id: Q86XT2 gene_symbol: VPS37D product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: VPS37D is a VPS37-family ESCRT-I subunit in TSG101-VPS28-VPS37-MVB12/UBAP-family complexes. The best-supported cellular function is ESCRT-I-dependent endosomal sorting of ubiquitinated cargo into multivesicular bodies, with late-endosome/endosome-membrane localization. Current local evidence does not support transferring VPS37A-specific phagophore-closure or VPS37B/VPS28 structural membrane-fission assays to VPS37D as core annotations. existing_annotations: - term: id: GO:0043162 label: ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway is supported as part of the core VPS37D/ESCRT-I endosomal cargo-sorting role. action: ACCEPT reason: VPS37D is annotated as an ESCRT-I subunit required for ubiquitin-dependent endosomal cargo sorting into multivesicular bodies. additional_reference_ids: &id001 - PMID:15218037 - PMID:18005716 - file:human/VPS37D/VPS37D-uniprot.txt - file:human/VPS37D/VPS37D-notes.md supported_by: &id002 - &id012 reference_id: file:human/VPS37D/VPS37D-uniprot.txt supporting_text: Required for the sorting of endocytic - &id013 reference_id: file:human/VPS37D/VPS37D-uniprot.txt supporting_text: ubiquitinated cargos into multivesicular bodies - &id014 reference_id: PMID:15218037 supporting_text: sorting ubiquitylated protein cargoes into multivesicular bodies - &id015 reference_id: PMID:18005716 supporting_text: plays essential roles in HIV budding and endosomal protein sorting - term: id: GO:0000813 label: ESCRT I complex evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: part_of review: summary: ESCRT-I complex membership is the central VPS37D cellular-component annotation. action: ACCEPT reason: VPS37D is a VPS37-family ESCRT-I subunit in TSG101-VPS28-VPS37-MVB12/UBAP variant complexes, although direct VPS37D-specific functional evidence is limited. The falcon deep research independently corroborates VPS37D as a bona fide core ESCRT-I subunit while cautioning that it is the least functionally characterized of the four human paralogs. additional_reference_ids: &id003 - PMID:15218037 - PMID:18005716 - PMID:22405001 - file:human/VPS37D/VPS37D-uniprot.txt - file:human/VPS37D/VPS37D-notes.md - file:human/VPS37D/VPS37D-deep-research-falcon.md supported_by: &id004 - &id005 reference_id: file:human/VPS37D/VPS37D-uniprot.txt supporting_text: Component of the ESCRT-I complex - &id006 reference_id: file:human/VPS37D/VPS37D-uniprot.txt supporting_text: which consists of TSG101, VPS28, a VPS37 - &id007 reference_id: file:human/VPS37D/VPS37D-uniprot.txt supporting_text: Interacts with TSG101 and MVB12A - &id008 reference_id: PMID:15218037 supporting_text: proteins (VPS37A-D) that share weak but significant sequence similarity - &id009 reference_id: PMID:18005716 supporting_text: All ESCRT-I complexes contain three common subunits (TSG101, VPS28, and VPS37) - &id021 reference_id: PMID:22405001 supporting_text: complex with Vps23/TSG101, VPS28, and VPS37 - &id022 reference_id: file:human/VPS37D/VPS37D-deep-research-falcon.md supporting_text: confirmed bona fide **human ESCRT-I core subunit**; included among mammalian VPS37A-D paralogs - &id023 reference_id: file:human/VPS37D/VPS37D-deep-research-falcon.md supporting_text: Least functionally characterized of the four human paralogs in primary mechanistic literature - term: id: GO:0006612 label: protein targeting to membrane evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: protein targeting to membrane is too broad for VPS37D ESCRT-I function. action: MODIFY reason: The supported process is ESCRT-I-dependent endosomal cargo sorting into the MVB pathway, not generic protein targeting. proposed_replacement_terms: - id: GO:0043162 label: ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway - id: GO:0036258 label: multivesicular body