope=too_broad_to_propagate GO=[GO:0061630 ubiquitin protein ligase activity]
  rationale: This class is a genuine E3-ligase context, but its descendants include catalytic ligases, cullin scaffolds, substrate receptors, adaptors, cofactors, regulators, and UBL modifier systems. A class-level propagation would over-annotate.
- [branch] Ubiquitin Proteasome System
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.

PN row 3: Ubiquitin Proteasome System | Ubiquitin and UBL binding | E3 ligase | RING / TRIM class IV | SIM

UniProt: Q9C035
In branches: ALP, UPS
Signature domains: PMID: 21490953
Auxiliary domains: IPR001841
PN references (titles):
- 21490953
PN-node mapping records (path + ancestors):
- [subtype] Ubiquitin Proteasome System|Ubiquitin and UBL binding|E3 ligase|RING / TRIM class IV|SIM
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a narrower enzyme-family, domain, or architecture subdivision already covered by a curated parent enzyme mapping. No additional direct GO mapping is needed at this node.
- [type] Ubiquitin Proteasome System|Ubiquitin and UBL binding|E3 ligase|RING / TRIM class IV
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a narrower enzyme-family, domain, or architecture subdivision already covered by a curated parent enzyme mapping. No additional direct GO mapping is needed at this node.
- [group] Ubiquitin Proteasome System|Ubiquitin and UBL binding|E3 ligase
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0061630 ubiquitin protein ligase activity]
  rationale: This PN group captures ubiquitin/UBL-binding factors that are E3 ligases. The shared molecular-function target is ubiquitin protein ligase activity.
- [class] Ubiquitin Proteasome System|Ubiquitin and UBL binding
  status=context_only scope=too_broad_to_propagate GO=[GO:0140036 ubiquitin-modified protein reader activity]
  rationale: This class records ubiquitin/UBL-reader context, but the subtree mixes ubiquitin, SUMO, UBL-domain, domain-architecture, catalytic, signaling, trafficking, and nucleic-acid process buckets. It is useful context, not a safe direct propagation.
- [branch] Ubiquitin Proteasome System
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.

Projected GO annotations (3)

GO:0098792 xenophagy | scope=ok_for_propagation_to_go | goa_status=more_specific_than_existing_goa | from=Autophagy-Lysosome Pathway|Autophagy substrate selection|Selective autophagy receptor|Xenophagy
GO:0061630 ubiquitin protein ligase activity | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Ubiquitin Proteasome System|E3 ubiquitin and UBL ligases|RING
GO:0061630 ubiquitin protein ligase activity | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Ubiquitin Proteasome System|Ubiquitin and UBL binding|E3 ligase

Note

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

📄 View Raw YAML

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.

TRIM5

Gene Description

Existing Annotations Review

Core Functions

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.

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.

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.

Self-multimerizes (homodimers/homotrimers via the coiled-coil and B-box) to achieve the avidity required for capsid-lattice recognition and restriction.

References

Suggested Questions for Experts

Suggested Experiments

📚 Additional Documentation

Notes

TRIM5 (TRIM5alpha) review notes

Domain architecture (RBCC/TRIM)

Core functions (from UniProt FUNCTION + experimental papers)

Localization

Notes on specific annotations

GO IDs verified relevant

Pn Notes

TRIM5 PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

PN row 1: Autophagy-Lysosome Pathway | Autophagy substrate selection | Selective autophagy receptor | Xenophagy

PN row 2: Ubiquitin Proteasome System | E3 ubiquitin and UBL ligases | RING | TRIM / class IV | SPRY

PN row 3: Ubiquitin Proteasome System | Ubiquitin and UBL binding | E3 ligase | RING / TRIM class IV | SIM

Projected GO annotations (3)

Note

📄 View Raw YAML