VPS4A

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0016197 endosomal transport	IBA GO_REF:0000033	ACCEPT	Summary: Supported as part of the core VPS4A endosomal/MVB sorting and ESCRT-recycling function. Reason: VPS4A ATPase activity recycles ESCRT-III assemblies, enabling MVB sorting, ILV formation, and late endosomal cargo transport. Supporting Evidence: UniProt:Q9UN37 Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly UniProt:Q9UN37 Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. PMID:10637304 The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking PMID:15075231 hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles
GO:0016887 ATP hydrolysis activity	IBA GO_REF:0000033	ACCEPT	Summary: Core VPS4A function: ATP-driven recognition, remodeling, and disassembly of ESCRT-III/protein assemblies. Reason: This is the central conserved molecular role of VPS4A and directly supports ESCRT recycling and downstream membrane remodeling. Supporting Evidence: UniProt:Q9UN37 Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly UniProt:Q9UN37 Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. PMID:17928862 VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly PMID:18606141 Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding.
GO:0043162 ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway	IBA GO_REF:0000033	ACCEPT	Summary: Supported as part of the core VPS4A endosomal/MVB sorting and ESCRT-recycling function. Reason: VPS4A ATPase activity recycles ESCRT-III assemblies, enabling MVB sorting, ILV formation, and late endosomal cargo transport. Supporting Evidence: UniProt:Q9UN37 Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly UniProt:Q9UN37 Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. PMID:10637304 The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking PMID:15075231 hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles
GO:0090611 obsolete ubiquitin-independent protein catabolic process via the multivesicular body sorting pathway	IBA GO_REF:0000033	MODIFY	Summary: The annotation captures a real ubiquitin-independent MVB-sorting context, but the current GO term is obsolete. Reason: Use a current MVB sorting pathway term rather than retaining an obsolete ubiquitin-independent protein catabolic process term. Proposed replacements: multivesicular body sorting pathway Supporting Evidence: PMID:10637304 The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking PMID:15075231 hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles
GO:0000922 spindle pole	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Supported cell-division or midbody/spindle context for VPS4A, downstream of its ESCRT ATPase function. 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. Supporting Evidence: PMID:20616062 depletion of VPS4A, VPS4B, or any of the 11 different human ESCRT-III (CHMP) proteins inhibited abscission PMID:24814515 ANCHR associates with VPS4 at the midbody ring following DNA segregation defects to control abscission timing
GO:0005524 ATP binding	IEA GO_REF:0000002	ACCEPT	Summary: Accept ATP binding as part of the core AAA ATPase mechanism that enables VPS4A ATP hydrolysis and ESCRT-III remodeling. 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. Supporting Evidence: UniProt:Q9UN37 Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly UniProt:Q9UN37 Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. PMID:17928862 VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly
GO:0005813 centrosome	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Supported cell-division or midbody/spindle context for VPS4A, downstream of its ESCRT ATPase function. 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. Supporting Evidence: PMID:20616062 depletion of VPS4A, VPS4B, or any of the 11 different human ESCRT-III (CHMP) proteins inhibited abscission PMID:24814515 ANCHR associates with VPS4 at the midbody ring following DNA segregation defects to control abscission timing
GO:0005819 spindle	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Supported cell-division or midbody/spindle context for VPS4A, downstream of its ESCRT ATPase function. 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. Supporting Evidence: PMID:20616062 depletion of VPS4A, VPS4B, or any of the 11 different human ESCRT-III (CHMP) proteins inhibited abscission PMID:24814515 ANCHR associates with VPS4 at the midbody ring following DNA segregation defects to control abscission timing
GO:0006997 nucleus organization	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Supported nuclear-envelope/nucleus-organization ESCRT context, but not the primary VPS4A molecular role. 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. Supporting Evidence: PMID:28242692 In mammals, VPS4 depletion induces nuclear morphology defects
GO:0007041 lysosomal transport	IEA GO_REF:0000117	MODIFY	Summary: The broad lysosomal transport annotation reflects VPS4A late-endosomal/MVB trafficking function. Reason: A more specific late endosome-to-lysosome/MVB sorting pathway term better captures the evidence. Proposed replacements: late endosome to lysosome transport via multivesicular body sorting pathway Supporting Evidence: PMID:10637304 The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking PMID:15075231 hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles
GO:0007080 mitotic metaphase chromosome alignment	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	Summary: VPS4A/ESCRT depletion can perturb spindle and chromosome phenotypes, but this does not show VPS4A is a metaphase chromosome-alignment factor. Reason: The term overstates a downstream cell-division phenotype relative to the direct ESCRT/VPS4 mechanism. Supporting Evidence: PMID:20616062 depletion of VPS4A, VPS4B, or any of the 11 different human ESCRT-III (CHMP) proteins inhibited abscission PMID:24814515 ANCHR associates with VPS4 at the midbody ring following DNA segregation defects to control abscission timing
GO:0010389 regulation of G2/M transition of mitotic cell cycle	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	Summary: The automated G2/M-transition annotation is too broad and indirect for VPS4A. Reason: Available evidence supports ESCRT-mediated abscission and membrane remodeling, not direct regulation of the G2/M transition. Supporting Evidence: PMID:20616062 depletion of VPS4A, VPS4B, or any of the 11 different human ESCRT-III (CHMP) proteins inhibited abscission PMID:24814515 ANCHR associates with VPS4 at the midbody ring following DNA segregation defects to control abscission timing
GO:0016887 ATP hydrolysis activity	IEA GO_REF:0000120	ACCEPT	Summary: Core VPS4A function: ATP-driven recognition, remodeling, and disassembly of ESCRT-III/protein assemblies. Reason: This is the central conserved molecular role of VPS4A and directly supports ESCRT recycling and downstream membrane remodeling. Supporting Evidence: UniProt:Q9UN37 Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly UniProt:Q9UN37 Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. PMID:17928862 VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly PMID:18606141 Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding.
GO:0030496 midbody	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Supported cell-division or midbody/spindle context for VPS4A, downstream of its ESCRT ATPase function. 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. Supporting Evidence: PMID:20616062 depletion of VPS4A, VPS4B, or any of the 11 different human ESCRT-III (CHMP) proteins inhibited abscission PMID:24814515 ANCHR associates with VPS4 at the midbody ring following DNA segregation defects to control abscission timing
GO:0031902 late endosome membrane	IEA GO_REF:0000044	ACCEPT	Summary: Supported localization for a cytosolic AAA ATPase that is recruited to endosomal/vacuolar membranes during ESCRT function. Reason: VPS4A cycles between cytosol and membrane-associated ESCRT assemblies; these compartments are consistent with the core endosomal/MVB role. Supporting Evidence: UniProt:Q9UN37 Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly UniProt:Q9UN37 Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. PMID:10637304 The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking PMID:15075231 hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles
GO:0039702 viral budding via host ESCRT complex	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Directly supported viral/plasma-membrane ESCRT context, but this is host-pathogen exploitation of VPS4A machinery rather than the core cellular function. Reason: Keep as a real non-core ESCRT output; do not use it to define the primary function of VPS4A. Supporting Evidence: PMID:11595185 Dominant negative mutant Vps4 proteins that inhibit vacuolar protein sorting also arrest HIV-1 and MLV budding. PMID:17940959 A lack of VPS4 adenosine triphosphatase activity reduced budding by up to 80%
GO:0043162 ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway	IEA GO_REF:0000117	ACCEPT	Summary: Supported as part of the core VPS4A endosomal/MVB sorting and ESCRT-recycling function. Reason: VPS4A ATPase activity recycles ESCRT-III assemblies, enabling MVB sorting, ILV formation, and late endosomal cargo transport. Supporting Evidence: UniProt:Q9UN37 Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly UniProt:Q9UN37 Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. PMID:10637304 The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking PMID:15075231 hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles
GO:0051261 protein depolymerization	IEA GO_REF:0000117	MODIFY	Summary: VPS4A depolymerizes/remodels ESCRT-III assemblies rather than depolymerizing proteins generally. Reason: ESCRT III complex disassembly is the specific process supported by the VPS4A mechanism. Proposed replacements: ESCRT III complex disassembly Supporting Evidence: UniProt:Q9UN37 Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly UniProt:Q9UN37 Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. PMID:17928862 VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly PMID:18606141 Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding.
