id: Q9UN37 gene_symbol: VPS4A product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: VPS4A is a conserved AAA-family ATPase that recognizes membrane-associated ESCRT-III assemblies through its MIT domain and uses ATP hydrolysis to remodel and disassemble ESCRT-III polymers. This recycling function supports ESCRT-dependent membrane remodeling in MVB/endosomal cargo sorting and related topologically equivalent events, including cytokinetic abscission, nuclear-envelope sealing, viral budding, plasma membrane repair, and exosome release. The core function is ATP-driven ESCRT-III remodeling/disassembly rather than generic protein binding or membership in the ESCRT-III complex itself. existing_annotations: - term: id: GO:0016197 label: endosomal transport evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: Supported as part of the core VPS4A endosomal/MVB sorting and ESCRT-recycling function. action: ACCEPT reason: VPS4A ATPase activity recycles ESCRT-III assemblies, enabling MVB sorting, ILV formation, and late endosomal cargo transport. supported_by: - reference_id: UniProt:Q9UN37 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly - reference_id: UniProt:Q9UN37 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:10637304 supporting_text: The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking - reference_id: PMID:15075231 supporting_text: hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles - term: id: GO:0016887 label: ATP hydrolysis activity evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables review: summary: 'Core VPS4A function: ATP-driven recognition, remodeling, and disassembly of ESCRT-III/protein assemblies.' action: ACCEPT reason: This is the central conserved molecular role of VPS4A and directly supports ESCRT recycling and downstream membrane remodeling. supported_by: - reference_id: UniProt:Q9UN37 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly - reference_id: UniProt:Q9UN37 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:17928862 supporting_text: VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly - reference_id: PMID:18606141 supporting_text: Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding. - 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: Supported as part of the core VPS4A endosomal/MVB sorting and ESCRT-recycling function. action: ACCEPT reason: VPS4A ATPase activity recycles ESCRT-III assemblies, enabling MVB sorting, ILV formation, and late endosomal cargo transport. supported_by: - reference_id: UniProt:Q9UN37 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly - reference_id: UniProt:Q9UN37 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:10637304 supporting_text: The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking - reference_id: PMID:15075231 supporting_text: hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles - term: id: GO:0090611 label: obsolete ubiquitin-independent protein catabolic process via the multivesicular body sorting pathway evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: involved_in review: summary: The annotation captures a real ubiquitin-independent MVB-sorting context, but the current GO term is obsolete. action: MODIFY reason: Use a current MVB sorting pathway term rather than retaining an obsolete ubiquitin-independent protein catabolic process term. supported_by: - reference_id: PMID:10637304 supporting_text: The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking - reference_id: PMID:15075231 supporting_text: hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles proposed_replacement_terms: - id: GO:0071985 label: multivesicular body sorting pathway - term: id: GO:0000922 label: spindle pole evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: located_in review: summary: Supported cell-division or midbody/spindle context for VPS4A, downstream of its ESCRT ATPase function. action: KEEP_AS_NON_CORE reason: This is a bona fide VPS4A cellular role but is context-specific and non-core relative to the conserved ATP-dependent ESCRT-III remodeling function. supported_by: - reference_id: PMID:20616062 supporting_text: depletion of VPS4A, VPS4B, or any of the 11 different human ESCRT-III (CHMP) proteins inhibited abscission - reference_id: PMID:24814515 supporting_text: ANCHR associates with VPS4 at the midbody ring following DNA segregation defects to control abscission timing - term: id: GO:0005524 label: ATP binding evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: summary: Accept ATP binding as part of the core AAA ATPase mechanism that enables VPS4A ATP hydrolysis and ESCRT-III remodeling. action: ACCEPT reason: ATP binding is a mechanistic prerequisite for the accepted ATP hydrolysis and ATP-dependent protein-disaggregase activity of VPS4A; it is less specific than hydrolysis but consistent with the core ATPase function. supported_by: - reference_id: UniProt:Q9UN37 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly - reference_id: UniProt:Q9UN37 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:17928862 supporting_text: VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly - term: id: GO:0005813 label: centrosome evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: located_in review: summary: Supported cell-division or midbody/spindle context for VPS4A, downstream of its ESCRT ATPase function. action: KEEP_AS_NON_CORE reason: This is a bona fide VPS4A cellular role but is context-specific and non-core relative to the conserved ATP-dependent ESCRT-III remodeling function. supported_by: - reference_id: PMID:20616062 supporting_text: depletion of VPS4A, VPS4B, or any of the 11 different human ESCRT-III (CHMP) proteins inhibited abscission - reference_id: PMID:24814515 supporting_text: ANCHR associates with VPS4 at the midbody ring following DNA segregation defects to control abscission timing - term: id: GO:0005819 label: spindle evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Supported cell-division or midbody/spindle context for VPS4A, downstream of its ESCRT ATPase function. action: KEEP_AS_NON_CORE reason: This is a bona fide VPS4A cellular role but is context-specific and non-core relative to the conserved ATP-dependent ESCRT-III remodeling function. supported_by: - reference_id: PMID:20616062 supporting_text: depletion of VPS4A, VPS4B, or any of the 11 different human ESCRT-III (CHMP) proteins inhibited abscission - reference_id: PMID:24814515 supporting_text: ANCHR associates with VPS4 at the midbody ring following DNA segregation defects to control abscission timing - term: id: GO:0006997 label: nucleus organization evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in review: summary: Supported nuclear-envelope/nucleus-organization ESCRT context, but not the primary VPS4A molecular role. action: KEEP_AS_NON_CORE reason: Keep as a non-core ESCRT membrane-sealing context; VPS4A acts through ESCRT-III remodeling rather than as a nucleus-organization factor per se. supported_by: - reference_id: PMID:28242692 supporting_text: In mammals, VPS4 depletion induces nuclear morphology defects - term: id: GO:0007041 label: lysosomal transport evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in review: summary: The broad lysosomal transport annotation reflects VPS4A late-endosomal/MVB trafficking function. action: MODIFY reason: A more specific late endosome-to-lysosome/MVB sorting pathway term better captures the evidence. supported_by: - reference_id: PMID:10637304 supporting_text: The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking - reference_id: PMID:15075231 supporting_text: hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles proposed_replacement_terms: - id: GO:0061764 label: late endosome to lysosome transport via multivesicular body sorting pathway - term: id: GO:0007080 label: mitotic metaphase chromosome alignment evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in review: summary: VPS4A/ESCRT depletion can perturb spindle and chromosome phenotypes, but this does not show VPS4A is a metaphase chromosome-alignment factor. action: MARK_AS_OVER_ANNOTATED reason: The term overstates a downstream cell-division phenotype relative to the direct ESCRT/VPS4 mechanism. supported_by: - reference_id: PMID:20616062 supporting_text: depletion of VPS4A, VPS4B, or any of the 11 different human ESCRT-III (CHMP) proteins inhibited abscission - reference_id: PMID:24814515 supporting_text: ANCHR associates with VPS4 at the midbody ring following DNA segregation defects to control abscission timing - term: id: GO:0010389 label: regulation of G2/M transition of mitotic cell cycle evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in review: summary: The automated G2/M-transition annotation is too broad and indirect for VPS4A. action: MARK_AS_OVER_ANNOTATED reason: Available evidence supports ESCRT-mediated abscission and membrane remodeling, not direct regulation of the G2/M transition. supported_by: - reference_id: PMID:20616062 supporting_text: depletion of VPS4A, VPS4B, or any of the 11 different human ESCRT-III (CHMP) proteins inhibited abscission - reference_id: PMID:24814515 supporting_text: ANCHR associates with VPS4 at the midbody ring following DNA segregation defects to control abscission timing - term: id: GO:0016887 label: ATP hydrolysis activity evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: enables review: summary: 'Core VPS4A function: ATP-driven recognition, remodeling, and disassembly of ESCRT-III/protein assemblies.' action: ACCEPT reason: This is the central conserved molecular role of VPS4A and directly supports ESCRT recycling and downstream membrane remodeling. supported_by: - reference_id: UniProt:Q9UN37 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly - reference_id: UniProt:Q9UN37 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:17928862 supporting_text: VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly - reference_id: PMID:18606141 supporting_text: Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding. - term: id: GO:0030496 label: midbody evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Supported cell-division or midbody/spindle context for VPS4A, downstream of its ESCRT ATPase function. action: KEEP_AS_NON_CORE reason: This is a bona fide VPS4A cellular role but is context-specific and non-core relative to the conserved ATP-dependent ESCRT-III remodeling function. supported_by: - reference_id: PMID:20616062 supporting_text: depletion of VPS4A, VPS4B, or any of the 11 different human ESCRT-III (CHMP) proteins inhibited abscission - reference_id: PMID:24814515 supporting_text: ANCHR associates with VPS4 at the midbody ring following DNA segregation defects to control abscission timing - term: id: GO:0031902 label: late endosome membrane evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Supported localization for a cytosolic AAA ATPase that is recruited to endosomal/vacuolar membranes during ESCRT function. action: ACCEPT reason: VPS4A cycles between cytosol and membrane-associated ESCRT assemblies; these compartments are consistent with the core endosomal/MVB role. supported_by: - reference_id: UniProt:Q9UN37 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly - reference_id: UniProt:Q9UN37 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:10637304 supporting_text: The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking - reference_id: PMID:15075231 supporting_text: hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles - term: id: GO:0039702 label: viral budding via host ESCRT complex evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in review: summary: Directly supported viral/plasma-membrane ESCRT context, but this is host-pathogen exploitation of VPS4A machinery rather than the core cellular function. action: KEEP_AS_NON_CORE reason: Keep as a real non-core ESCRT output; do not use it to define the primary function of VPS4A. supported_by: - reference_id: PMID:11595185 supporting_text: Dominant negative mutant Vps4 proteins that inhibit vacuolar protein sorting also arrest HIV-1 and MLV budding. - reference_id: PMID:17940959 supporting_text: A lack of VPS4 adenosine triphosphatase activity reduced budding by up to 80% - term: id: GO:0043162 label: ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in review: summary: Supported as part of the core VPS4A endosomal/MVB sorting and ESCRT-recycling function. action: ACCEPT reason: VPS4A ATPase activity recycles ESCRT-III assemblies, enabling MVB sorting, ILV formation, and late endosomal cargo transport. supported_by: - reference_id: UniProt:Q9UN37 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly - reference_id: UniProt:Q9UN37 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:10637304 supporting_text: The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking - reference_id: PMID:15075231 supporting_text: hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles - term: id: GO:0051261 label: protein depolymerization evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in review: summary: VPS4A depolymerizes/remodels ESCRT-III assemblies rather than depolymerizing proteins generally. action: MODIFY reason: ESCRT III complex disassembly is the specific process supported by the VPS4A mechanism. supported_by: - reference_id: UniProt:Q9UN37 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly - reference_id: UniProt:Q9UN37 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:17928862 supporting_text: VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly - reference_id: PMID:18606141 supporting_text: Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding. proposed_replacement_terms: - id: GO:1904903 label: ESCRT III complex disassembly - term: id: GO:0061952 label: midbody abscission evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in review: summary: Supported cell-division or midbody/spindle context for VPS4A, downstream of its ESCRT ATPase function. action: KEEP_AS_NON_CORE reason: This is a bona fide VPS4A cellular role but is context-specific and non-core relative to the conserved ATP-dependent ESCRT-III remodeling function. supported_by: - reference_id: PMID:20616062 supporting_text: depletion of VPS4A, VPS4B, or any of the 11 different human ESCRT-III (CHMP) proteins inhibited abscission - reference_id: PMID:24814515 supporting_text: ANCHR associates with VPS4 at the midbody ring following DNA segregation defects to control abscission timing - term: id: GO:0090543 label: Flemming body evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: located_in review: summary: Supported cell-division or midbody/spindle context for VPS4A, downstream of its ESCRT ATPase function. action: KEEP_AS_NON_CORE reason: This is a bona fide VPS4A cellular role but is context-specific and non-core relative to the conserved ATP-dependent ESCRT-III remodeling function. supported_by: - reference_id: PMID:20616062 supporting_text: depletion of VPS4A, VPS4B, or any of the 11 different human ESCRT-III (CHMP) proteins inhibited abscission - reference_id: PMID:24814515 supporting_text: ANCHR associates with VPS4 at the midbody