id: Q9Y577 gene_symbol: TRIM17 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- TRIM17 (terf, testis RING finger protein; RNF16) is a RING-type E3 ubiquitin ligase of the TRIM/RBCC family with the canonical architecture of an N-terminal RING-HC zinc finger (conferring E3 ubiquitin ligase activity, EC 2.3.2.27), a B-box, a coiled-coil and a C-terminal B30.2/SPRY domain; it is expressed almost exclusively in testis and undergoes autoubiquitination. TRIM17 is a key regulator of neuronal apoptosis: it ubiquitinates and degrades the anti-apoptotic protein MCL1 to initiate neuronal death, and it controls NFAT transcription factors (NFATC3/NFATC4) by preventing their nuclear localization and thereby inhibiting their transcriptional activity. It also modulates selective autophagy in a target-selective manner: it inhibits autophagic degradation of diverse substrates while contributing to autophagy of midbodies, with its autophagy-inhibitory activity involving MCL1, which TRIM17 assembles into complexes with the autophagy regulator BECN1. Additional reported activities include stimulating proteasomal degradation of the kinetochore protein ZWINT to negatively regulate cell proliferation, antagonizing other TRIM ligases (it prevents TRIM28 from ubiquitinating the anti-apoptotic BCL2A1, and decreases TRIM41-mediated degradation of ZSCAN-family substrates to promote alpha-synuclein/SNCA transcription in neurons), and being stabilized through interaction with TRIM44. TRIM17 localizes to the cytoplasm and lysosome. alternative_products: - name: '1' id: Q9Y577-1 - name: '2' id: Q9Y577-2 sequence_note: VSP_040994, VSP_040995 existing_annotations: - term: id: GO:0005737 label: cytoplasm evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: Phylogenetic inference of cytoplasmic activity; the core compartment for TRIM17. action: ACCEPT reason: Correct core localization; consistent with experimental EXP cytoplasm evidence. supported_by: - reference_id: file:human/TRIM17/TRIM17-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:27562068}.' - term: id: GO:0045087 label: innate immune response evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Family-level phylogenetic inference of innate immune involvement; TRIM17's documented roles are in apoptosis, autophagy and proliferation rather than innate immunity. action: MARK_AS_OVER_ANNOTATED reason: Over-propagated TRIM-family IBA; there is no specific experimental support for an innate-immune function of TRIM17, whose characterized roles are neuronal apoptosis and selective-autophagy regulation. supported_by: - reference_id: file:human/TRIM17/TRIM17-uniprot.txt supporting_text: E3 ubiquitin ligase that plays important roles in the - term: id: GO:0010468 label: regulation of gene expression evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Phylogenetic inference of regulation of gene expression; TRIM17 indirectly affects transcription (NFAT localization, ZSCAN/SNCA). action: KEEP_AS_NON_CORE reason: Indirectly supported (NFAT nuclear-localization control; ZSCAN/SNCA) but a broad term and secondary to the core ligase/apoptosis/autophagy roles. supported_by: - reference_id: file:human/TRIM17/TRIM17-uniprot.txt supporting_text: regulation of neuronal apoptosis, selective autophagy or cell - 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 RING-HC domain and experimental evidence. action: ACCEPT reason: Core molecular function; TRIM17 is a RING-type E3 ubiquitin ligase. supported_by: - reference_id: file:human/TRIM17/TRIM17-uniprot.txt supporting_text: E3 ubiquitin ligase that plays important roles in the - term: id: GO:0004842 label: ubiquitin-protein transferase activity evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: enables review: summary: ARBA machine-learning assignment of ubiquitin-protein transferase activity; core function. action: ACCEPT reason: Core molecular function corroborated by experimental RING-dependent E3 ligase activity. supported_by: - reference_id: file:human/TRIM17/TRIM17-uniprot.txt supporting_text: E3 ubiquitin ligase that plays important roles in the - 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 the experimental EXP cytoplasm annotation. supported_by: - reference_id: file:human/TRIM17/TRIM17-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:27562068}.' - term: id: GO:0005764 label: lysosome evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Electronic transfer of lysosomal localization from the UniProt subcellular location, consistent with the autophagy role. action: ACCEPT reason: Correct localization; redundant with the experimental EXP lysosome annotation. supported_by: - reference_id: file:human/TRIM17/TRIM17-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:27562068}. Lysosome' - 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-HC and B-box zinc fingers. action: KEEP_AS_NON_CORE reason: Correct (RING/B-box coordinate Zn2+) and underpins ligase activity, but generic; the informative MF is ubiquitin ligase activity. supported_by: - reference_id: file:human/TRIM17/TRIM17-uniprot.txt supporting_text: E3 ubiquitin