GO:0061952 midbody abscission	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Supported cell-division or midbody/spindle context for VPS4A, downstream of its ESCRT ATPase function. 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. Supporting Evidence: PMID:20616062 depletion of VPS4A, VPS4B, or any of the 11 different human ESCRT-III (CHMP) proteins inhibited abscission PMID:24814515 ANCHR associates with VPS4 at the midbody ring following DNA segregation defects to control abscission timing
GO:0090543 Flemming body	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Supported cell-division or midbody/spindle context for VPS4A, downstream of its ESCRT ATPase function. 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. Supporting Evidence: PMID:20616062 depletion of VPS4A, VPS4B, or any of the 11 different human ESCRT-III (CHMP) proteins inhibited abscission PMID:24814515 ANCHR associates with VPS4 at the midbody ring following DNA segregation defects to control abscission timing
GO:0090611 obsolete ubiquitin-independent protein catabolic process via the multivesicular body sorting pathway	IEA GO_REF:0000117	MODIFY	Summary: The annotation captures a real ubiquitin-independent MVB-sorting context, but the current GO term is obsolete. Reason: Use a current MVB sorting pathway term rather than retaining an obsolete ubiquitin-independent protein catabolic process term. Proposed replacements: multivesicular body sorting pathway Supporting Evidence: PMID:10637304 The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking PMID:15075231 hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles
GO:1903543 positive regulation of exosomal secretion	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: Supported exosome-release context for VPS4A/B but not the primary cellular function. Reason: Exosome secretion is one downstream ESCRT-dependent output of VPS4A activity, so retain as non-core. Supporting Evidence: UniProt:Q9UN37 VPS4A/B are required for the exosomal release of SDCBP, CD63 and syndecan
GO:0005515 protein binding	IPI PMID:16730941 A systematic analysis of human CHMP protein interactions: ad...	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: file:human/VPS4A/VPS4A-notes.md Plain `GO:0005515 protein binding` rows should not be retained as informative functions. PMID:17928862 VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly PMID:18606141 Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding.
GO:0005515 protein binding	IPI PMID:17110338 Hsp90 cochaperone Aha1 downregulation rescues misfolding of ...	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: file:human/VPS4A/VPS4A-notes.md Plain `GO:0005515 protein binding` rows should not be retained as informative functions. PMID:17928862 VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly PMID:18606141 Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding.
GO:0005515 protein binding	IPI PMID:17928862 ESCRT-III recognition by VPS4 ATPases.	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: file:human/VPS4A/VPS4A-notes.md Plain `GO:0005515 protein binding` rows should not be retained as informative functions. PMID:17928862 VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly PMID:18606141 Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding.
GO:0005515 protein binding	IPI PMID:24814515 ANCHR mediates Aurora-B-dependent abscission checkpoint cont...	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: file:human/VPS4A/VPS4A-notes.md Plain `GO:0005515 protein binding` rows should not be retained as informative functions. PMID:17928862 VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly PMID:18606141 Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding.
GO:0005515 protein binding	IPI PMID:26618866 ∆F508 CFTR interactome remodelling promotes rescue of cystic...	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: file:human/VPS4A/VPS4A-notes.md Plain `GO:0005515 protein binding` rows should not be retained as informative functions. PMID:17928862 VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly PMID:18606141 Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding.
GO:0005515 protein binding	IPI PMID:31324722 Inhibition of calpain 1 restores plasma membrane stability t...	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: file:human/VPS4A/VPS4A-notes.md Plain `GO:0005515 protein binding` rows should not be retained as informative functions. PMID:17928862 VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly PMID:18606141 Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: file:human/VPS4A/VPS4A-notes.md Plain `GO:0005515 protein binding` rows should not be retained as informative functions. PMID:17928862 VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly PMID:18606141 Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: file:human/VPS4A/VPS4A-notes.md Plain `GO:0005515 protein binding` rows should not be retained as informative functions. PMID:17928862 VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly PMID:18606141 Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding.
GO:0005515 protein binding	IPI PMID:35156780 CFTR interactome mapping using the mammalian membrane two-hy...	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: file:human/VPS4A/VPS4A-notes.md Plain `GO:0005515 protein binding` rows should not be retained as informative functions. PMID:17928862 VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly PMID:18606141 Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding.