ring following DNA segregation defects to control abscission timing - term: id: GO:0090611 label: obsolete ubiquitin-independent protein catabolic process via the multivesicular body sorting pathway evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in review: summary: The annotation captures a real ubiquitin-independent MVB-sorting context, but the current GO term is obsolete. action: MODIFY reason: Use a current MVB sorting pathway term rather than retaining an obsolete ubiquitin-independent protein catabolic process term. supported_by: - reference_id: PMID:10637304 supporting_text: The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking - reference_id: PMID:15075231 supporting_text: hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles proposed_replacement_terms: - id: GO:0071985 label: multivesicular body sorting pathway - term: id: GO:1903543 label: positive regulation of exosomal secretion evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in review: summary: Supported exosome-release context for VPS4A/B but not the primary cellular function. action: KEEP_AS_NON_CORE reason: Exosome secretion is one downstream ESCRT-dependent output of VPS4A activity, so retain as non-core. supported_by: - reference_id: UniProt:Q9UN37 supporting_text: VPS4A/B are required for the exosomal release of SDCBP, CD63 and syndecan - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:16730941 qualifier: enables review: summary: The underlying interaction evidence may be useful context, especially for ESCRT-III, IST1, ZFYVE19/ANCHR, VPS4B, SPAST, or high-throughput interactome partners, but GO:0005515 is too generic to describe VPS4A molecular function. action: MARK_AS_OVER_ANNOTATED reason: VPS4A function is better represented by ATP-dependent ESCRT-III remodeling/disassembly and, where supported, protein-containing complex binding. A generic protein-binding annotation obscures the actual function. supported_by: - reference_id: file:human/VPS4A/VPS4A-notes.md supporting_text: Plain `GO:0005515 protein binding` rows should not be retained as informative functions. - reference_id: PMID:17928862 supporting_text: VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly - reference_id: PMID:18606141 supporting_text: Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:17110338 qualifier: enables review: summary: The underlying interaction evidence may be useful context, especially for ESCRT-III, IST1, ZFYVE19/ANCHR, VPS4B, SPAST, or high-throughput interactome partners, but GO:0005515 is too generic to describe VPS4A molecular function. action: MARK_AS_OVER_ANNOTATED reason: VPS4A function is better represented by ATP-dependent ESCRT-III remodeling/disassembly and, where supported, protein-containing complex binding. A generic protein-binding annotation obscures the actual function. supported_by: - reference_id: file:human/VPS4A/VPS4A-notes.md supporting_text: Plain `GO:0005515 protein binding` rows should not be retained as informative functions. - reference_id: PMID:17928862 supporting_text: VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly - reference_id: PMID:18606141 supporting_text: Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:17928862 qualifier: enables review: summary: The underlying interaction evidence may be useful context, especially for ESCRT-III, IST1, ZFYVE19/ANCHR, VPS4B, SPAST, or high-throughput interactome partners, but GO:0005515 is too generic to describe VPS4A molecular function. action: MARK_AS_OVER_ANNOTATED reason: VPS4A function is better represented by ATP-dependent ESCRT-III remodeling/disassembly and, where supported, protein-containing complex binding. A generic protein-binding annotation obscures the actual function. supported_by: - reference_id: file:human/VPS4A/VPS4A-notes.md supporting_text: Plain `GO:0005515 protein binding` rows should not be retained as informative functions. - reference_id: PMID:17928862 supporting_text: VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly - reference_id: PMID:18606141 supporting_text: Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:24814515 qualifier: enables review: summary: The underlying interaction evidence may be useful context, especially for ESCRT-III, IST1, ZFYVE19/ANCHR, VPS4B, SPAST, or high-throughput interactome partners, but GO:0005515 is too generic to describe VPS4A molecular function. action: MARK_AS_OVER_ANNOTATED reason: VPS4A function is better represented by ATP-dependent ESCRT-III remodeling/disassembly and, where supported, protein-containing complex binding. A generic protein-binding annotation obscures the actual function. supported_by: - reference_id: file:human/VPS4A/VPS4A-notes.md supporting_text: Plain `GO:0005515 protein binding` rows should not be retained as informative functions. - reference_id: PMID:17928862 supporting_text: VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly - reference_id: PMID:18606141 supporting_text: Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:26618866 qualifier: enables review: summary: The underlying interaction evidence may be useful context, especially for ESCRT-III, IST1, ZFYVE19/ANCHR, VPS4B, SPAST, or high-throughput interactome partners, but GO:0005515 is too generic to describe VPS4A molecular function. action: MARK_AS_OVER_ANNOTATED reason: VPS4A function is better represented by ATP-dependent ESCRT-III remodeling/disassembly and, where supported, protein-containing complex binding. A generic protein-binding annotation obscures the actual function. supported_by: - reference_id: file:human/VPS4A/VPS4A-notes.md supporting_text: Plain `GO:0005515 protein binding` rows should not be retained as informative functions. - reference_id: PMID:17928862 supporting_text: VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly - reference_id: PMID:18606141 supporting_text: Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:31324722 qualifier: enables review: summary: The underlying interaction evidence may be useful context, especially for ESCRT-III, IST1, ZFYVE19/ANCHR, VPS4B, SPAST, or high-throughput interactome partners, but GO:0005515 is too generic to describe VPS4A molecular function. action: MARK_AS_OVER_ANNOTATED reason: VPS4A function is better represented by ATP-dependent ESCRT-III remodeling/disassembly and, where supported, protein-containing complex binding. A generic protein-binding annotation obscures the actual function. supported_by: - reference_id: file:human/VPS4A/VPS4A-notes.md supporting_text: Plain `GO:0005515 protein binding` rows should not be retained as informative functions. - reference_id: PMID:17928862 supporting_text: VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly - reference_id: PMID:18606141 supporting_text: Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32296183 qualifier: enables review: summary: The underlying interaction evidence may be useful context, especially for ESCRT-III, IST1, ZFYVE19/ANCHR, VPS4B, SPAST, or high-throughput interactome partners, but GO:0005515 is too generic to describe VPS4A molecular function. action: MARK_AS_OVER_ANNOTATED reason: VPS4A function is better represented by ATP-dependent ESCRT-III remodeling/disassembly and, where supported, protein-containing complex binding. A generic protein-binding annotation obscures the actual function. supported_by: - reference_id: file:human/VPS4A/VPS4A-notes.md supporting_text: Plain `GO:0005515 protein binding` rows should not be retained as informative functions. - reference_id: PMID:17928862 supporting_text: VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly - reference_id: PMID:18606141 supporting_text: Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:33961781 qualifier: enables review: summary: The underlying interaction evidence may be useful context, especially for ESCRT-III, IST1, ZFYVE19/ANCHR, VPS4B, SPAST, or high-throughput interactome partners, but GO:0005515 is too generic to describe VPS4A molecular function. action: MARK_AS_OVER_ANNOTATED reason: VPS4A function is better represented by ATP-dependent ESCRT-III remodeling/disassembly and, where supported, protein-containing complex binding. A generic protein-binding annotation obscures the actual function. supported_by: - reference_id: file:human/VPS4A/VPS4A-notes.md supporting_text: Plain `GO:0005515 protein binding` rows should not be retained as informative functions. - reference_id: PMID:17928862 supporting_text: VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly - reference_id: PMID:18606141 supporting_text: Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:35156780 qualifier: enables review: summary: The underlying interaction evidence may be useful context, especially for ESCRT-III, IST1, ZFYVE19/ANCHR, VPS4B, SPAST, or high-throughput interactome partners, but GO:0005515 is too generic to describe VPS4A molecular function. action: MARK_AS_OVER_ANNOTATED reason: VPS4A function is better represented by ATP-dependent ESCRT-III remodeling/disassembly and, where supported, protein-containing complex binding. A generic protein-binding annotation obscures the actual function. supported_by: - reference_id: file:human/VPS4A/VPS4A-notes.md supporting_text: Plain `GO:0005515 protein binding` rows should not be retained as informative functions. - reference_id: PMID:17928862 supporting_text: VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly - reference_id: PMID:18606141 supporting_text: Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:35271311 qualifier: enables review: summary: The underlying interaction evidence may be useful context, especially for ESCRT-III, IST1, ZFYVE19/ANCHR, VPS4B, SPAST, or high-throughput interactome partners, but GO:0005515 is too generic to describe VPS4A molecular function. action: MARK_AS_OVER_ANNOTATED reason: VPS4A function is better represented by ATP-dependent ESCRT-III remodeling/disassembly and, where supported, protein-containing complex binding. A generic protein-binding annotation obscures the actual function. supported_by: - reference_id: file:human/VPS4A/VPS4A-notes.md supporting_text: Plain `GO:0005515 protein binding` rows should not be retained as informative functions. - reference_id: PMID:17928862 supporting_text: VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly - reference_id: PMID:18606141 supporting_text: Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:36012204 qualifier: enables review: summary: The underlying interaction evidence may be useful context, especially for ESCRT-III, IST1, ZFYVE19/ANCHR, VPS4B, SPAST, or high-throughput interactome partners, but GO:0005515 is too generic to describe VPS4A molecular function. action: MARK_AS_OVER_ANNOTATED reason: VPS4A function is better represented by ATP-dependent ESCRT-III remodeling/disassembly and, where supported, protein-containing complex binding. A generic protein-binding annotation obscures the actual function. supported_by: - reference_id: file:human/VPS4A/VPS4A-notes.md supporting_text: Plain `GO:0005515 protein binding` rows should not be retained as informative functions. - reference_id: PMID:17928862 supporting_text: VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly - reference_id: PMID:18606141 supporting_text: Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding. - term: id: GO:0005737 label: cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: located_in review: summary: Supported localization for a cytosolic AAA ATPase that is recruited to endosomal/vacuolar membranes during ESCRT function. action: ACCEPT reason: VPS4A cycles between cytosol and membrane-associated ESCRT assemblies; these compartments are consistent with the core endosomal/MVB role. supported_by: - reference_id: UniProt:Q9UN37 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly - reference_id: UniProt:Q9UN37 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:10637304 supporting_text: The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking - reference_id: PMID:15075231 supporting_text: hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles - term: id: GO:0036258 label: multivesicular body assembly evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: Supported as part of the core VPS4A endosomal/MVB sorting and ESCRT-recycling function. action: ACCEPT reason: VPS4A ATPase activity recycles ESCRT-III assemblies, enabling MVB sorting, ILV formation, and late endosomal cargo transport. supported_by: - reference_id: UniProt:Q9UN37 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly - reference_id: UniProt:Q9UN37 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:10637304 supporting_text: The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking - reference_id: PMID:15075231 supporting_text: hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles - term: id: GO:0046761 label: viral budding from plasma membrane evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: involved_in review: summary: Directly supported viral/plasma-membrane ESCRT context, but this is host-pathogen exploitation of VPS4A machinery rather than the core cellular function. action: KEEP_AS_NON_CORE reason: Keep as a real non-core ESCRT output; do not use it to define the primary function of VPS4A. supported_by: - reference_id: PMID:11595185 supporting_text: Dominant negative mutant Vps4 proteins that inhibit vacuolar protein sorting also arrest HIV-1 and MLV budding. - reference_id: PMID:17940959 supporting_text: A lack of VPS4 adenosine triphosphatase activity reduced budding by up to 80% - term: id: GO:0048471 label: perinuclear region of cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: located_in review: summary: Supported localization or pathway context, but not central enough to define VPS4A core function. action: KEEP_AS_NON_CORE reason: Keep as a non-core context attached to the broader ESCRT ATPase role. supported_by: - reference_id: PMID:10637304 supporting_text: The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking - reference_id: PMID:15075231 supporting_text: hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles - term: id: GO:0061738 label: late endosomal microautophagy evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: Late endosomal microautophagy is a plausible ESCRT-dependent process, but this specific human VPS4A annotation is based on transferred or automated evidence in the local files. action: UNDECIDED reason: Retain uncertainty pending direct human evidence or a reviewed source tying VPS4A specifically to late endosomal microautophagy. supported_by: - reference_id: PMID:17428789 supporting_text: deletion of VPS4 and VPS36 caused impaired maturation of the vacuolar proaminopeptidase I (pAPI) via autophagy or the cytosol to vacuole targeting pathway - reference_id: PMID:20588296 supporting_text: ESCRT-III-mediated membrane neck cleavage is crucial for many processes, including the biogenesis of multivesicular bodies, viral budding, cytokinesis, and probably autophagy. - term: id: GO:0030496 label: midbody evidence_type: IDA original_reference_id: GO_REF:0000052 qualifier: located_in review: summary: Supported cell-division or midbody/spindle context for