assembly additional_reference_ids: *id001 supported_by: *id002 - term: id: GO:0006623 label: protein targeting to vacuole evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: protein targeting to vacuole is too broad for VPS37D ESCRT-I function. action: MODIFY reason: The supported process is ESCRT-I-dependent endosomal cargo sorting into the MVB pathway, not generic protein targeting. proposed_replacement_terms: - id: GO:0043162 label: ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway - id: GO:0036258 label: multivesicular body assembly additional_reference_ids: *id001 supported_by: *id002 - term: id: GO:0000813 label: ESCRT I complex evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: part_of review: summary: ESCRT-I complex membership is the central VPS37D cellular-component annotation. action: ACCEPT reason: VPS37D is a VPS37-family ESCRT-I subunit in TSG101-VPS28-VPS37-MVB12/UBAP variant complexes, although direct VPS37D-specific functional evidence is limited. additional_reference_ids: *id003 supported_by: *id004 - term: id: GO:0031902 label: late endosome membrane evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: late endosome membrane localization is supported and relevant to VPS37D/ESCRT-I function. action: ACCEPT reason: VPS37D is a peripheral late-endosome/endosome-membrane ESCRT-I component in local and Reactome context. additional_reference_ids: &id019 - file:human/VPS37D/VPS37D-uniprot.txt - file:human/VPS37D/VPS37D-notes.md supported_by: &id020 - &id010 reference_id: file:human/VPS37D/VPS37D-uniprot.txt supporting_text: Late endosome membrane - &id011 reference_id: file:human/VPS37D/VPS37D-uniprot.txt supporting_text: Peripheral membrane protein - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32296183 qualifier: enables review: summary: Protein binding is too generic to represent VPS37D function. action: MARK_AS_OVER_ANNOTATED reason: The informative annotations are ESCRT-I complex membership and endosomal MVB sorting, not generic protein binding from a broad interaction screen. The falcon deep research notes that, unlike VPS37B/C, VPS37D does not have the selective SH3YL1 or CDIP1 interactions reported for those paralogs, so no specific informative interaction partner can be assigned to VPS37D from the literature to replace this generic term. proposed_replacement_terms: - id: GO:0000813 label: ESCRT I complex additional_reference_ids: - PMID:32296183 - file:human/VPS37D/VPS37D-notes.md - file:human/VPS37D/VPS37D-deep-research-falcon.md supported_by: - reference_id: file:human/VPS37D/VPS37D-notes.md supporting_text: The generic `protein binding` row comes from a broad interactome annotation - reference_id: file:human/VPS37D/VPS37D-deep-research-falcon.md supporting_text: does **not** show the same highlighted SH3YL1 or CDIP1 preference reported for VPS37B/C - term: id: GO:0000813 label: ESCRT I complex evidence_type: IPI original_reference_id: PMID:18005716 qualifier: part_of review: summary: ESCRT-I complex membership is the central VPS37D cellular-component annotation. action: ACCEPT reason: VPS37D is a VPS37-family ESCRT-I subunit in TSG101-VPS28-VPS37-MVB12/UBAP variant complexes, although direct VPS37D-specific functional evidence is limited. additional_reference_ids: *id003 supported_by: *id004 - term: id: GO:0000813 label: ESCRT I complex evidence_type: IPI original_reference_id: PMID:21757351 qualifier: part_of review: summary: ESCRT-I complex membership is correct for VPS37D, but PMID:21757351 is indirect for this isoform. action: ACCEPT reason: The term is correct from UniProt and shared ESCRT-I evidence; PMID:21757351 mainly defines an endosome-specific UBAP1/VPS37A complex and should not be treated as direct VPS37D functional support. additional_reference_ids: - PMID:18005716 - PMID:21757351 - file:human/VPS37D/VPS37D-uniprot.txt - file:human/VPS37D/VPS37D-notes.md supported_by: - *id005 - *id006 - *id007 - *id008 - *id009 - reference_id: PMID:21757351 supporting_text: contains VPS37A but not VPS37C - term: id: GO:0010008 label: endosome membrane evidence_type: NAS original_reference_id: PMID:32424346 qualifier: located_in review: summary: endosome membrane is correct for VPS37D, but PMID:32424346 is indirect for this isoform. action: ACCEPT reason: Endosome-membrane localization is supported by VPS37D context; PMID:32424346 supports general ESCRT-I mechanism using a VPS37B-containing headpiece. additional_reference_ids: - PMID:32424346 - file:human/VPS37D/VPS37D-uniprot.txt - file:human/VPS37D/VPS37D-notes.md supported_by: - *id010 - *id011 - &id016 reference_id: PMID:32424346 supporting_text: comprising TSG101-VPS28-VPS37B-MVB12A - term: id: GO:0036258 label: multivesicular body assembly evidence_type: NAS original_reference_id: PMID:32424346 qualifier: involved_in review: summary: multivesicular body assembly is biologically consistent with VPS37D ESCRT-I function, but PMID:32424346 is indirect for this isoform. action: ACCEPT reason: The term is supported by VPS37D ESCRT-I/MVB context; PMID:32424346 supports general ESCRT-I mechanism using a VPS37B-containing headpiece. additional_reference_ids: - PMID:32424346 - PMID:15218037 - PMID:18005716 - file:human/VPS37D/VPS37D-uniprot.txt - file:human/VPS37D/VPS37D-notes.md supported_by: - *id012 - *id013 - *id014 - *id015 - *id016 - term: id: GO:0043328 label: protein transport to vacuole involved in ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway evidence_type: NAS original_reference_id: PMID:32424346 qualifier: involved_in review: summary: protein transport to vacuole involved in ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway is biologically consistent with VPS37D ESCRT-I function, but PMID:32424346 is indirect for this isoform. action: ACCEPT reason: The term is supported by VPS37D ESCRT-I/MVB context; PMID:32424346 supports general ESCRT-I mechanism using a VPS37B-containing headpiece. additional_reference_ids: - PMID:32424346 - PMID:15218037 - PMID:18005716 - file:human/VPS37D/VPS37D-uniprot.txt - file:human/VPS37D/VPS37D-notes.md supported_by: - *id012 - *id013 - *id014 - *id015 - *id016 - term: id: GO:0090148 label: membrane fission evidence_type: NAS original_reference_id: PMID:32424346 qualifier: involved_in review: summary: Membrane fission is a broad ESCRT-I mechanism annotation and is over-transferred for VPS37D as written. action: MARK_AS_OVER_ANNOTATED reason: The cited structural/autophagy work directly tested a VPS37B-containing headpiece and VPS28 interface mutants, not VPS37D; the safer VPS37D annotations are ESCRT-I complex and MVB sorting. proposed_replacement_terms: - id: GO:0000813 label: ESCRT I complex - id: GO:0036258 label: multivesicular body assembly additional_reference_ids: - PMID:32424346 - file:human/VPS37D/VPS37D-notes.md supported_by: - *id016 - reference_id: PMID:32424346 supporting_text: ESCRT-I is not merely a bridging adaptor - term: id: GO:0016236 label: macroautophagy evidence_type: TAS original_reference_id: PMID:20588296 qualifier: involved_in review: summary: Macroautophagy is over-annotated for VPS37D. action: MARK_AS_OVER_ANNOTATED reason: The accessible ESCRT autophagy evidence is broad or VPS37A-specific; there is not enough direct evidence to make VPS37D a phagophore-closure/autophagosome assembly factor. The autophagy-specialized ESCRT-I module is built on VPS37A's N-terminal ubiquitin E2 variant-like (UEVL) region; the falcon deep research notes that no equivalent VPS37A-like autophagy UEVL specialization has been established for VPS37D, reinforcing that macroautophagy should not be a VPS37D core annotation. proposed_replacement_terms: - id: GO:0000813 label: ESCRT I complex additional_reference_ids: - PMID:20588296 - PMID:31519728 - PMID:32424346 - file:human/VPS37D/VPS37D-notes.md - file:human/VPS37D/VPS37D-deep-research-falcon.md supported_by: - reference_id: PMID:20588296 supporting_text: viral budding, cytokinesis and, probably, autophagy - reference_id: PMID:20588296 supporting_text: direct neck closure reaction in autophagy - reference_id: PMID:31519728 supporting_text: identify the ESCRT-I subunit VPS37A as a critical component - reference_id: PMID:31519728 supporting_text: required for autophagosome completion - reference_id: file:human/VPS37D/VPS37D-deep-research-falcon.md supporting_text: no VPS37A-like autophagy UEVL specialization has been established in the cited studies - term: id: GO:0000813 label: ESCRT I complex evidence_type: TAS original_reference_id: PMID:20588296 qualifier: part_of review: summary: ESCRT-I complex membership is the central VPS37D cellular-component annotation. action: ACCEPT reason: VPS37D is a VPS37-family ESCRT-I subunit in TSG101-VPS28-VPS37-MVB12/UBAP variant complexes, although direct VPS37D-specific functional evidence is limited. additional_reference_ids: *id003 supported_by: *id004 - term: id: GO:0036258 label: multivesicular body assembly evidence_type: TAS original_reference_id: PMID:20588296 qualifier: involved_in review: summary: multivesicular body assembly is supported as part of the core VPS37D/ESCRT-I endosomal cargo-sorting role. action: ACCEPT reason: VPS37D is annotated as an ESCRT-I subunit required for ubiquitin-dependent endosomal cargo sorting into multivesicular bodies. additional_reference_ids: *id001 supported_by: *id002 - term: id: GO:0039702 label: viral budding via host ESCRT complex evidence_type: TAS original_reference_id: PMID:20588296 qualifier: involved_in review: summary: Viral budding via host ESCRT complex is a supported ESCRT context but is not the core VPS37D proteostasis function. action: KEEP_AS_NON_CORE reason: Viral budding uses ESCRT-I machinery, but VPS37D-specific direct viral-budding evidence is limited and the core cellular role remains endosomal ESCRT-I cargo sorting. additional_reference_ids: - PMID:18005716 - PMID:20588296 - file:human/VPS37D/VPS37D-uniprot.txt - file:human/VPS37D/VPS37D-notes.md supported_by: - reference_id: PMID:18005716 supporting_text: plays essential roles in HIV budding and endosomal protein sorting - reference_id: PMID:20588296 supporting_text: viral budding, cytokinesis and, probably, autophagy - term: id: GO:0000813 label: ESCRT I complex evidence_type: IDA original_reference_id: PMID:18005716 qualifier: part_of review: summary: ESCRT-I complex membership is the central VPS37D cellular-component annotation. action: ACCEPT reason: VPS37D is a VPS37-family ESCRT-I subunit in TSG101-VPS28-VPS37-MVB12/UBAP variant complexes, although direct VPS37D-specific functional evidence is limited. additional_reference_ids: *id003 supported_by: *id004 - term: id: GO:0070062 label: extracellular exosome evidence_type: HDA original_reference_id: PMID:23533145 qualifier: located_in review: summary: Extracellular exosome is a high-throughput proteomics/localization context and not a core VPS37D annotation. action: KEEP_AS_NON_CORE reason: Exosome detection is not the central VPS37D ESCRT-I endosomal sorting function. additional_reference_ids: &id017 - PMID:19056867 - PMID:23533145 - file:human/VPS37D/VPS37D-notes.md supported_by: &id018 - reference_id: PMID:19056867 supporting_text: Large-scale proteomics and phosphoproteomics of urinary exosomes - reference_id: PMID:23533145 supporting_text: In-depth proteomic analyses of exosomes - term: id: GO:0070062 label: extracellular exosome evidence_type: HDA original_reference_id: PMID:19056867 qualifier: located_in review: summary: Extracellular exosome is a high-throughput proteomics/localization context and not a core VPS37D annotation. action: KEEP_AS_NON_CORE reason: Exosome detection is not the central VPS37D ESCRT-I endosomal sorting function. additional_reference_ids: *id017 supported_by: *id018 - term: id: GO:0000813 label: ESCRT I complex evidence_type: IDA original_reference_id: PMID:22405001 qualifier: part_of review: summary: ESCRT-I complex membership is the central VPS37D cellular-component annotation. action: ACCEPT reason: VPS37D is a VPS37-family ESCRT-I subunit in TSG101-VPS28-VPS37-MVB12/UBAP variant complexes, although direct VPS37D-specific functional evidence is limited. additional_reference_ids: *id003 supported_by: *id004 - term: id: GO:0010008 label: endosome membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-184269 qualifier: located_in review: summary: endosome membrane localization is supported and relevant to VPS37D/ESCRT-I function. action: ACCEPT reason: VPS37D is a peripheral late-endosome/endosome-membrane ESCRT-I component in local and Reactome context. additional_reference_ids: *id019 supported_by: *id020 - term: id: GO:0010008 label: endosome membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-3149434 qualifier: located_in review: summary: endosome membrane localization is supported and relevant to VPS37D/ESCRT-I function. action: ACCEPT reason: VPS37D is a peripheral late-endosome/endosome-membrane ESCRT-I component in local and Reactome context. additional_reference_ids: *id019 supported_by: *id020 - term: id: GO:0010008 label: endosome membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-3159232 qualifier: located_in review: summary: endosome membrane localization is supported and relevant to VPS37D/ESCRT-I function. action: ACCEPT reason: VPS37D is a peripheral late-endosome/endosome-membrane ESCRT-I component in local and Reactome context. additional_reference_ids: *id019 supported_by: *id020 - term: id: GO:0010008 label: endosome membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-917696 qualifier: located_in review: summary: endosome membrane localization is supported and relevant to VPS37D/ESCRT-I function. action: ACCEPT reason: VPS37D is a peripheral late-endosome/endosome-membrane ESCRT-I component in local and Reactome context. additional_reference_ids: *id019 supported_by: *id020 - term: id: GO:0010008 label: endosome membrane evidence_type: TAS original_reference_id: Reactome:R-HSA-917730 qualifier: located_in review: summary: endosome membrane localization is supported and relevant to VPS37D/ESCRT-I function. action: ACCEPT reason: VPS37D is a peripheral late-endosome/endosome-membrane ESCRT-I component in local and Reactome context. additional_reference_ids: *id019 supported_by: *id020 references: - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees 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:18005716 title: Identification of human MVB12 proteins as ESCRT-I subunits that function in HIV budding. findings: [] - id: PMID:19056867 title: Large-scale proteomics and phosphoproteomics of urinary exosomes. findings: [] - id: PMID:20588296 title: 'Membrane budding and scission by the ESCRT machinery: it''s all in the neck.' findings: [] - id: PMID:21757351 title: UBAP1 is a component of an endosome-specific ESCRT-I complex that is essential for MVB sorting. findings: [] - id: PMID:22405001 title: The UBAP1 subunit of ESCRT-I interacts with ubiquitin via a SOUBA domain. findings: [] - id: PMID:23533145 title: In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine. findings: [] - id: PMID:32296183 title: A reference map of the human binary protein interactome. findings: [] - id: PMID:32424346 title: A helical assembly of human ESCRT-I scaffolds reverse-topology membrane scission. findings: [] - id: Reactome:R-HSA-184269 title: Monoubiquitinated N-myristoyl GAG polyprotein is targeted to the late endosomal vesicle membrane by the ESCRT-I complex findings: [] - id: Reactome:R-HSA-3149434 title: Transport of GAG to the Plasma Membrane findings: [] - id: Reactome:R-HSA-3159232 title: Recruitment Of HIV Virion Budding Machinery findings: [] - id: Reactome:R-HSA-917696 title: Cargo Sequestration findings: [] - id: Reactome:R-HSA-917730 title: Cargo Recognition And Sorting findings: [] - id: PMID:15218037 title: The human endosomal sorting complex required for transport (ESCRT-I) and its role in HIV-1 budding. findings: [] - id: PMID:31519728 title: VPS37A directs ESCRT recruitment for phagophore closure. findings: [] - id: file:human/VPS37D/VPS37D-uniprot.txt title: UniProtKB record for human VPS37D findings: [] - id: file:human/VPS37D/VPS37D-notes.md title: VPS37D review notes findings: [] - id: file:human/VPS37D/VPS37D-deep-research-falcon.md title: Falcon deep research report for VPS37D reference_review: relevance: MEDIUM correctness: UNVERIFIED review_notes: >- LLM-synthesized deep-research report. The VPS37D-specific claims it makes are appropriately hedged and consistent with the existing review: VPS37D is the least functionally characterized of the four human VPS37 paralogs, is a bona fide core ESCRT-I structural subunit, does NOT show the SH3YL1/CDIP1 selective interactions reported for VPS37B/C, and has no VPS37A-like autophagy UEVL specialization established in the cited literature; it explicitly states that direct VPS37D-specific mechanistic evidence remains limited. The one novel VPS37D-specific assertion (breast-cancer biomarker association from chen2025escrtmayfunction; negligible VPS37D expression in colorectal tissue from kolmus2021) is disease/expression context, not a molecular-function or core-process claim, and was not used to change any GO annotation. All other pathway content (autophagosome closure, cytokinetic abscission, membrane/NE repair, viral budding) is ESCRT-I holo-complex or VPS37A-C paralog inference and is NOT attributed to the VPS37D subunit. Underlying primary PMIDs were not independently re-verified here, hence UNVERIFIED. core_functions: - description: VPS37D is a VPS37-family ESCRT-I subunit that supports ESCRT-I complex organization and ubiquitin-dependent endosomal cargo sorting into multivesicular bodies. directly_involved_in: - id: GO:0043162 label: ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway - id: GO:0036258 label: multivesicular body assembly locations: - id: GO:0010008 label: endosome membrane - id: GO:0031902 label: late endosome membrane in_complex: id: GO:0000813 label: ESCRT I complex supported_by: - *id005 - *id006 - *id007 - *id008 - *id009 - *id021 - *id012 - *id013 - *id014 - *id015 - *id010 - *id011 proposed_new_terms: [] suggested_questions: - question: Should VPS37D macroautophagy annotations be retired or kept non-core given that the direct phagophore-closure evidence is VPS37A-specific? experts: - GO autophagy editors - GO ESCRT curators - question: Should generic VPS37D protein-binding annotations be replaced by ESCRT-I complex membership and specific endosomal sorting terms? experts: - GO molecular function editors - UniProt curators suggested_experiments: - experiment_type: VPS37 paralog phagophore closure comparison hypothesis: VPS37A, but not necessarily VPS37D, is the VPS37 paralog specialized for phagophore closure. description: Compare VPS37A, VPS37B, VPS37C, and VPS37D depletion/rescue in HT-LC3 autophagosome closure assays and parallel EGFR or tetherin MVB-sorting assays, using endogenous expression or matched rescue levels. - experiment_type: VPS37D-specific ESCRT-I cargo-sorting assay hypothesis: VPS37D participates in a subset of ESCRT-I cargo-sorting contexts but lacks direct evidence for autophagosome closure. description: Use VPS37D-specific knockout-rescue with quantitative cargo degradation and ESCRT recruitment readouts, controlling for VPS37A/B/C compensation.