GO:0005515 protein binding	IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce...	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: file:human/VPS4A/VPS4A-notes.md Plain `GO:0005515 protein binding` rows should not be retained as informative functions. PMID:17928862 VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly PMID:18606141 Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding.
GO:0005515 protein binding	IPI PMID:36012204 Differential CFTR-Interactome Proximity Labeling Procedures ...	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: file:human/VPS4A/VPS4A-notes.md Plain `GO:0005515 protein binding` rows should not be retained as informative functions. PMID:17928862 VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly PMID:18606141 Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding.
GO:0005737 cytoplasm	IEA GO_REF:0000120	ACCEPT	Summary: Supported localization for a cytosolic AAA ATPase that is recruited to endosomal/vacuolar membranes during ESCRT function. Reason: VPS4A cycles between cytosol and membrane-associated ESCRT assemblies; these compartments are consistent with the core endosomal/MVB role. Supporting Evidence: UniProt:Q9UN37 Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly UniProt:Q9UN37 Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. PMID:10637304 The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking PMID:15075231 hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles
GO:0036258 multivesicular body assembly	IEA GO_REF:0000107	ACCEPT	Summary: Supported as part of the core VPS4A endosomal/MVB sorting and ESCRT-recycling function. Reason: VPS4A ATPase activity recycles ESCRT-III assemblies, enabling MVB sorting, ILV formation, and late endosomal cargo transport. Supporting Evidence: UniProt:Q9UN37 Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly UniProt:Q9UN37 Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. PMID:10637304 The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking PMID:15075231 hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles
GO:0046761 viral budding from plasma membrane	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Directly supported viral/plasma-membrane ESCRT context, but this is host-pathogen exploitation of VPS4A machinery rather than the core cellular function. Reason: Keep as a real non-core ESCRT output; do not use it to define the primary function of VPS4A. Supporting Evidence: PMID:11595185 Dominant negative mutant Vps4 proteins that inhibit vacuolar protein sorting also arrest HIV-1 and MLV budding. PMID:17940959 A lack of VPS4 adenosine triphosphatase activity reduced budding by up to 80%
GO:0048471 perinuclear region of cytoplasm	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Supported localization or pathway context, but not central enough to define VPS4A core function. Reason: Keep as a non-core context attached to the broader ESCRT ATPase role. Supporting Evidence: PMID:10637304 The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking PMID:15075231 hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles
GO:0061738 late endosomal microautophagy	IEA GO_REF:0000107	UNDECIDED	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. Reason: Retain uncertainty pending direct human evidence or a reviewed source tying VPS4A specifically to late endosomal microautophagy. Supporting Evidence: PMID:17428789 deletion of VPS4 and VPS36 caused impaired maturation of the vacuolar proaminopeptidase I (pAPI) via autophagy or the cytosol to vacuole targeting pathway PMID:20588296 ESCRT-III-mediated membrane neck cleavage is crucial for many processes, including the biogenesis of multivesicular bodies, viral budding, cytokinesis, and probably autophagy.
GO:0030496 midbody	IDA GO_REF:0000052	KEEP AS NON CORE	Summary: Supported cell-division or midbody/spindle context for VPS4A, downstream of its ESCRT ATPase function. 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. Supporting Evidence: PMID:20616062 depletion of VPS4A, VPS4B, or any of the 11 different human ESCRT-III (CHMP) proteins inhibited abscission PMID:24814515 ANCHR associates with VPS4 at the midbody ring following DNA segregation defects to control abscission timing
GO:0090148 membrane fission	IDA PMID:36604498 Structural basis of CHMP2A-CHMP3 ESCRT-III polymer assembly ...	ACCEPT	Summary: Supported as part of the ESCRT-III/VPS4 membrane-remodeling machinery. Reason: Recent CHMP2A-CHMP3-VPS4 reconstitution supports VPS4 participation in membrane constriction and cleavage; this is a core ESCRT output. Supporting Evidence: PMID:36604498 VPS4 can constrict and cleave CHMP2A-CHMP3 membrane tubes PMID:36604498 CHMP2A-CHMP3-VPS4 act as a minimal membrane fission machinery. UniProt:Q9UN37 Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly UniProt:Q9UN37 Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting.