VPS4A, downstream of its ESCRT ATPase function. action: KEEP_AS_NON_CORE reason: This is a bona fide VPS4A cellular role but is context-specific and non-core relative to the conserved ATP-dependent ESCRT-III remodeling function. supported_by: - reference_id: PMID:20616062 supporting_text: depletion of VPS4A, VPS4B, or any of the 11 different human ESCRT-III (CHMP) proteins inhibited abscission - reference_id: PMID:24814515 supporting_text: ANCHR associates with VPS4 at the midbody ring following DNA segregation defects to control abscission timing - term: id: GO:0090148 label: membrane fission evidence_type: IDA original_reference_id: PMID:36604498 qualifier: involved_in review: summary: Supported as part of the ESCRT-III/VPS4 membrane-remodeling machinery. action: ACCEPT reason: Recent CHMP2A-CHMP3-VPS4 reconstitution supports VPS4 participation in membrane constriction and cleavage; this is a core ESCRT output. supported_by: - reference_id: PMID:36604498 supporting_text: VPS4 can constrict and cleave CHMP2A-CHMP3 membrane tubes - reference_id: PMID:36604498 supporting_text: CHMP2A-CHMP3-VPS4 act as a minimal membrane fission machinery. - reference_id: UniProt:Q9UN37 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly - reference_id: UniProt:Q9UN37 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - term: id: GO:0140545 label: ATP-dependent protein disaggregase activity evidence_type: IDA original_reference_id: PMID:36604498 qualifier: enables review: summary: 'Core VPS4A function: ATP-driven recognition, remodeling, and disassembly of ESCRT-III/protein assemblies.' action: ACCEPT reason: This is the central conserved molecular role of VPS4A and directly supports ESCRT recycling and downstream membrane remodeling. supported_by: - reference_id: UniProt:Q9UN37 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly - reference_id: UniProt:Q9UN37 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:17928862 supporting_text: VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly - reference_id: PMID:18606141 supporting_text: Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding. - term: id: GO:0001778 label: plasma membrane repair evidence_type: NAS original_reference_id: PMID:24482116 qualifier: involved_in review: summary: Supported plasma membrane repair context for ESCRT machinery, retained as a non-core VPS4A output. action: KEEP_AS_NON_CORE reason: Plasma membrane repair uses ESCRT-mediated shedding/fission but is a specialized context of the core ESCRT remodeling machinery. supported_by: - reference_id: PMID:24482116 supporting_text: ESCRT proteins were recruited within seconds to plasma membrane wounds - reference_id: PMID:24482116 supporting_text: repair of certain wounds is ensured by ESCRT-mediated extracellular shedding of wounded portions. - term: id: GO:0005643 label: nuclear pore evidence_type: NAS original_reference_id: PMID:16505166 qualifier: part_of review: summary: Supported nuclear-envelope/nucleus-organization ESCRT context, but not the primary VPS4A molecular role. action: KEEP_AS_NON_CORE reason: Keep as a non-core ESCRT membrane-sealing context; VPS4A acts through ESCRT-III remodeling rather than as a nucleus-organization factor per se. supported_by: - reference_id: PMID:28242692 supporting_text: In mammals, VPS4 depletion induces nuclear morphology defects - term: id: GO:0005886 label: plasma membrane evidence_type: NAS original_reference_id: PMID:19234443 qualifier: located_in review: summary: Directly supported viral/plasma-membrane ESCRT context, but this is host-pathogen exploitation of VPS4A machinery rather than the core cellular function. action: KEEP_AS_NON_CORE reason: Keep as a real non-core ESCRT output; do not use it to define the primary function of VPS4A. supported_by: - reference_id: PMID:11595185 supporting_text: Dominant negative mutant Vps4 proteins that inhibit vacuolar protein sorting also arrest HIV-1 and MLV budding. - reference_id: PMID:17940959 supporting_text: A lack of VPS4 adenosine triphosphatase activity reduced budding by up to 80% - term: id: GO:0006914 label: autophagy evidence_type: NAS original_reference_id: PMID:17428789 qualifier: involved_in review: summary: Autophagy connection is plausible for ESCRT machinery, but the local cached evidence for this specific VPS4A annotation is yeast-only or review-level rather than direct human VPS4A evidence. action: MARK_AS_OVER_ANNOTATED reason: The annotation overstates the direct evidence for human VPS4A in macroautophagy/autophagosome maturation. The core supported role remains ESCRT-III disassembly and membrane remodeling. supported_by: - reference_id: PMID:17428789 supporting_text: deletion of VPS4 and VPS36 caused impaired maturation of the vacuolar proaminopeptidase I (pAPI) via autophagy or the cytosol to vacuole targeting pathway - reference_id: PMID:20588296 supporting_text: ESCRT-III-mediated membrane neck cleavage is crucial for many processes, including the biogenesis of multivesicular bodies, viral budding, cytokinesis, and probably autophagy. - term: id: GO:0006997 label: nucleus organization evidence_type: NAS original_reference_id: PMID:20616062 qualifier: involved_in review: summary: Supported nuclear-envelope/nucleus-organization ESCRT context, but not the primary VPS4A molecular role. action: KEEP_AS_NON_CORE reason: Keep as a non-core ESCRT membrane-sealing context; VPS4A acts through ESCRT-III remodeling rather than as a nucleus-organization factor per se. supported_by: - reference_id: PMID:28242692 supporting_text: In mammals, VPS4 depletion induces nuclear morphology defects - term: id: GO:0030496 label: midbody evidence_type: NAS original_reference_id: PMID:26040712 qualifier: located_in review: summary: Supported cell-division or midbody/spindle context for VPS4A, downstream of its ESCRT ATPase function. action: KEEP_AS_NON_CORE reason: This is a bona fide VPS4A cellular role but is context-specific and non-core relative to the conserved ATP-dependent ESCRT-III remodeling function. supported_by: - reference_id: PMID:20616062 supporting_text: depletion of VPS4A, VPS4B, or any of the 11 different human ESCRT-III (CHMP) proteins inhibited abscission - reference_id: PMID:24814515 supporting_text: ANCHR associates with VPS4 at the midbody ring following DNA segregation defects to control abscission timing - term: id: GO:0031468 label: nuclear membrane reassembly evidence_type: NAS original_reference_id: PMID:26040713 qualifier: involved_in review: summary: Supported nuclear-envelope/nucleus-organization ESCRT context, but not the primary VPS4A molecular role. action: KEEP_AS_NON_CORE reason: Keep as a non-core ESCRT membrane-sealing context; VPS4A acts through ESCRT-III remodeling rather than as a nucleus-organization factor per se. supported_by: - reference_id: PMID:28242692 supporting_text: In mammals, VPS4 depletion induces nuclear morphology defects - term: id: GO:0036258 label: multivesicular body assembly evidence_type: NAS original_reference_id: PMID:16505166 qualifier: involved_in review: summary: Supported as part of the core VPS4A endosomal/MVB sorting and ESCRT-recycling function. action: ACCEPT reason: VPS4A ATPase activity recycles ESCRT-III assemblies, enabling MVB sorting, ILV formation, and late endosomal cargo transport. supported_by: - reference_id: UniProt:Q9UN37 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly - reference_id: UniProt:Q9UN37 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:10637304 supporting_text: The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking - reference_id: PMID:15075231 supporting_text: hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles - term: id: GO:0046761 label: viral budding from plasma membrane evidence_type: IMP original_reference_id: PMID:16193069 qualifier: involved_in review: summary: Directly supported viral/plasma-membrane ESCRT context, but this is host-pathogen exploitation of VPS4A machinery rather than the core cellular function. action: KEEP_AS_NON_CORE reason: Keep as a real non-core ESCRT output; do not use it to define the primary function of VPS4A. supported_by: - reference_id: PMID:11595185 supporting_text: Dominant negative mutant Vps4 proteins that inhibit vacuolar protein sorting also arrest HIV-1 and MLV budding. - reference_id: PMID:17940959 supporting_text: A lack of VPS4 adenosine triphosphatase activity reduced budding by up to 80% - term: id: GO:0061764 label: late endosome to lysosome transport via multivesicular body sorting pathway evidence_type: NAS original_reference_id: PMID:9211789 qualifier: involved_in review: summary: Supported as part of the core VPS4A endosomal/MVB sorting and ESCRT-recycling function. action: ACCEPT reason: VPS4A ATPase activity recycles ESCRT-III assemblies, enabling MVB sorting, ILV formation, and late endosomal cargo transport. supported_by: - reference_id: UniProt:Q9UN37 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly - reference_id: UniProt:Q9UN37 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:10637304 supporting_text: The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking - reference_id: PMID:15075231 supporting_text: hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles - term: id: GO:0061952 label: midbody abscission evidence_type: NAS original_reference_id: PMID:20616062 qualifier: involved_in review: summary: Supported cell-division or midbody/spindle context for VPS4A, downstream of its ESCRT ATPase function. action: KEEP_AS_NON_CORE reason: This is a bona fide VPS4A cellular role but is context-specific and non-core relative to the conserved ATP-dependent ESCRT-III remodeling function. supported_by: - reference_id: PMID:20616062 supporting_text: depletion of VPS4A, VPS4B, or any of the 11 different human ESCRT-III (CHMP) proteins inhibited abscission - reference_id: PMID:24814515 supporting_text: ANCHR associates with VPS4 at the midbody ring following DNA segregation defects to control abscission timing - term: id: GO:0071985 label: multivesicular body sorting pathway evidence_type: NAS original_reference_id: PMID:16505166 qualifier: involved_in review: summary: Supported as part of the core VPS4A endosomal/MVB sorting and ESCRT-recycling function. action: ACCEPT reason: VPS4A ATPase activity recycles ESCRT-III assemblies, enabling MVB sorting, ILV formation, and late endosomal cargo transport. supported_by: - reference_id: UniProt:Q9UN37 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly - reference_id: UniProt:Q9UN37 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:10637304 supporting_text: The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking - reference_id: PMID:15075231 supporting_text: hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles - term: id: GO:0090148 label: membrane fission evidence_type: NAS original_reference_id: PMID:19234443 qualifier: involved_in review: summary: Supported as part of the ESCRT-III/VPS4 membrane-remodeling machinery. action: ACCEPT reason: Recent CHMP2A-CHMP3-VPS4 reconstitution supports VPS4 participation in membrane constriction and cleavage; this is a core ESCRT output. supported_by: - reference_id: PMID:36604498 supporting_text: VPS4 can constrict and cleave CHMP2A-CHMP3 membrane tubes - reference_id: PMID:36604498 supporting_text: CHMP2A-CHMP3-VPS4 act as a minimal membrane fission machinery. - reference_id: UniProt:Q9UN37 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly - reference_id: UniProt:Q9UN37 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - term: id: GO:0097352 label: autophagosome maturation evidence_type: NAS original_reference_id: PMID:9211789 qualifier: involved_in review: summary: Autophagy connection is plausible for ESCRT machinery, but the local cached evidence for this specific VPS4A annotation is yeast-only or review-level rather than direct human VPS4A evidence. action: MARK_AS_OVER_ANNOTATED reason: The annotation overstates the direct evidence for human VPS4A in macroautophagy/autophagosome maturation. The core supported role remains ESCRT-III disassembly and membrane remodeling. supported_by: - reference_id: PMID:17428789 supporting_text: deletion of VPS4 and VPS36 caused impaired maturation of the vacuolar proaminopeptidase I (pAPI) via autophagy or the cytosol to vacuole targeting pathway - reference_id: PMID:20588296 supporting_text: ESCRT-III-mediated membrane neck cleavage is crucial for many processes, including the biogenesis of multivesicular bodies, viral budding, cytokinesis, and probably autophagy. - term: id: GO:1904949 label: ATPase complex evidence_type: NAS original_reference_id: PMID:19278657 qualifier: part_of review: summary: 'Core VPS4A function: ATP-driven recognition, remodeling, and disassembly of ESCRT-III/protein assemblies.' action: ACCEPT reason: This is the central conserved molecular role of VPS4A and directly supports ESCRT recycling and downstream membrane remodeling. supported_by: - reference_id: UniProt:Q9UN37 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly - reference_id: UniProt:Q9UN37 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:17928862 supporting_text: VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly - reference_id: PMID:18606141 supporting_text: Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding. - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-3159232 qualifier: located_in review: summary: Supported localization for a cytosolic AAA ATPase that is recruited to endosomal/vacuolar membranes during ESCRT function. action: ACCEPT reason: VPS4A cycles between cytosol and membrane-associated ESCRT assemblies; these compartments are consistent with the core endosomal/MVB role. supported_by: - reference_id: UniProt:Q9UN37 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly - reference_id: UniProt:Q9UN37 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:10637304 supporting_text: The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking - reference_id: PMID:15075231 supporting_text: hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-917693 qualifier: located_in review: summary: Supported localization for a cytosolic AAA ATPase that is recruited to endosomal/vacuolar membranes during ESCRT function. action: ACCEPT reason: VPS4A cycles between cytosol and membrane-associated ESCRT assemblies; these compartments are consistent with the core endosomal/MVB role. supported_by: - reference_id: UniProt:Q9UN37 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly - reference_id: UniProt:Q9UN37 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:10637304 supporting_text: The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking - reference_id: PMID:15075231 supporting_text: hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9610942 qualifier: located_in review: summary: Supported localization for a cytosolic AAA ATPase that is recruited to endosomal/vacuolar membranes during ESCRT function. action: ACCEPT reason: VPS4A cycles between cytosol and membrane-associated ESCRT assemblies; these compartments are consistent with the core endosomal/MVB role. supported_by: - reference_id: UniProt:Q9UN37 