ligase that plays important roles in the - term: id: GO:0051865 label: protein autoubiquitination evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in review: summary: ARBA machine-learning assignment of autoubiquitination, consistent with the experimental IDA evidence. action: ACCEPT reason: Core activity; TRIM17 is autoubiquitinated (RING-dependent), redundant with the IDA annotation. supported_by: - reference_id: file:human/TRIM17/TRIM17-uniprot.txt supporting_text: Auto-ubiquitinated. - 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/TRIM17/TRIM17-uniprot.txt supporting_text: EC=2.3.2.27 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:16189514 qualifier: enables review: summary: Interaction (TRIM39, Q9HCM9) from a proteome-scale interaction map. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: High-throughput interactome; bare protein binding is uninformative per curation guidelines. supported_by: - reference_id: file:human/TRIM17/TRIM17-uniprot.txt supporting_text: 'Q9Y577; Q9HCM9: TRIM39; NbExp=8; IntAct=EBI-743894, EBI-739510;' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:22493164 qualifier: enables review: summary: Interactions (TRIM41, TRIM39) from a dimeric E3-RING interaction screen. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: High-throughput E3-RING dimer screen; bare protein binding is uninformative. supported_by: - reference_id: file:human/TRIM17/TRIM17-uniprot.txt supporting_text: 'Q9Y577; Q8WV44: TRIM41; NbExp=4; IntAct=EBI-743894, EBI-725997;' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:26871637 qualifier: enables review: summary: Interaction (HGS, O14964) from an alternative-splicing interaction study. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: High-throughput interactome; bare protein binding is uninformative. supported_by: - reference_id: file:human/TRIM17/TRIM17-uniprot.txt supporting_text: 'Q9Y577; O14964: HGS; NbExp=6; IntAct=EBI-743894, EBI-740220;' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:29892012 qualifier: enables review: summary: Interaction (TRIM39, Q9HCM9) from an interactome-perturbation study. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: High-throughput interactome; bare protein binding is uninformative. supported_by: - reference_id: file:human/TRIM17/TRIM17-uniprot.txt supporting_text: 'Q9Y577; Q9HCM9: TRIM39; NbExp=8; IntAct=EBI-743894, EBI-739510;' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:31515488 qualifier: enables review: summary: Interaction (TRIM39, Q9HCM9) from a population-variant interaction study. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: High-throughput interactome; bare protein binding is uninformative. supported_by: - reference_id: file:human/TRIM17/TRIM17-uniprot.txt supporting_text: 'Q9Y577; Q9HCM9: TRIM39; NbExp=8; IntAct=EBI-743894, EBI-739510;' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32296183 qualifier: enables review: summary: Interactions (TRIM41, MEOX2, HGS) from the binary interactome reference map. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: High-throughput interactome; bare protein binding is uninformative. supported_by: - reference_id: file:human/TRIM17/TRIM17-uniprot.txt supporting_text: 'Q9Y577; Q6FHY5: MEOX2; NbExp=3; IntAct=EBI-743894, EBI-16439278;' - 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 autoubiquitination and substrate-degradation roles better capture the activity. supported_by: - reference_id: file:human/TRIM17/TRIM17-uniprot.txt supporting_text: 'PATHWAY: Protein modification; protein ubiquitination.' - term: id: GO:0005737 label: cytoplasm evidence_type: EXP original_reference_id: PMID:27562068 qualifier: located_in review: summary: Experimental evidence of cytoplasmic localization in the midbody-autophagy study. Core localization. action: ACCEPT reason: Core cellular component, experimentally demonstrated. supported_by: - reference_id: file:human/TRIM17/TRIM17-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:27562068}.' - term: id: GO:0005764 label: lysosome evidence_type: EXP original_reference_id: PMID:27562068 qualifier: located_in review: summary: Experimental evidence of lysosomal localization in the midbody-autophagy study, consistent with the autophagy role. action: ACCEPT reason: Experimentally supported localization consistent with TRIM17's selective-autophagy function. supported_by: - reference_id: file:human/TRIM17/TRIM17-uniprot.txt supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:27562068}. Lysosome' - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:25127057 qualifier: enables review: summary: Interactions with autophagy machinery (BECN1, ULK1, SQSTM1, ATG8 proteins) from the TRIM-autophagy study. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records real, functionally relevant autophagy interactions but bare protein binding is uninformative; better captured by the adaptor-activity and autophagy annotations. supported_by: - reference_id: PMID:25127057 supporting_text: TRIM proteins regulate autophagy and can target autophagic substrates by direct recognition. - term: id: GO:0030674 label: protein-macromolecule adaptor activity evidence_type: IPI original_reference_id: PMID:25127057 qualifier: enables review: summary: TRIM17 bridges autophagy machinery and regulators (e.g. MCL1/BECN1, ULK1), acting as a molecular adaptor/scaffold in selective autophagy. action: ACCEPT reason: Informative molecular function capturing TRIM17's scaffold/adaptor role in selective-autophagy regulation. supported_by: - reference_id: file:human/TRIM17/TRIM17-uniprot.txt supporting_text: Autophagy-inhibitory activity involves MCL1, which TRIM17 - term: id: GO:0160247 label: autophagy cargo adaptor activity evidence_type: IMP original_reference_id: PMID:27562068 qualifier: enables review: summary: TRIM17 has a selective-autophagy adaptor/receptor role, especially in the target-selective midbody-autophagy context, while also inhibiting degradation of other cargo classes. action: NEW reason: PN showed that GO:0160247 is the best existing GO MF for the selective-autophagy adaptor component of TRIM17's role. This is kept as a scoped NEW recommendation for the midbody-selective activity rather than the core MF, because TRIM17's broader autophagy role is often inhibitory through MCL1/BECN1 stabilization. supported_by: - reference_id: PMID:27562068 supporting_text: TRIM17 promoted the removal of midbodies reference_section_type: ABSTRACT - reference_id: PMID:25127057 supporting_text: TRIMs associate with autophagy factors and act as platforms assembling ULK1 and Beclin 1 reference_section_type: ABSTRACT - term: id: GO:0006914 label: autophagy evidence_type: IDA original_reference_id: PMID:25127057 qualifier: involved_in review: summary: Direct evidence that TRIM17 functions in (regulation of) selective autophagy. Core process. action: ACCEPT reason: Core biological process; TRIM17 regulates selective autophagy (inhibiting degradation of many targets while contributing to midbody autophagy). supported_by: - reference_id: file:human/TRIM17/TRIM17-uniprot.txt supporting_text: degradation of diverse known targets while contributing to autophagy of - 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 TRIM17 regulates localization of autophagy components/regulators (and, more broadly, NFAT nuclear localization). action: KEEP_AS_NON_CORE reason: Supported but a broad process term reflecting the autophagy-scaffold and NFAT-localization roles. supported_by: - reference_id: file:human/TRIM17/TRIM17-uniprot.txt supporting_text: Autophagy-inhibitory activity involves MCL1, which TRIM17 - term: id: GO:0051865 label: protein autoubiquitination evidence_type: IDA original_reference_id: PMID:19358823 qualifier: involved_in review: summary: Direct evidence that TRIM17/terf is autoubiquitinated (RING-dependent). Core activity. action: ACCEPT reason: Core biological process; RING-dependent autoubiquitination is a hallmark of TRIM17 ligase activity. supported_by: - reference_id: file:human/TRIM17/TRIM17-uniprot.txt supporting_text: Auto-ubiquitinated. - term: id: GO:0004842 label: ubiquitin-protein transferase activity evidence_type: IDA original_reference_id: PMID:19358823 qualifier: enables review: summary: Direct evidence that TRIM17/terf is a ubiquitin E3 ligase (transferase). Core MF. action: ACCEPT reason: Core molecular function; demonstrated RING E3 ligase activity. supported_by: - reference_id: PMID:19358823 supporting_text: TRIM44 interacts with and stabilizes terf, a TRIM ubiquitin E3 ligase. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:19358823 qualifier: enables review: summary: Interaction with TRIM44 (via coiled coil), which stabilizes TRIM17. Bare protein binding is uninformative. action: KEEP_AS_NON_CORE reason: Records a real, functionally relevant TRIM44 interaction but bare protein binding is uninformative. supported_by: - reference_id: file:human/TRIM17/TRIM17-uniprot.txt supporting_text: Interacts (via coiled coil) with TRIM44 (via coiled coil) references: - id: GO_REF:0000002 title: Gene Ontology annotation through association of InterPro records with GO terms findings: [] - id: GO_REF:0000003 title: Gene Ontology annotation based on Enzyme Commission mapping findings: [] - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000041 title: Gene Ontology annotation based on UniPathway vocabulary mapping findings: [] - id: GO_REF:0000044 title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt findings: [] - id: GO_REF:0000117 title: Electronic Gene Ontology annotations created by ARBA machine learning models findings: [] - id: PMID:16189514 title: Towards a proteome-scale map of the human protein-protein interaction network. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: High-throughput interactome; source of a bare protein binding (TRIM39) annotation. - id: PMID:19358823 title: TRIM44 interacts with and stabilizes terf, a TRIM ubiquitin E3 ligase. findings: - statement: TRIM17/terf is a TRIM ubiquitin E3 ligase that is autoubiquitinated; TRIM44 interacts with (via coiled coil) and stabilizes TRIM17. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: Full text available. Establishes TRIM17/terf as an E3 ligase (transferase, autoubiquitination) and the TRIM44 interaction. "terf" is testis RING finger = TRIM17. - id: PMID:22023800 title: Terf/TRIM17 stimulates degradation of kinetochore protein ZWINT and regulates cell proliferation. findings: - statement: TRIM17/terf interacts with ZWINT, down-regulates ZWINT protein levels, and negatively regulates cell proliferation. reference_section_type: ABSTRACT reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: PubMed-cached abstract supports the ZWINT/proliferation activity in the description; it does not directly support the MCL1 apoptosis claim. - 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 (TRIM41/TRIM39) annotations. - id: PMID:25127057 title: TRIM proteins regulate autophagy and can target autophagic substrates by direct recognition. findings: - statement: TRIM17 is among TRIMs that regulate autophagy; it interacts with autophagy machinery and acts as an adaptor/scaffold, regulating protein localization. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: Cached abstract-only. Supports TRIM17 autophagy involvement, adaptor activity and regulation of protein localization. - id: PMID:26871637 title: Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: High-throughput interactome (alternative splicing); source of a bare protein binding (HGS) annotation. - id: PMID:27562068 title: TRIM17 contributes to autophagy of midbodies while actively sparing other targets from degradation. findings: - statement: TRIM17 contributes to autophagy of midbodies while inhibiting autophagic degradation of other targets (via MCL1 assembled with BECN1); it localizes to the cytoplasm and lysosome. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: Full text available. Establishes TRIM17's target-selective autophagy role and cytoplasm/lysosome localization. - id: PMID:29892012 title: An interactome perturbation framework prioritizes damaging missense mutations for developmental disorders. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: High-throughput interactome; source of a bare protein binding (TRIM39) annotation. - id: PMID:31515488 title: Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: High-throughput interactome; source of a bare protein binding (TRIM39) annotation. - id: PMID:32296183 title: A reference map of the human binary protein interactome. findings: [] reference_review: relevance: LOW correctness: VERIFIED review_notes: Binary interactome reference map; source of bare protein binding (TRIM41, MEOX2, HGS) annotations. core_functions: - description: Functions as a RING-type E3 ubiquitin ligase that regulates neuronal apoptosis by ubiquitinating and degrading the anti-apoptotic protein MCL1 to initiate neuronal death, and undergoes RING-dependent autoubiquitination. molecular_function: id: GO:0061630 label: ubiquitin protein ligase activity locations: - id: GO:0005737 label: cytoplasm supported_by: - reference_id: file:human/TRIM17/TRIM17-uniprot.txt supporting_text: ubiquitination and degradation of MCL1 to initiate neuronal death. - reference_id: PMID:19358823 supporting_text: TRIM44 interacts with and stabilizes terf, a TRIM ubiquitin E3 ligase. directly_involved_in: - id: GO:0051865 label: protein autoubiquitination - description: Modulates selective autophagy in a target-selective manner - inhibiting autophagic degradation of diverse substrates while contributing to autophagy of midbodies - acting as an adaptor/scaffold that assembles MCL1 with BECN1 and engages autophagy machinery. molecular_function: id: GO:0030674 label: protein-macromolecule adaptor activity locations: - id: GO:0005737 label: cytoplasm - id: GO:0005764 label: lysosome supported_by: - reference_id: file:human/TRIM17/TRIM17-uniprot.txt supporting_text: degradation of diverse known targets while contributing to autophagy of - reference_id: PMID:27562068 supporting_text: TRIM17 contributes to autophagy of midbodies while actively sparing other targets from degradation. directly_involved_in: - id: GO:0006914 label: autophagy proposed_new_terms: [] suggested_questions: - question: How does TRIM17 achieve target selectivity in autophagy - inhibiting degradation of most substrates while promoting autophagy of midbodies - and what determines whether a bound partner (e.g. MCL1, BECN1) is protected or degraded? - question: Given TRIM17's near testis-exclusive expression yet prominent roles described in neurons (MCL1, NFAT, SNCA), how is its function partitioned across tissues and which roles are physiologically dominant in vivo? suggested_experiments: - description: Perform ubiquitinome and degradation-rate profiling in TRIM17-knockout versus wild-type neurons to define the endogenous substrate repertoire (MCL1, ZWINT, others) and separate direct ubiquitination targets from indirectly stabilized proteins. - description: Use RING-dead and substrate-binding TRIM17 mutants to dissect which functions (MCL1 degradation/apoptosis, NFAT localization control, midbody autophagy versus autophagy inhibition) require catalytic E3 activity versus a non-catalytic scaffold/adaptor role.