GO:0140545 ATP-dependent protein disaggregase activity	IDA PMID:36604498 Structural basis of CHMP2A-CHMP3 ESCRT-III polymer assembly ...	ACCEPT	Summary: Core VPS4A function: ATP-driven recognition, remodeling, and disassembly of ESCRT-III/protein assemblies. Reason: This is the central conserved molecular role of VPS4A and directly supports ESCRT recycling and downstream membrane remodeling. Supporting Evidence: UniProt:Q9UN37 Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly UniProt:Q9UN37 Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. PMID:17928862 VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly PMID:18606141 Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding.
GO:0001778 plasma membrane repair	NAS PMID:24482116 ESCRT machinery is required for plasma membrane repair.	KEEP AS NON CORE	Summary: Supported plasma membrane repair context for ESCRT machinery, retained as a non-core VPS4A output. Reason: Plasma membrane repair uses ESCRT-mediated shedding/fission but is a specialized context of the core ESCRT remodeling machinery. Supporting Evidence: PMID:24482116 ESCRT proteins were recruited within seconds to plasma membrane wounds PMID:24482116 repair of certain wounds is ensured by ESCRT-mediated extracellular shedding of wounded portions.
GO:0005643 nuclear pore	NAS PMID:16505166 Recycling of ESCRTs by the AAA-ATPase Vps4 is regulated by a...	KEEP AS NON CORE	Summary: Supported nuclear-envelope/nucleus-organization ESCRT context, but not the primary VPS4A molecular role. 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. Supporting Evidence: PMID:28242692 In mammals, VPS4 depletion induces nuclear morphology defects
GO:0005886 plasma membrane	NAS PMID:19234443 Membrane scission by the ESCRT-III complex.	KEEP AS NON CORE	Summary: Directly supported viral/plasma-membrane ESCRT context, but this is host-pathogen exploitation of VPS4A machinery rather than the core cellular function. Reason: Keep as a real non-core ESCRT output; do not use it to define the primary function of VPS4A. Supporting Evidence: PMID:11595185 Dominant negative mutant Vps4 proteins that inhibit vacuolar protein sorting also arrest HIV-1 and MLV budding. PMID:17940959 A lack of VPS4 adenosine triphosphatase activity reduced budding by up to 80%
GO:0006914 autophagy	NAS PMID:17428789 Phosphatidylethanolamine, a limiting factor of autophagy in ...	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: PMID:17428789 deletion of VPS4 and VPS36 caused impaired maturation of the vacuolar proaminopeptidase I (pAPI) via autophagy or the cytosol to vacuole targeting pathway PMID:20588296 ESCRT-III-mediated membrane neck cleavage is crucial for many processes, including the biogenesis of multivesicular bodies, viral budding, cytokinesis, and probably autophagy.
GO:0006997 nucleus organization	NAS PMID:20616062 Human ESCRT-III and VPS4 proteins are required for centrosom...	KEEP AS NON CORE	Summary: Supported nuclear-envelope/nucleus-organization ESCRT context, but not the primary VPS4A molecular role. 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. Supporting Evidence: PMID:28242692 In mammals, VPS4 depletion induces nuclear morphology defects
GO:0030496 midbody	NAS PMID:26040712 Spastin and ESCRT-III coordinate mitotic spindle disassembly...	KEEP AS NON CORE	Summary: Supported cell-division or midbody/spindle context for VPS4A, downstream of its ESCRT ATPase function. 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. Supporting Evidence: PMID:20616062 depletion of VPS4A, VPS4B, or any of the 11 different human ESCRT-III (CHMP) proteins inhibited abscission PMID:24814515 ANCHR associates with VPS4 at the midbody ring following DNA segregation defects to control abscission timing
GO:0031468 nuclear membrane reassembly	NAS PMID:26040713 ESCRT-III controls nuclear envelope reformation.	KEEP AS NON CORE	Summary: Supported nuclear-envelope/nucleus-organization ESCRT context, but not the primary VPS4A molecular role. 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. Supporting Evidence: PMID:28242692 In mammals, VPS4 depletion induces nuclear morphology defects