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly - reference_id: UniProt:Q9UN37 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:10637304 supporting_text: The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking - reference_id: PMID:15075231 supporting_text: hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9610954 qualifier: located_in review: summary: Supported localization for a cytosolic AAA ATPase that is recruited to endosomal/vacuolar membranes during ESCRT function. action: ACCEPT reason: VPS4A cycles between cytosol and membrane-associated ESCRT assemblies; these compartments are consistent with the core endosomal/MVB role. supported_by: - reference_id: UniProt:Q9UN37 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly - reference_id: UniProt:Q9UN37 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:10637304 supporting_text: The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking - reference_id: PMID:15075231 supporting_text: hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9668389 qualifier: located_in review: summary: Supported localization for a cytosolic AAA ATPase that is recruited to endosomal/vacuolar membranes during ESCRT function. action: ACCEPT reason: VPS4A cycles between cytosol and membrane-associated ESCRT assemblies; these compartments are consistent with the core endosomal/MVB role. supported_by: - reference_id: UniProt:Q9UN37 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly - reference_id: UniProt:Q9UN37 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:10637304 supporting_text: The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking - reference_id: PMID:15075231 supporting_text: hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9668415 qualifier: located_in review: summary: Supported localization for a cytosolic AAA ATPase that is recruited to endosomal/vacuolar membranes during ESCRT function. action: ACCEPT reason: VPS4A cycles between cytosol and membrane-associated ESCRT assemblies; these compartments are consistent with the core endosomal/MVB role. supported_by: - reference_id: UniProt:Q9UN37 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly - reference_id: UniProt:Q9UN37 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:10637304 supporting_text: The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking - reference_id: PMID:15075231 supporting_text: hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles - term: id: GO:0016887 label: ATP hydrolysis activity evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: enables review: summary: 'Core VPS4A function: ATP-driven recognition, remodeling, and disassembly of ESCRT-III/protein assemblies.' action: ACCEPT reason: This is the central conserved molecular role of VPS4A and directly supports ESCRT recycling and downstream membrane remodeling. supported_by: - reference_id: UniProt:Q9UN37 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly - reference_id: UniProt:Q9UN37 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:17928862 supporting_text: VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly - reference_id: PMID:18606141 supporting_text: Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding. - term: id: GO:0031902 label: late endosome membrane evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: located_in review: summary: Supported localization for a cytosolic AAA ATPase that is recruited to endosomal/vacuolar membranes during ESCRT function. action: ACCEPT reason: VPS4A cycles between cytosol and membrane-associated ESCRT assemblies; these compartments are consistent with the core endosomal/MVB role. supported_by: - reference_id: UniProt:Q9UN37 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly - reference_id: UniProt:Q9UN37 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:10637304 supporting_text: The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking - reference_id: PMID:15075231 supporting_text: hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles - term: id: GO:0061952 label: midbody abscission evidence_type: IMP original_reference_id: PMID:24814515 qualifier: involved_in review: summary: Supported cell-division or midbody/spindle context for VPS4A, downstream of its ESCRT ATPase function. action: KEEP_AS_NON_CORE reason: This is a bona fide VPS4A cellular role but is context-specific and non-core relative to the conserved ATP-dependent ESCRT-III remodeling function. supported_by: - reference_id: PMID:20616062 supporting_text: depletion of VPS4A, VPS4B, or any of the 11 different human ESCRT-III (CHMP) proteins inhibited abscission - reference_id: PMID:24814515 supporting_text: ANCHR associates with VPS4 at the midbody ring following DNA segregation defects to control abscission timing - term: id: GO:0016887 label: ATP hydrolysis activity evidence_type: TAS original_reference_id: Reactome:R-HSA-9668415 qualifier: enables review: summary: 'Core VPS4A function: ATP-driven recognition, remodeling, and disassembly of ESCRT-III/protein assemblies.' action: ACCEPT reason: This is the central conserved molecular role of VPS4A and directly supports ESCRT recycling and downstream membrane remodeling. supported_by: - reference_id: UniProt:Q9UN37 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly - reference_id: UniProt:Q9UN37 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:17928862 supporting_text: VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly - reference_id: PMID:18606141 supporting_text: Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding. - term: id: GO:0007084 label: mitotic nuclear membrane reassembly evidence_type: TAS original_reference_id: Reactome:R-HSA-2995410 qualifier: involved_in review: summary: Supported nuclear-envelope/nucleus-organization ESCRT context, but not the primary VPS4A molecular role. action: KEEP_AS_NON_CORE reason: Keep as a non-core ESCRT membrane-sealing context; VPS4A acts through ESCRT-III remodeling rather than as a nucleus-organization factor per se. supported_by: - reference_id: PMID:28242692 supporting_text: In mammals, VPS4 depletion induces nuclear morphology defects - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:18606141 qualifier: enables review: summary: The underlying interaction evidence may be useful context, especially for ESCRT-III, IST1, ZFYVE19/ANCHR, VPS4B, SPAST, or high-throughput interactome partners, but GO:0005515 is too generic to describe VPS4A molecular function. action: MARK_AS_OVER_ANNOTATED reason: VPS4A function is better represented by ATP-dependent ESCRT-III remodeling/disassembly and, where supported, protein-containing complex binding. A generic protein-binding annotation obscures the actual function. supported_by: - reference_id: file:human/VPS4A/VPS4A-notes.md supporting_text: Plain `GO:0005515 protein binding` rows should not be retained as informative functions. - reference_id: PMID:17928862 supporting_text: VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly - reference_id: PMID:18606141 supporting_text: Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding. - term: id: GO:0000916 label: actomyosin contractile ring contraction evidence_type: TAS original_reference_id: PMID:28242692 qualifier: involved_in review: summary: The evidence supports cytokinetic abscission rather than the broader or less accurate cell-division term currently used. action: MODIFY reason: VPS4A acts in the ESCRT-mediated abscission stage of cytokinesis, so midbody abscission is the better term. supported_by: - reference_id: PMID:20616062 supporting_text: depletion of VPS4A, VPS4B, or any of the 11 different human ESCRT-III (CHMP) proteins inhibited abscission - reference_id: PMID:24814515 supporting_text: ANCHR associates with VPS4 at the midbody ring following DNA segregation defects to control abscission timing proposed_replacement_terms: - id: GO:0061952 label: midbody abscission - term: id: GO:0140545 label: ATP-dependent protein disaggregase activity evidence_type: NAS original_reference_id: PMID:28242692 qualifier: enables review: summary: 'Core VPS4A function: ATP-driven recognition, remodeling, and disassembly of ESCRT-III/protein assemblies.' action: ACCEPT reason: This is the central conserved molecular role of VPS4A and directly supports ESCRT recycling and downstream membrane remodeling. supported_by: - reference_id: UniProt:Q9UN37 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly - reference_id: UniProt:Q9UN37 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:17928862 supporting_text: VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly - reference_id: PMID:18606141 supporting_text: Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:16174732 qualifier: enables review: summary: The underlying interaction evidence may be useful context, especially for ESCRT-III, IST1, ZFYVE19/ANCHR, VPS4B, SPAST, or high-throughput interactome partners, but GO:0005515 is too generic to describe VPS4A molecular function. action: MARK_AS_OVER_ANNOTATED reason: VPS4A function is better represented by ATP-dependent ESCRT-III remodeling/disassembly and, where supported, protein-containing complex binding. A generic protein-binding annotation obscures the actual function. supported_by: - reference_id: file:human/VPS4A/VPS4A-notes.md supporting_text: Plain `GO:0005515 protein binding` rows should not be retained as informative functions. - reference_id: PMID:17928862 supporting_text: VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly - reference_id: PMID:18606141 supporting_text: Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding. - term: id: GO:0046761 label: viral budding from plasma membrane evidence_type: IMP original_reference_id: PMID:17940959 qualifier: involved_in review: summary: Directly supported viral/plasma-membrane ESCRT context, but this is host-pathogen exploitation of VPS4A machinery rather than the core cellular function. action: KEEP_AS_NON_CORE reason: Keep as a real non-core ESCRT output; do not use it to define the primary function of VPS4A. supported_by: - reference_id: PMID:11595185 supporting_text: Dominant negative mutant Vps4 proteins that inhibit vacuolar protein sorting also arrest HIV-1 and MLV budding. - reference_id: PMID:17940959 supporting_text: A lack of VPS4 adenosine triphosphatase activity reduced budding by up to 80% - term: id: GO:0032880 label: regulation of protein localization evidence_type: IMP original_reference_id: PMID:18005716 qualifier: involved_in review: summary: Reviewed as a peripheral or insufficiently specific VPS4A annotation relative to the core ESCRT ATPase role. action: KEEP_AS_NON_CORE reason: The annotation is not central enough to define VPS4A core function, but no direct contradiction was found in the local evidence. supported_by: - reference_id: UniProt:Q9UN37 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly - reference_id: UniProt:Q9UN37 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - term: id: GO:0010008 label: endosome membrane evidence_type: IMP original_reference_id: PMID:18606141 qualifier: located_in review: summary: Supported localization for a cytosolic AAA ATPase that is recruited to endosomal/vacuolar membranes during ESCRT function. action: ACCEPT reason: VPS4A cycles between cytosol and membrane-associated ESCRT assemblies; these compartments are consistent with the core endosomal/MVB role. supported_by: - reference_id: UniProt:Q9UN37 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly - reference_id: UniProt:Q9UN37 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:10637304 supporting_text: The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking - reference_id: PMID:15075231 supporting_text: hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles - term: id: GO:0044877 label: protein-containing complex binding evidence_type: IPI original_reference_id: PMID:18606141 qualifier: enables review: summary: 'Core VPS4A function: ATP-driven recognition, remodeling, and disassembly of ESCRT-III/protein assemblies.' action: ACCEPT reason: This is the central conserved molecular role of VPS4A and directly supports ESCRT recycling and downstream membrane remodeling. supported_by: - reference_id: UniProt:Q9UN37 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly - reference_id: UniProt:Q9UN37 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:17928862 supporting_text: VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly - reference_id: PMID:18606141 supporting_text: Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding. - term: id: GO:0061952 label: midbody abscission evidence_type: IMP original_reference_id: PMID:20616062 qualifier: involved_in review: summary: Supported cell-division or midbody/spindle context for VPS4A, downstream of its ESCRT ATPase function. action: KEEP_AS_NON_CORE reason: This is a bona fide VPS4A cellular role but is context-specific and non-core relative to the conserved ATP-dependent ESCRT-III remodeling function. supported_by: - reference_id: PMID:20616062 supporting_text: depletion of VPS4A, VPS4B, or any of the 11 different human ESCRT-III (CHMP) proteins inhibited abscission - reference_id: PMID:24814515 supporting_text: ANCHR associates with VPS4 at the midbody ring following DNA segregation defects to control abscission timing - term: id: GO:0006998 label: nuclear envelope organization evidence_type: TAS original_reference_id: PMID:28242692 qualifier: involved_in review: summary: Supported nuclear-envelope/nucleus-organization ESCRT context, but not the primary VPS4A molecular role. action: KEEP_AS_NON_CORE reason: Keep as a non-core ESCRT membrane-sealing context; VPS4A acts through ESCRT-III remodeling rather than as a nucleus-organization factor per se. supported_by: - reference_id: PMID:28242692 supporting_text: In mammals, VPS4 depletion induces nuclear morphology defects - term: id: GO:0031468 label: nuclear membrane reassembly evidence_type: TAS original_reference_id: PMID:28242692 qualifier: involved_in review: summary: Supported nuclear-envelope/nucleus-organization ESCRT context, but not the primary VPS4A molecular role. action: KEEP_AS_NON_CORE reason: Keep as a non-core ESCRT membrane-sealing context; VPS4A acts through ESCRT-III remodeling rather than as a nucleus-organization factor per se. supported_by: - reference_id: PMID:28242692 supporting_text: In mammals, VPS4 depletion induces nuclear morphology defects - term: id: GO:1904903 label: ESCRT III complex disassembly evidence_type: NAS original_reference_id: PMID:28242692 qualifier: involved_in review: summary: 'Core VPS4A function: ATP-driven recognition, remodeling, and disassembly of ESCRT-III/protein assemblies.' action: ACCEPT reason: This is the central conserved molecular role of VPS4A and directly supports ESCRT recycling and downstream membrane remodeling. supported_by: - reference_id: UniProt:Q9UN37 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly - reference_id: UniProt:Q9UN37 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:17928862 supporting_text: VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly - reference_id: PMID:18606141 supporting_text: Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding. - term: id: GO:0006622 label: protein targeting to lysosome evidence_type: IMP original_reference_id: PMID:16973552 qualifier: involved_in review: summary: Supported as part of the core VPS4A endosomal/MVB sorting and ESCRT-recycling function. action: ACCEPT reason: VPS4A ATPase activity recycles ESCRT-III assemblies, enabling MVB sorting, ILV formation, and late endosomal cargo transport. supported_by: - reference_id: UniProt:Q9UN37 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly - reference_id: UniProt:Q9UN37 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:10637304 supporting_text: The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking - reference_id: PMID:15075231 supporting_text: hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles - term: id: GO:0044878 label: mitotic cytokinesis checkpoint signaling evidence_type: IMP original_reference_id: PMID:24814515 qualifier: involved_in review: summary: Supported cell-division or midbody/spindle context for VPS4A, downstream of its ESCRT ATPase function. action: KEEP_AS_NON_CORE reason: This is a bona fide VPS4A cellular role but is context-specific and non-core relative to the conserved ATP-dependent ESCRT-III remodeling function. supported_by: - reference_id: PMID:20616062 supporting_text: depletion of VPS4A, VPS4B, or any of the 11 different human ESCRT-III (CHMP) proteins inhibited abscission - reference_id: PMID:24814515 supporting_text: ANCHR associates with VPS4 at the midbody ring following DNA segregation defects to control abscission timing - term: id: GO:0030496 label: midbody evidence_type: TAS original_reference_id: PMID:28242692 qualifier: colocalizes_with review: summary: Supported cell-division or midbody/spindle context for VPS4A, downstream of its ESCRT ATPase function. action: KEEP_AS_NON_CORE reason: This is a bona fide VPS4A cellular role but is context-specific and non-core relative to the conserved ATP-dependent ESCRT-III remodeling function. supported_by: - reference_id: PMID:20616062 supporting_text: depletion of VPS4A, VPS4B, or any of the 11 different human ESCRT-III (CHMP) proteins inhibited abscission - reference_id: PMID:24814515 supporting_text: ANCHR associates with VPS4 at the midbody ring following DNA segregation defects to control abscission timing - term: id: GO:0061640 label: cytoskeleton-dependent cytokinesis evidence_type: TAS original_reference_id: PMID:28242692 qualifier: involved_in review: summary: Supported cell-division or midbody/spindle context for VPS4A, downstream of its ESCRT ATPase function. action: KEEP_AS_NON_CORE reason: This is a bona fide VPS4A cellular role but is context-specific and non-core relative to the conserved ATP-dependent ESCRT-III remodeling function. supported_by: - reference_id: PMID:20616062 supporting_text: depletion of VPS4A, VPS4B, or any of the 11 different human ESCRT-III (CHMP) proteins inhibited abscission - reference_id: PMID:24814515 supporting_text: ANCHR associates with VPS4 at the midbody ring following DNA segregation defects to control abscission timing - term: id: GO:0016236 label: macroautophagy evidence_type: NAS original_reference_id: PMID:20588296 qualifier: involved_in review: summary: Autophagy connection is plausible for ESCRT machinery, but the local cached evidence for this specific VPS4A annotation is yeast-only or review-level rather than direct human VPS4A evidence. action: MARK_AS_OVER_ANNOTATED reason: The annotation overstates the direct evidence for human VPS4A in macroautophagy/autophagosome maturation. The core supported role remains ESCRT-III disassembly and membrane remodeling. supported_by: - reference_id: PMID:17428789 supporting_text: deletion of VPS4 and VPS36 caused impaired maturation of the vacuolar proaminopeptidase I (pAPI) via autophagy or the cytosol to vacuole targeting pathway - reference_id: PMID:20588296 supporting_text: ESCRT-III-mediated membrane neck cleavage is crucial for many processes, including the biogenesis of multivesicular bodies, viral budding, cytokinesis, and probably autophagy. - term: id: GO:0036258 label: multivesicular body assembly evidence_type: NAS original_reference_id: PMID:20588296 qualifier: involved_in review: summary: Supported as part of the core VPS4A endosomal/MVB sorting and ESCRT-recycling function. action: ACCEPT reason: VPS4A ATPase activity recycles ESCRT-III assemblies, enabling MVB sorting, ILV formation, and late endosomal cargo transport. supported_by: - reference_id: UniProt:Q9UN37 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly - reference_id: UniProt:Q9UN37 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:10637304 supporting_text: The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking - reference_id: PMID:15075231 supporting_text: hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles - term: id: GO:1904903 label: ESCRT III complex disassembly evidence_type: NAS original_reference_id: PMID:20588296 qualifier: involved_in review: summary: 'Core VPS4A function: ATP-driven recognition, remodeling, and disassembly of ESCRT-III/protein assemblies.' action: ACCEPT reason: This is the central conserved molecular role of VPS4A and directly supports ESCRT recycling and downstream membrane remodeling. supported_by: - reference_id: UniProt:Q9UN37 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly - reference_id: UniProt:Q9UN37 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:17928862 supporting_text: VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly - reference_id: PMID:18606141 supporting_text: Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding. - term: id: GO:1904896 label: ESCRT complex disassembly evidence_type: NAS original_reference_id: PMID:21118109 qualifier: involved_in review: summary: 'Core VPS4A function: ATP-driven recognition, remodeling, and disassembly of ESCRT-III/protein assemblies.' action: ACCEPT reason: This is the central conserved molecular role of VPS4A and directly supports ESCRT recycling and downstream membrane remodeling. supported_by: - reference_id: UniProt:Q9UN37 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly - reference_id: UniProt:Q9UN37 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:17928862 supporting_text: VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly - reference_id: PMID:18606141 supporting_text: Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding. - term: id: GO:0036258 label: multivesicular body assembly evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: Supported as part of the core VPS4A endosomal/MVB sorting and ESCRT-recycling function. action: ACCEPT reason: VPS4A ATPase activity recycles ESCRT-III assemblies, enabling MVB sorting, ILV formation, and late endosomal cargo transport. supported_by: - reference_id: UniProt:Q9UN37 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly - reference_id: UniProt:Q9UN37 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:10637304 supporting_text: The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking - reference_id: PMID:15075231 supporting_text: hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles - term: id: GO:0061738 label: late endosomal microautophagy evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: involved_in review: summary: Late endosomal microautophagy is a plausible ESCRT-dependent process, but this specific human VPS4A annotation is based on transferred or automated evidence in the local files. action: UNDECIDED reason: Retain uncertainty pending direct human evidence or a reviewed source tying VPS4A specifically to late endosomal microautophagy. supported_by: - reference_id: PMID:17428789 supporting_text: deletion of VPS4 and VPS36 caused impaired maturation of the vacuolar proaminopeptidase I (pAPI) via autophagy or the cytosol to vacuole targeting pathway - reference_id: PMID:20588296 supporting_text: ESCRT-III-mediated membrane neck cleavage is crucial for many processes, including the biogenesis of multivesicular bodies, viral budding, cytokinesis, and probably autophagy. - term: id: GO:0005524 label: ATP binding evidence_type: IMP original_reference_id: PMID:10637304 qualifier: enables review: summary: Accept ATP binding as part of the core AAA ATPase mechanism that enables VPS4A ATP hydrolysis and ESCRT-III remodeling. action: ACCEPT reason: ATP binding is a mechanistic prerequisite for the accepted ATP hydrolysis and ATP-dependent protein-disaggregase activity of VPS4A; it is less specific than hydrolysis but consistent with the core ATPase function. supported_by: - reference_id: UniProt:Q9UN37 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly - reference_id: UniProt:Q9UN37 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:17928862 supporting_text: VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly - term: id: GO:0005764 label: lysosome evidence_type: IDA original_reference_id: PMID:10637304 qualifier: located_in review: summary: Supported localization or pathway context, but not central enough to define VPS4A core function. action: KEEP_AS_NON_CORE reason: Keep as a non-core context attached to the broader ESCRT ATPase role. supported_by: - reference_id: PMID:10637304 supporting_text: The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking - reference_id: PMID:15075231 supporting_text: hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles - term: id: GO:0005769 label: early endosome evidence_type: IDA original_reference_id: PMID:10637304 qualifier: located_in review: summary: Supported localization for a cytosolic AAA ATPase that is recruited to endosomal/vacuolar membranes during ESCRT function. action: ACCEPT reason: VPS4A cycles between cytosol and membrane-associated ESCRT assemblies; these compartments are consistent with the core endosomal/MVB role. supported_by: - reference_id: UniProt:Q9UN37 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly - reference_id: UniProt:Q9UN37 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:10637304 supporting_text: The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking - reference_id: PMID:15075231 supporting_text: hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles - term: id: GO:0005770 label: late endosome evidence_type: IDA original_reference_id: PMID:10637304 qualifier: located_in review: summary: Supported localization for a cytosolic AAA ATPase that is recruited to endosomal/vacuolar membranes during ESCRT function. action: ACCEPT reason: VPS4A cycles between cytosol and membrane-associated ESCRT assemblies; these compartments are consistent with the core endosomal/MVB role. supported_by: - reference_id: UniProt:Q9UN37 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly - reference_id: UniProt:Q9UN37 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:10637304 supporting_text: The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking - reference_id: PMID:15075231 supporting_text: hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles - term: id: GO:0005774 label: vacuolar membrane evidence_type: IDA original_reference_id: PMID:10637304 qualifier: located_in review: summary: Supported localization for a cytosolic AAA ATPase that is recruited to endosomal/vacuolar membranes during ESCRT function. action: ACCEPT reason: VPS4A cycles between cytosol and membrane-associated ESCRT assemblies; these compartments are consistent with the core endosomal/MVB role. supported_by: - reference_id: UniProt:Q9UN37 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly - reference_id: UniProt:Q9UN37 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:10637304 supporting_text: The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking - reference_id: PMID:15075231 supporting_text: hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles - term: id: GO:0005829 label: cytosol evidence_type: IDA original_reference_id: PMID:10637304 qualifier: located_in review: summary: Supported localization for a cytosolic AAA ATPase that is recruited to endosomal/vacuolar membranes during ESCRT function. action: ACCEPT reason: VPS4A cycles between cytosol and membrane-associated ESCRT assemblies; these compartments are consistent with the core endosomal/MVB role. supported_by: - reference_id: UniProt:Q9UN37 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly - reference_id: UniProt:Q9UN37 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:10637304 supporting_text: The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking - reference_id: PMID:15075231 supporting_text: hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles - term: id: GO:0016197 label: endosomal transport evidence_type: IMP original_reference_id: PMID:10637304 qualifier: involved_in review: summary: Supported as part of the core VPS4A endosomal/MVB sorting and ESCRT-recycling function. action: ACCEPT reason: VPS4A ATPase activity recycles ESCRT-III assemblies, enabling MVB sorting, ILV formation, and late endosomal cargo transport. supported_by: - reference_id: UniProt:Q9UN37 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly - reference_id: UniProt:Q9UN37 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:10637304 supporting_text: The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking - reference_id: PMID:15075231 supporting_text: hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles - term: id: GO:0016887 label: ATP hydrolysis activity evidence_type: IMP original_reference_id: PMID:10637304 qualifier: enables review: summary: 'Core VPS4A function: ATP-driven recognition, remodeling, and disassembly of ESCRT-III/protein assemblies.' action: ACCEPT reason: This is the central conserved molecular role of VPS4A and directly supports ESCRT recycling and downstream membrane remodeling. supported_by: - reference_id: UniProt:Q9UN37 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly - reference_id: UniProt:Q9UN37 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:17928862 supporting_text: VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly - reference_id: PMID:18606141 supporting_text: Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding. - term: id: GO:0032367 label: intracellular cholesterol transport evidence_type: IMP original_reference_id: PMID:10637304 qualifier: involved_in review: summary: ATPase-defective hVPS4 produces cholesterol-enriched endosomal compartments, but VPS4A is not a cholesterol transporter. action: MODIFY reason: The cholesterol phenotype is a consequence of disrupted postendosomal trafficking; endosomal transport better captures the supported role. supported_by: - reference_id: PMID:10637304 supporting_text: The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking - reference_id: PMID:15075231 supporting_text: hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles proposed_replacement_terms: - id: GO:0016197 label: endosomal transport - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:18385515 qualifier: enables review: summary: The underlying interaction evidence may be useful context, especially for ESCRT-III, IST1, ZFYVE19/ANCHR, VPS4B, SPAST, or high-throughput interactome partners, but GO:0005515 is too generic to describe VPS4A molecular function. action: MARK_AS_OVER_ANNOTATED reason: VPS4A function is better represented by ATP-dependent ESCRT-III remodeling/disassembly and, where supported, protein-containing complex binding. A generic protein-binding annotation obscures the actual function. supported_by: - reference_id: file:human/VPS4A/VPS4A-notes.md supporting_text: Plain `GO:0005515 protein binding` rows should not be retained as informative functions. - reference_id: PMID:17928862 supporting_text: VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly - reference_id: PMID:18606141 supporting_text: Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:23105106 qualifier: enables review: summary: The underlying interaction evidence may be useful context, especially for ESCRT-III, IST1, ZFYVE19/ANCHR, VPS4B, SPAST, or high-throughput interactome partners, but GO:0005515 is too generic to describe VPS4A molecular function. action: MARK_AS_OVER_ANNOTATED reason: VPS4A function is better represented by ATP-dependent ESCRT-III remodeling/disassembly and, where supported, protein-containing complex binding. A generic protein-binding annotation obscures the actual function. supported_by: - reference_id: file:human/VPS4A/VPS4A-notes.md supporting_text: Plain `GO:0005515 protein binding` rows should not be retained as informative functions. - reference_id: PMID:17928862 supporting_text: VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly - reference_id: PMID:18606141 supporting_text: Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding. - term: id: GO:0034058 label: endosomal vesicle fusion evidence_type: IMP original_reference_id: PMID:15075231 qualifier: involved_in review: summary: The hVPS4(EQ) evidence supports ILV formation and coat disassembly on endosomal vacuoles, not endosomal vesicle fusion. action: MODIFY reason: The biological effect is MVB/ILV biogenesis; fusion is the wrong process for this evidence. supported_by: - reference_id: PMID:10637304 supporting_text: The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking - reference_id: PMID:15075231 supporting_text: hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles proposed_replacement_terms: - id: GO:0036258 label: multivesicular body assembly - term: id: GO:0005737 label: cytoplasm evidence_type: IDA original_reference_id: PMID:15075231 qualifier: located_in review: summary: Supported localization for a cytosolic AAA ATPase that is recruited to endosomal/vacuolar membranes during ESCRT function. action: ACCEPT reason: VPS4A cycles between cytosol and membrane-associated ESCRT assemblies; these compartments are consistent with the core endosomal/MVB role. supported_by: - reference_id: UniProt:Q9UN37 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly - reference_id: UniProt:Q9UN37 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:10637304 supporting_text: The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking - reference_id: PMID:15075231 supporting_text: hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles - term: id: GO:0005769 label: early endosome evidence_type: IDA original_reference_id: PMID:15075231 qualifier: located_in review: summary: Supported localization for a cytosolic AAA ATPase that is recruited to endosomal/vacuolar membranes during ESCRT function. action: ACCEPT reason: VPS4A cycles between cytosol and membrane-associated ESCRT assemblies; these compartments are consistent with the core endosomal/MVB role. supported_by: - reference_id: UniProt:Q9UN37 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly - reference_id: UniProt:Q9UN37 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:10637304 supporting_text: The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking - reference_id: PMID:15075231 supporting_text: hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles - term: id: GO:0005770 label: late endosome evidence_type: IDA original_reference_id: PMID:15075231 qualifier: located_in review: summary: Supported localization for a cytosolic AAA ATPase that is recruited to endosomal/vacuolar membranes during ESCRT function. action: ACCEPT reason: VPS4A cycles between cytosol and membrane-associated ESCRT assemblies; these compartments are consistent with the core endosomal/MVB role. supported_by: - reference_id: UniProt:Q9UN37 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly - reference_id: UniProt:Q9UN37 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:10637304 supporting_text: The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking - reference_id: PMID:15075231 supporting_text: hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles - term: id: GO:0006900 label: vesicle budding from membrane evidence_type: IMP original_reference_id: PMID:15075231 qualifier: involved_in review: summary: Supported endosomal ILV formation/coat-disassembly role downstream of VPS4A ATPase activity. action: ACCEPT reason: ATPase-deficient hVPS4 reduces internal endosomal vesicles and stabilizes coats, consistent with this MVB biogenesis function. supported_by: - reference_id: PMID:10637304 supporting_text: The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking - reference_id: PMID:15075231 supporting_text: hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles - term: id: GO:0072319 label: vesicle uncoating evidence_type: IMP original_reference_id: PMID:15075231 qualifier: involved_in review: summary: Supported endosomal ILV formation/coat-disassembly role downstream of VPS4A ATPase activity. action: ACCEPT reason: ATPase-deficient hVPS4 reduces internal endosomal vesicles and stabilizes coats, consistent with this MVB biogenesis function. supported_by: - reference_id: PMID:10637304 supporting_text: The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking - reference_id: PMID:15075231 supporting_text: hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:18997780 qualifier: enables review: summary: The underlying interaction evidence may be useful context, especially for ESCRT-III, IST1, ZFYVE19/ANCHR, VPS4B, SPAST, or high-throughput interactome partners, but GO:0005515 is too generic to describe VPS4A molecular function. action: MARK_AS_OVER_ANNOTATED reason: VPS4A function is better represented by ATP-dependent ESCRT-III remodeling/disassembly and, where supported, protein-containing complex binding. A generic protein-binding annotation obscures the actual function. supported_by: - reference_id: file:human/VPS4A/VPS4A-notes.md supporting_text: Plain `GO:0005515 protein binding` rows should not be retained as informative functions. - reference_id: PMID:17928862 supporting_text: VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly - reference_id: PMID:18606141 supporting_text: Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding. - term: id: GO:0019076 label: viral release from host cell evidence_type: IMP original_reference_id: PMID:11595185 qualifier: involved_in review: summary: Directly supported viral/plasma-membrane ESCRT context, but this is host-pathogen exploitation of VPS4A machinery rather than the core cellular function. action: KEEP_AS_NON_CORE reason: Keep as a real non-core ESCRT output; do not use it to define the primary function of VPS4A. supported_by: - reference_id: PMID:11595185 supporting_text: Dominant negative mutant Vps4 proteins that inhibit vacuolar protein sorting also arrest HIV-1 and MLV budding. - reference_id: PMID:17940959 supporting_text: A lack of VPS4 adenosine triphosphatase activity reduced budding by up to 80% - term: id: GO:0005768 label: endosome evidence_type: IDA original_reference_id: PMID:17940959 qualifier: located_in review: summary: Supported localization for a cytosolic AAA ATPase that is recruited to endosomal/vacuolar membranes during ESCRT function. action: ACCEPT reason: VPS4A cycles between cytosol and membrane-associated ESCRT assemblies; these compartments are consistent with the core endosomal/MVB role. supported_by: - reference_id: UniProt:Q9UN37 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly - reference_id: UniProt:Q9UN37 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:10637304 supporting_text: The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking - reference_id: PMID:15075231 supporting_text: hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles - term: id: GO:0005886 label: plasma membrane evidence_type: IDA original_reference_id: PMID:17940959 qualifier: located_in review: summary: Directly supported viral/plasma-membrane ESCRT context, but this is host-pathogen exploitation of VPS4A machinery rather than the core cellular function. action: KEEP_AS_NON_CORE reason: Keep as a real non-core ESCRT output; do not use it to define the primary function of VPS4A. supported_by: - reference_id: PMID:11595185 supporting_text: Dominant negative mutant Vps4 proteins that inhibit vacuolar protein sorting also arrest HIV-1 and MLV budding. - reference_id: PMID:17940959 supporting_text: A lack of VPS4 adenosine triphosphatase activity reduced budding by up to 80% - term: id: GO:0051301 label: cell division evidence_type: IDA original_reference_id: PMID:17853893 qualifier: involved_in review: summary: The evidence supports cytokinetic abscission rather than the broader or less accurate cell-division term currently used. action: MODIFY reason: VPS4A acts in the ESCRT-mediated abscission stage of cytokinesis, so midbody abscission is the better term. supported_by: - reference_id: PMID:20616062 supporting_text: depletion of VPS4A, VPS4B, or any of the 11 different human ESCRT-III (CHMP) proteins inhibited abscission - reference_id: PMID:24814515 supporting_text: ANCHR associates with VPS4 at the midbody ring following DNA segregation defects to control abscission timing proposed_replacement_terms: - id: GO:0061952 label: midbody abscission - term: id: GO:1903076 label: regulation of protein localization to plasma membrane evidence_type: IMP original_reference_id: PMID:24878737 qualifier: involved_in review: summary: Directly supported viral/plasma-membrane ESCRT context, but this is host-pathogen exploitation of VPS4A machinery rather than the core cellular function. action: KEEP_AS_NON_CORE reason: Keep as a real non-core ESCRT output; do not use it to define the primary function of VPS4A. supported_by: - reference_id: PMID:11595185 supporting_text: Dominant negative mutant Vps4 proteins that inhibit vacuolar protein sorting also arrest HIV-1 and MLV budding. - reference_id: PMID:17940959 supporting_text: A lack of VPS4 adenosine triphosphatase activity reduced budding by up to 80% - term: id: GO:1903774 label: positive regulation of viral budding via host ESCRT complex evidence_type: IMP original_reference_id: PMID:24878737 qualifier: involved_in review: summary: Directly supported viral/plasma-membrane ESCRT context, but this is host-pathogen exploitation of VPS4A machinery rather than the core cellular function. action: KEEP_AS_NON_CORE reason: Keep as a real non-core ESCRT output; do not use it to define the primary function of VPS4A. supported_by: - reference_id: PMID:11595185 supporting_text: Dominant negative mutant Vps4 proteins that inhibit vacuolar protein sorting also arrest HIV-1 and MLV budding. - reference_id: PMID:17940959 supporting_text: A lack of VPS4 adenosine triphosphatase activity reduced budding by up to 80% - term: id: GO:0000922 label: spindle pole evidence_type: IDA original_reference_id: PMID:20616062 qualifier: located_in review: summary: Supported cell-division or midbody/spindle context for VPS4A, downstream of its ESCRT ATPase function. action: KEEP_AS_NON_CORE reason: This is a bona fide VPS4A cellular role but is context-specific and non-core relative to the conserved ATP-dependent ESCRT-III remodeling function. supported_by: - reference_id: PMID:20616062 supporting_text: depletion of VPS4A, VPS4B, or any of the 11 different human ESCRT-III (CHMP) proteins inhibited abscission - reference_id: PMID:24814515 supporting_text: ANCHR associates with VPS4 at the midbody ring following DNA segregation defects to control abscission timing - term: id: GO:0005634 label: nucleus evidence_type: IDA original_reference_id: PMID:20616062 qualifier: located_in review: summary: Supported nuclear-envelope/nucleus-organization ESCRT context, but not the primary VPS4A molecular role. action: KEEP_AS_NON_CORE reason: Keep as a non-core ESCRT membrane-sealing context; VPS4A acts through ESCRT-III remodeling rather than as a nucleus-organization factor per se. supported_by: - reference_id: PMID:28242692 supporting_text: In mammals, VPS4 depletion induces nuclear morphology defects - term: id: GO:0005737 label: cytoplasm evidence_type: IDA original_reference_id: PMID:20616062 qualifier: located_in review: summary: Supported localization for a cytosolic AAA ATPase that is recruited to endosomal/vacuolar membranes during ESCRT function. action: ACCEPT reason: VPS4A cycles between cytosol and membrane-associated ESCRT assemblies; these compartments are consistent with the core endosomal/MVB role. supported_by: - reference_id: UniProt:Q9UN37 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly - reference_id: UniProt:Q9UN37 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:10637304 supporting_text: The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking - reference_id: PMID:15075231 supporting_text: hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles - term: id: GO:0005813 label: centrosome evidence_type: IDA original_reference_id: PMID:20616062 qualifier: located_in review: summary: Supported cell-division or midbody/spindle context for VPS4A, downstream of its ESCRT ATPase function. action: KEEP_AS_NON_CORE reason: This is a bona fide VPS4A cellular role but is context-specific and non-core relative to the conserved ATP-dependent ESCRT-III remodeling function. supported_by: - reference_id: PMID:20616062 supporting_text: depletion of VPS4A, VPS4B, or any of the 11 different human ESCRT-III (CHMP) proteins inhibited abscission - reference_id: PMID:24814515 supporting_text: ANCHR associates with VPS4 at the midbody ring following DNA segregation defects to control abscission timing - term: id: GO:0006997 label: nucleus organization evidence_type: IMP original_reference_id: PMID:20616062 qualifier: involved_in review: summary: Supported nuclear-envelope/nucleus-organization ESCRT context, but not the primary VPS4A molecular role. action: KEEP_AS_NON_CORE reason: Keep as a non-core ESCRT membrane-sealing context; VPS4A acts through ESCRT-III remodeling rather than as a nucleus-organization factor per se. supported_by: - reference_id: PMID:28242692 supporting_text: In mammals, VPS4 depletion induces nuclear morphology defects - term: id: GO:0007080 label: mitotic metaphase chromosome alignment evidence_type: IMP original_reference_id: PMID:20616062 qualifier: involved_in review: summary: VPS4A/ESCRT depletion can perturb spindle and chromosome phenotypes, but this does not show VPS4A is a metaphase chromosome-alignment factor. action: MARK_AS_OVER_ANNOTATED reason: The term overstates a downstream cell-division phenotype relative to the direct ESCRT/VPS4 mechanism. supported_by: - reference_id: PMID:20616062 supporting_text: depletion of VPS4A, VPS4B, or any of the 11 different human ESCRT-III (CHMP) proteins inhibited abscission - reference_id: PMID:24814515 supporting_text: ANCHR associates with VPS4 at the midbody ring following DNA segregation defects to control abscission timing - term: id: GO:0090543 label: Flemming body evidence_type: IDA original_reference_id: PMID:20616062 qualifier: located_in review: summary: Supported cell-division or midbody/spindle context for VPS4A, downstream of its ESCRT ATPase function. action: KEEP_AS_NON_CORE reason: This is a bona fide VPS4A cellular role but is context-specific and non-core relative to the conserved ATP-dependent ESCRT-III remodeling function. supported_by: - reference_id: PMID:20616062 supporting_text: depletion of VPS4A, VPS4B, or any of the 11 different human ESCRT-III (CHMP) proteins inhibited abscission - reference_id: PMID:24814515 supporting_text: ANCHR associates with VPS4 at the midbody ring following DNA segregation defects to control abscission timing - term: id: GO:0090611 label: obsolete ubiquitin-independent protein catabolic process via the multivesicular body sorting pathway evidence_type: IMP original_reference_id: PMID:22547407 qualifier: involved_in review: summary: The annotation captures a real ubiquitin-independent MVB-sorting context, but the current GO term is obsolete. action: MODIFY reason: Use a current MVB sorting pathway term rather than retaining an obsolete ubiquitin-independent protein catabolic process term. supported_by: - reference_id: PMID:10637304 supporting_text: The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking - reference_id: PMID:15075231 supporting_text: hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles proposed_replacement_terms: - id: GO:0071985 label: multivesicular body sorting pathway - term: id: GO:1903543 label: positive regulation of exosomal secretion evidence_type: IMP original_reference_id: PMID:22660413 qualifier: involved_in review: summary: Supported exosome-release context for VPS4A/B but not the primary cellular function. action: KEEP_AS_NON_CORE reason: Exosome secretion is one downstream ESCRT-dependent output of VPS4A activity, so retain as non-core. supported_by: - reference_id: UniProt:Q9UN37 supporting_text: VPS4A/B are required for the exosomal release of SDCBP, CD63 and syndecan - term: id: GO:0039702 label: viral budding via host ESCRT complex evidence_type: IGI original_reference_id: PMID:24107264 qualifier: involved_in review: summary: Directly supported viral/plasma-membrane ESCRT context, but this is host-pathogen exploitation of VPS4A machinery rather than the core cellular function. action: KEEP_AS_NON_CORE reason: Keep as a real non-core ESCRT output; do not use it to define the primary function of VPS4A. supported_by: - reference_id: PMID:11595185 supporting_text: Dominant negative mutant Vps4 proteins that inhibit vacuolar protein sorting also arrest HIV-1 and MLV budding. - reference_id: PMID:17940959 supporting_text: A lack of VPS4 adenosine triphosphatase activity reduced budding by up to 80% - term: id: GO:0043162 label: ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway evidence_type: IMP original_reference_id: PMID:22547407 qualifier: involved_in review: summary: Supported as part of the core VPS4A endosomal/MVB sorting and ESCRT-recycling function. action: ACCEPT reason: VPS4A ATPase activity recycles ESCRT-III assemblies, enabling MVB sorting, ILV formation, and late endosomal cargo transport. supported_by: - reference_id: UniProt:Q9UN37 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly - reference_id: UniProt:Q9UN37 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:10637304 supporting_text: The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking - reference_id: PMID:15075231 supporting_text: hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles - term: id: GO:0070062 label: extracellular exosome evidence_type: HDA original_reference_id: PMID:23533145 qualifier: located_in review: summary: High-throughput exosome proteomics does not establish extracellular exosome as a core VPS4A localization. action: MARK_AS_OVER_ANNOTATED reason: VPS4A is a cytosolic/endosomal ESCRT ATPase involved in exosome biogenesis; HDA exosome detection is not an informative localization for its core function. supported_by: - reference_id: UniProt:Q9UN37 supporting_text: VPS4A/B are required for the exosomal release of SDCBP, CD63 and syndecan - term: id: GO:0030496 label: midbody evidence_type: IDA original_reference_id: PMID:24814515 qualifier: located_in review: summary: Supported cell-division or midbody/spindle context for VPS4A, downstream of its ESCRT ATPase function. action: KEEP_AS_NON_CORE reason: This is a bona fide VPS4A cellular role but is context-specific and non-core relative to the conserved ATP-dependent ESCRT-III remodeling function. supported_by: - reference_id: PMID:20616062 supporting_text: depletion of VPS4A, VPS4B, or any of the 11 different human ESCRT-III (CHMP) proteins inhibited abscission - reference_id: PMID:24814515 supporting_text: ANCHR associates with VPS4 at the midbody ring following DNA segregation defects to control abscission timing - term: id: GO:0032466 label: negative regulation of cytokinesis evidence_type: IMP original_reference_id: PMID:24814515 qualifier: involved_in review: summary: Supported cell-division or midbody/spindle context for VPS4A, downstream of its ESCRT ATPase function. action: KEEP_AS_NON_CORE reason: This is a bona fide VPS4A cellular role but is context-specific and non-core relative to the conserved ATP-dependent ESCRT-III remodeling function. supported_by: - reference_id: PMID:20616062 supporting_text: depletion of VPS4A, VPS4B, or any of the 11 different human ESCRT-III (CHMP) proteins inhibited abscission - reference_id: PMID:24814515 supporting_text: ANCHR associates with VPS4 at the midbody ring following DNA segregation defects to control abscission timing - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:14519844 qualifier: enables review: summary: The underlying interaction evidence may be useful context, especially for ESCRT-III, IST1, ZFYVE19/ANCHR, VPS4B, SPAST, or high-throughput interactome partners, but GO:0005515 is too generic to describe VPS4A molecular function. action: MARK_AS_OVER_ANNOTATED reason: VPS4A function is better represented by ATP-dependent ESCRT-III remodeling/disassembly and, where supported, protein-containing complex binding. A generic protein-binding annotation obscures the actual function. supported_by: - reference_id: file:human/VPS4A/VPS4A-notes.md supporting_text: Plain `GO:0005515 protein binding` rows should not be retained as informative functions. - reference_id: PMID:17928862 supporting_text: VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly - reference_id: PMID:18606141 supporting_text: Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:14505570 qualifier: enables review: summary: The underlying interaction evidence may be useful context, especially for ESCRT-III, IST1, ZFYVE19/ANCHR, VPS4B, SPAST, or high-throughput interactome partners, but GO:0005515 is too generic to describe VPS4A molecular function. action: MARK_AS_OVER_ANNOTATED reason: VPS4A function is better represented by ATP-dependent ESCRT-III remodeling/disassembly and, where supported, protein-containing complex binding. A generic protein-binding annotation obscures the actual function. supported_by: - reference_id: file:human/VPS4A/VPS4A-notes.md supporting_text: Plain `GO:0005515 protein binding` rows should not be retained as informative functions. - reference_id: PMID:17928862 supporting_text: VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly - reference_id: PMID:18606141 supporting_text: Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding. - term: id: GO:0070062 label: extracellular exosome evidence_type: HDA original_reference_id: PMID:19199708 qualifier: located_in review: summary: High-throughput exosome proteomics does not establish extracellular exosome as a core VPS4A localization. action: MARK_AS_OVER_ANNOTATED reason: VPS4A is a cytosolic/endosomal ESCRT ATPase involved in exosome biogenesis; HDA exosome detection is not an informative localization for its core function. supported_by: - reference_id: UniProt:Q9UN37 supporting_text: VPS4A/B are required for the exosomal release of SDCBP, CD63 and syndecan - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:21543490 qualifier: enables review: summary: The underlying interaction evidence may be useful context, especially for ESCRT-III, IST1, ZFYVE19/ANCHR, VPS4B, SPAST, or high-throughput interactome partners, but GO:0005515 is too generic to describe VPS4A molecular function. action: MARK_AS_OVER_ANNOTATED reason: VPS4A function is better represented by ATP-dependent ESCRT-III remodeling/disassembly and, where supported, protein-containing complex binding. A generic protein-binding annotation obscures the actual function. supported_by: - reference_id: file:human/VPS4A/VPS4A-notes.md supporting_text: Plain `GO:0005515 protein binding` rows should not be retained as informative functions. - reference_id: PMID:17928862 supporting_text: VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly - reference_id: PMID:18606141 supporting_text: Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:19129480 qualifier: enables review: summary: The underlying interaction evidence may be useful context, especially for ESCRT-III, IST1, ZFYVE19/ANCHR, VPS4B, SPAST, or high-throughput interactome partners, but GO:0005515 is too generic to describe VPS4A molecular function. action: MARK_AS_OVER_ANNOTATED reason: VPS4A function is better represented by ATP-dependent ESCRT-III remodeling/disassembly and, where supported, protein-containing complex binding. A generic protein-binding annotation obscures the actual function. supported_by: - reference_id: file:human/VPS4A/VPS4A-notes.md supporting_text: Plain `GO:0005515 protein binding` rows should not be retained as informative functions. - reference_id: PMID:17928862 supporting_text: VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly - reference_id: PMID:18606141 supporting_text: Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding. - term: id: GO:0030496 label: midbody evidence_type: IDA original_reference_id: PMID:19129479 qualifier: located_in review: summary: Supported cell-division or midbody/spindle context for VPS4A, downstream of its ESCRT ATPase function. action: KEEP_AS_NON_CORE reason: This is a bona fide VPS4A cellular role but is context-specific and non-core relative to the conserved ATP-dependent ESCRT-III remodeling function. supported_by: - reference_id: PMID:20616062 supporting_text: depletion of VPS4A, VPS4B, or any of the 11 different human ESCRT-III (CHMP) proteins inhibited abscission - reference_id: PMID:24814515 supporting_text: ANCHR associates with VPS4 at the midbody ring following DNA segregation defects to control abscission timing - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:19129479 qualifier: enables review: summary: The underlying interaction evidence may be useful context, especially for ESCRT-III, IST1, ZFYVE19/ANCHR, VPS4B, SPAST, or high-throughput interactome partners, but GO:0005515 is too generic to describe VPS4A molecular function. action: MARK_AS_OVER_ANNOTATED reason: VPS4A function is better represented by ATP-dependent ESCRT-III remodeling/disassembly and, where supported, protein-containing complex binding. A generic protein-binding annotation obscures the actual function. supported_by: - reference_id: file:human/VPS4A/VPS4A-notes.md supporting_text: Plain `GO:0005515 protein binding` rows should not be retained as informative functions. - reference_id: PMID:17928862 supporting_text: VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly - reference_id: PMID:18606141 supporting_text: Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding. - term: id: GO:0030496 label: midbody evidence_type: IDA original_reference_id: PMID:17853893 qualifier: located_in review: summary: Supported cell-division or midbody/spindle context for VPS4A, downstream of its ESCRT ATPase function. action: KEEP_AS_NON_CORE reason: This is a bona fide VPS4A cellular role but is context-specific and non-core relative to the conserved ATP-dependent ESCRT-III remodeling function. supported_by: - reference_id: PMID:20616062 supporting_text: depletion of VPS4A, VPS4B, or any of the 11 different human ESCRT-III (CHMP) proteins inhibited abscission - reference_id: PMID:24814515 supporting_text: ANCHR associates with VPS4 at the midbody ring following DNA segregation defects to control abscission timing - term: id: GO:0016197 label: endosomal transport evidence_type: IMP original_reference_id: PMID:11559748 qualifier: involved_in review: summary: Supported as part of the core VPS4A endosomal/MVB sorting and ESCRT-recycling function. action: ACCEPT reason: VPS4A ATPase activity recycles ESCRT-III assemblies, enabling MVB sorting, ILV formation, and late endosomal cargo transport. supported_by: - reference_id: UniProt:Q9UN37 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly - reference_id: UniProt:Q9UN37 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:10637304 supporting_text: The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking - reference_id: PMID:15075231 supporting_text: hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:11559748 qualifier: enables review: summary: The underlying interaction evidence may be useful context, especially for ESCRT-III, IST1, ZFYVE19/ANCHR, VPS4B, SPAST, or high-throughput interactome partners, but GO:0005515 is too generic to describe VPS4A molecular function. action: MARK_AS_OVER_ANNOTATED reason: VPS4A function is better represented by ATP-dependent ESCRT-III remodeling/disassembly and, where supported, protein-containing complex binding. A generic protein-binding annotation obscures the actual function. supported_by: - reference_id: file:human/VPS4A/VPS4A-notes.md supporting_text: Plain `GO:0005515 protein binding` rows should not be retained as informative functions. - reference_id: PMID:17928862 supporting_text: VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly - reference_id: PMID:18606141 supporting_text: Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:11563910 qualifier: enables review: summary: The underlying interaction evidence may be useful context, especially for ESCRT-III, IST1, ZFYVE19/ANCHR, VPS4B, SPAST, or high-throughput interactome partners, but GO:0005515 is too generic to describe VPS4A molecular function. action: MARK_AS_OVER_ANNOTATED reason: VPS4A function is better represented by ATP-dependent ESCRT-III remodeling/disassembly and, where supported, protein-containing complex binding. A generic protein-binding annotation obscures the actual function. supported_by: - reference_id: file:human/VPS4A/VPS4A-notes.md supporting_text: Plain `GO:0005515 protein binding` rows should not be retained as informative functions. - reference_id: PMID:17928862 supporting_text: VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly - reference_id: PMID:18606141 supporting_text: Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding. - term: id: GO:0005737 label: cytoplasm evidence_type: IDA original_reference_id: PMID:11563910 qualifier: located_in review: summary: Supported localization for a cytosolic AAA ATPase that is recruited to endosomal/vacuolar membranes during ESCRT function. action: ACCEPT reason: VPS4A cycles between cytosol and membrane-associated ESCRT assemblies; these compartments are consistent with the core endosomal/MVB role. supported_by: - reference_id: UniProt:Q9UN37 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly - reference_id: UniProt:Q9UN37 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:10637304 supporting_text: The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking - reference_id: PMID:15075231 supporting_text: hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles - term: id: GO:0016192 label: vesicle-mediated transport evidence_type: IDA original_reference_id: PMID:11563910 qualifier: involved_in review: summary: Supported as part of the core VPS4A endosomal/MVB sorting and ESCRT-recycling function. action: ACCEPT reason: VPS4A ATPase activity recycles ESCRT-III assemblies, enabling MVB sorting, ILV formation, and late endosomal cargo transport. supported_by: - reference_id: UniProt:Q9UN37 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly - reference_id: UniProt:Q9UN37 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:10637304 supporting_text: The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking - reference_id: PMID:15075231 supporting_text: hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles - term: id: GO:0048471 label: perinuclear region of cytoplasm evidence_type: IDA original_reference_id: PMID:11563910 qualifier: located_in review: summary: Supported localization or pathway context, but not central enough to define VPS4A core function. action: KEEP_AS_NON_CORE reason: Keep as a non-core context attached to the broader ESCRT ATPase role. supported_by: - reference_id: PMID:10637304 supporting_text: The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking - reference_id: PMID:15075231 supporting_text: hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles references: - id: GO_REF:0000002 title: Gene Ontology annotation through association of InterPro records with GO terms 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: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:0000107 title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara findings: [] - id: GO_REF:0000117 title: Electronic Gene Ontology annotations created by ARBA machine learning models findings: [] - id: GO_REF:0000120 title: Combined Automated Annotation using Multiple IEA Methods findings: [] - id: PMID:10637304 title: ATPase-defective mammalian VPS4 localizes to aberrant endosomes and impairs cholesterol trafficking. findings: - statement: ATPase-defective hVPS4 localizes to endocytic vacuoles and impairs postendosomal cholesterol sorting, supporting an endosomal trafficking role. - id: PMID:11559748 title: CHMP1 functions as a member of a newly defined family of vesicle trafficking proteins. findings: [] - id: PMID:11563910 title: Mammalian cells express two VPS4 proteins both of which are involved in intracellular protein trafficking. findings: [] - id: PMID:11595185 title: Tsg101 and the vacuolar protein sorting pathway are essential for HIV-1 budding. findings: [] - id: PMID:14505570 title: The protein network of HIV budding. findings: [] - id: PMID:14519844 title: Divergent retroviral late-budding domains recruit vacuolar protein sorting factors by using alternative adaptor proteins. findings: [] - id: PMID:15075231 title: ATPase-deficient hVPS4 impairs formation of internal endosomal vesicles and stabilizes bilayered clathrin coats on endosomal vacuoles. findings: - statement: ATPase-deficient hVPS4 reduces internal endosomal vesicles and stabilizes bilayered coats, supporting MVB/ILV biogenesis and coat disassembly functions. - id: PMID:16174732 title: Structure and ESCRT-III protein interactions of the MIT domain of human VPS4A. findings: [] - id: PMID:16193069 title: Structural and mechanistic studies of VPS4 proteins. findings: [] - id: PMID:16505166 title: Recycling of ESCRTs by the AAA-ATPase Vps4 is regulated by a conserved VSL region in Vta1. findings: [] - id: PMID:16730941 title: 'A systematic analysis of human CHMP protein interactions: additional MIT domain-containing proteins bind to multiple components of the human ESCRT III complex.' findings: [] - id: PMID:16973552 title: Human ESCRT-II complex and its role in human immunodeficiency virus type 1 release. findings: [] - id: PMID:17110338 title: Hsp90 cochaperone Aha1 downregulation rescues misfolding of CFTR in cystic fibrosis. findings: [] - id: PMID:17428789 title: Phosphatidylethanolamine, a limiting factor of autophagy in yeast strains bearing a defect in the carboxypeptidase Y pathway of vacuolar targeting. findings: [] - id: PMID:17853893 title: Human ESCRT and ALIX proteins interact with proteins of the midbody and function in cytokinesis. findings: [] - id: PMID:17928862 title: ESCRT-III recognition by VPS4 ATPases. findings: - statement: VPS4A/VPS4B MIT domains recognize CHMP/ESCRT-III motifs; mutations block recruitment, endosomal sorting, and HIV budding. - id: PMID:17940959 title: Involvement of vacuolar protein sorting pathway in Ebola virus release independent of TSG101 interaction. findings: [] - id: PMID:18005716 title: Identification of human MVB12 proteins as ESCRT-I subunits that function in HIV budding. findings: [] - id: PMID:18385515 title: Novel interactions of ESCRT-III with LIP5 and VPS4 and their implications for ESCRT-III disassembly. findings: [] - id: PMID:18606141 title: Two distinct modes of ESCRT-III recognition are required for VPS4 functions in lysosomal protein targeting and HIV-1 budding. findings: - statement: A second MIT-MIM2 recognition mode is required for VPS4 recruitment, lysosomal protein targeting, and HIV budding. - id: PMID:18997780 title: Structural basis for midbody targeting of spastin by the ESCRT-III protein CHMP1B. findings: [] - id: PMID:19129479 title: Biochemical analyses of human IST1 and its function in cytokinesis. findings: [] - id: PMID:19129480 title: Essential role of hIST1 in cytokinesis. findings: [] - id: PMID:19199708 title: Proteomic analysis of human parotid gland exosomes by multidimensional protein identification technology (MudPIT). findings: [] - id: PMID:19234443 title: Membrane scission by the ESCRT-III complex. findings: [] - id: PMID:19278657 title: 'Three-dimensional structure of AAA ATPase Vps4: advancing structural insights into the mechanisms of endosomal sorting and enveloped virus budding.' findings: [] - id: PMID:20588296 title: 'Membrane budding and scission by the ESCRT machinery: it''s all in the neck.' findings: - statement: Review-level ESCRT/autophagy statements are treated cautiously because they do not directly establish human VPS4A macroautophagy as a core function. - id: PMID:20616062 title: Human ESCRT-III and VPS4 proteins are required for centrosome and spindle maintenance. findings: - statement: VPS4A/B and ESCRT-III proteins are required for abscission and centrosome/spindle maintenance; this is retained as a non-core cell-division context. - id: PMID:21118109 title: The role of ESCRT proteins in fusion events involving lysosomes, endosomes and autophagosomes. findings: [] - id: PMID:21543490 title: Mechanism of inhibition of retrovirus release from cells by interferon-induced gene ISG15. findings: [] - id: PMID:22547407 title: ALIX binds a YPX(3)L motif of the GPCR PAR1 and mediates ubiquitin-independent ESCRT-III/MVB sorting. findings: [] - id: PMID:22660413 title: Syndecan-syntenin-ALIX regulates the biogenesis of exosomes. findings: [] - id: PMID:23105106 title: Interactions of the human LIP5 regulatory protein with endosomal sorting complexes required for transport. findings: [] - id: PMID:23533145 title: In-depth proteomic analyses of exosomes isolated from expressed prostatic secretions in urine. findings: [] - id: PMID:24107264 title: ESCRT requirements for EIAV budding. findings: [] - id: PMID:24482116 title: ESCRT machinery is required for plasma membrane repair. findings: [] - id: PMID:24814515 title: ANCHR mediates Aurora-B-dependent abscission checkpoint control through retention of VPS4. findings: [] - id: PMID:24878737 title: Structure of cellular ESCRT-III spirals and their relationship to HIV budding. findings: [] - id: PMID:26040712 title: Spastin and ESCRT-III coordinate mitotic spindle disassembly and nuclear envelope sealing. findings: [] - id: PMID:26040713 title: ESCRT-III controls nuclear envelope reformation. findings: [] - id: PMID:26618866 title: "\u2206F508 CFTR interactome remodelling promotes rescue of cystic fibrosis." findings: [] - id: PMID:28242692 title: LEM2 recruits CHMP7 for ESCRT-mediated nuclear envelope closure in fission yeast and human cells. findings: [] - id: PMID:31324722 title: Inhibition of calpain 1 restores plasma membrane stability to pharmacologically rescued Phe508del-CFTR variant. findings: [] - id: PMID:32296183 title: A reference map of the human binary protein interactome. findings: [] - id: PMID:33961781 title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. findings: [] - id: PMID:35156780 title: CFTR interactome mapping using the mammalian membrane two-hybrid high-throughput screening system. findings: [] - id: PMID:35271311 title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.' findings: [] - id: PMID:36012204 title: Differential CFTR-Interactome Proximity Labeling Procedures Identify Enrichment in Multiple SLC Transporters. findings: [] - id: PMID:36604498 title: Structural basis of CHMP2A-CHMP3 ESCRT-III polymer assembly and membrane cleavage. findings: - statement: CHMP2A-CHMP3-VPS4 can constrict and cleave membrane tubes, supporting VPS4 participation in ESCRT membrane fission. - id: PMID:9211789 title: The VPS4 gene is involved in protein transport out of a yeast pre-vacuolar endosome-like compartment. findings: [] - id: Reactome:R-HSA-2995410 title: Nuclear Envelope (NE) Reassembly findings: [] - id: Reactome:R-HSA-3159232 title: Recruitment Of HIV Virion Budding Machinery findings: [] - id: Reactome:R-HSA-917693 title: ESCRT Disassembly findings: [] - id: Reactome:R-HSA-9610942 title: HCMV Formation of Final Envelopment Complex findings: [] - id: Reactome:R-HSA-9610954 title: HCMV Final Envelopment findings: [] - id: Reactome:R-HSA-9668389 title: VPS4 binds ESCRT-III assemblies at nuclear envelope (NE) fenestrations findings: [] - id: Reactome:R-HSA-9668415 title: VPS4 mediates disassembly of ESCRTIII subunits to promote sealing of holes in the nuclear envelope findings: [] - id: UniProt:Q9UN37 title: UniProt entry for VPS4A (Q9UN37) findings: - statement: VPS4A is an AAA ATPase that recognizes and disassembles membrane-associated ESCRT-III assemblies for further rounds of MVB sorting. - id: file:human/VPS4A/VPS4A-notes.md title: Local curation notes for VPS4A findings: - statement: Local synthesis identifies ATP-dependent ESCRT-III remodeling/disassembly as the core VPS4A function and treats PN autophagy rows as context unless directly supported. core_functions: - description: ATP-dependent remodeling and disassembly of ESCRT-III assemblies during endosomal/MVB sorting and related ESCRT membrane-remodeling events. supported_by: - reference_id: UniProt:Q9UN37 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly - reference_id: UniProt:Q9UN37 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:17928862 supporting_text: VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly - reference_id: PMID:18606141 supporting_text: Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding. - reference_id: PMID:36604498 supporting_text: VPS4 can constrict and cleave CHMP2A-CHMP3 membrane tubes - reference_id: PMID:36604498 supporting_text: CHMP2A-CHMP3-VPS4 act as a minimal membrane fission machinery. molecular_function: id: GO:0140545 label: ATP-dependent protein disaggregase activity directly_involved_in: - id: GO:1904903 label: ESCRT III complex disassembly - id: GO:1904896 label: ESCRT complex disassembly - id: GO:0090148 label: membrane fission locations: - id: GO:0005829 label: cytosol - id: GO:0010008 label: endosome membrane - id: GO:0031902 label: late endosome membrane - description: ESCRT-dependent endosomal cargo sorting and multivesicular-body/intralumenal-vesicle biogenesis. supported_by: - reference_id: PMID:10637304 supporting_text: The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking - reference_id: PMID:15075231 supporting_text: hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles - reference_id: UniProt:Q9UN37 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly - reference_id: UniProt:Q9UN37 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. molecular_function: id: GO:0016887 label: ATP hydrolysis activity directly_involved_in: - id: GO:0016197 label: endosomal transport - id: GO:0036258 label: multivesicular body assembly - id: GO:0071985 label: multivesicular body sorting pathway - id: GO:0043162 label: ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway locations: - id: GO:0005768 label: endosome - id: GO:0005770 label: late endosome - id: GO:0005829 label: cytosol proposed_new_terms: [] suggested_questions: - question: Which ESCRT-dependent cellular contexts require VPS4A specifically rather than VPS4B or mixed VPS4A/VPS4B assemblies? - question: Is there direct human-cell evidence that VPS4A participates in phagophore closure, late endosomal microautophagy, or another autophagy subtype independent of its generic ESCRT-III disassembly role? - question: Which disease-associated VPS4A variants selectively perturb ATP hydrolysis, ESCRT-III recognition, hexamer assembly, or recruitment to specific membrane compartments? suggested_experiments: - description: Use rescue assays after VPS4A/VPS4B double depletion with wild-type, ATPase-dead, and MIT-interface VPS4A mutants across MVB cargo sorting, cytokinesis, nuclear-envelope sealing, and autophagy assays. hypothesis: ATPase activity and ESCRT-III recognition are separable requirements whose importance differs by ESCRT-dependent cellular context. - description: Measure endogenous VPS4A recruitment and ESCRT-III turnover during phagophore closure or late endosomal microautophagy with live-cell imaging and acute VPS4A-specific perturbation. hypothesis: If VPS4A has a direct autophagy role, it should be transiently recruited to the relevant membrane and required for ESCRT-III turnover there. - description: Biochemically compare VPS4A and VPS4B disassembly of defined human CHMP2A-CHMP3, CHMP4, and mixed ESCRT-III polymers. hypothesis: VPS4A has conserved ATP-driven ESCRT-III disassembly activity but may differ from VPS4B in substrate preference or kinetics.