GO:0036258 multivesicular body assembly	NAS PMID:16505166 Recycling of ESCRTs by the AAA-ATPase Vps4 is regulated by a...	ACCEPT	Summary: Supported as part of the core VPS4A endosomal/MVB sorting and ESCRT-recycling function. Reason: VPS4A ATPase activity recycles ESCRT-III assemblies, enabling MVB sorting, ILV formation, and late endosomal cargo transport. Supporting Evidence: UniProt:Q9UN37 Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly UniProt:Q9UN37 Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. PMID:10637304 The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking PMID:15075231 hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles
GO:0046761 viral budding from plasma membrane	IMP PMID:16193069 Structural and mechanistic studies of VPS4 proteins.	KEEP AS NON CORE	Summary: Directly supported viral/plasma-membrane ESCRT context, but this is host-pathogen exploitation of VPS4A machinery rather than the core cellular function. Reason: Keep as a real non-core ESCRT output; do not use it to define the primary function of VPS4A. Supporting Evidence: PMID:11595185 Dominant negative mutant Vps4 proteins that inhibit vacuolar protein sorting also arrest HIV-1 and MLV budding. PMID:17940959 A lack of VPS4 adenosine triphosphatase activity reduced budding by up to 80%
GO:0061764 late endosome to lysosome transport via multivesicular body sorting pathway	NAS PMID:9211789 The VPS4 gene is involved in protein transport out of a yeas...	ACCEPT	Summary: Supported as part of the core VPS4A endosomal/MVB sorting and ESCRT-recycling function. Reason: VPS4A ATPase activity recycles ESCRT-III assemblies, enabling MVB sorting, ILV formation, and late endosomal cargo transport. Supporting Evidence: UniProt:Q9UN37 Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly UniProt:Q9UN37 Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. PMID:10637304 The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking PMID:15075231 hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles
GO:0061952 midbody abscission	NAS PMID:20616062 Human ESCRT-III and VPS4 proteins are required for centrosom...	KEEP AS NON CORE	Summary: Supported cell-division or midbody/spindle context for VPS4A, downstream of its ESCRT ATPase function. 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. Supporting Evidence: PMID:20616062 depletion of VPS4A, VPS4B, or any of the 11 different human ESCRT-III (CHMP) proteins inhibited abscission PMID:24814515 ANCHR associates with VPS4 at the midbody ring following DNA segregation defects to control abscission timing
GO:0071985 multivesicular body sorting pathway	NAS PMID:16505166 Recycling of ESCRTs by the AAA-ATPase Vps4 is regulated by a...	ACCEPT	Summary: Supported as part of the core VPS4A endosomal/MVB sorting and ESCRT-recycling function. Reason: VPS4A ATPase activity recycles ESCRT-III assemblies, enabling MVB sorting, ILV formation, and late endosomal cargo transport. Supporting Evidence: UniProt:Q9UN37 Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly UniProt:Q9UN37 Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. PMID:10637304 The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking PMID:15075231 hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles
GO:0090148 membrane fission	NAS PMID:19234443 Membrane scission by the ESCRT-III complex.	ACCEPT	Summary: Supported as part of the ESCRT-III/VPS4 membrane-remodeling machinery. Reason: Recent CHMP2A-CHMP3-VPS4 reconstitution supports VPS4 participation in membrane constriction and cleavage; this is a core ESCRT output. Supporting Evidence: PMID:36604498 VPS4 can constrict and cleave CHMP2A-CHMP3 membrane tubes PMID:36604498 CHMP2A-CHMP3-VPS4 act as a minimal membrane fission machinery. UniProt:Q9UN37 Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly UniProt:Q9UN37 Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting.
GO:0097352 autophagosome maturation	NAS PMID:9211789 The VPS4 gene is involved in protein transport out of a yeas...	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: PMID:17428789 deletion of VPS4 and VPS36 caused impaired maturation of the vacuolar proaminopeptidase I (pAPI) via autophagy or the cytosol to vacuole targeting pathway PMID:20588296 ESCRT-III-mediated membrane neck cleavage is crucial for many processes, including the biogenesis of multivesicular bodies, viral budding, cytokinesis, and probably autophagy.
GO:1904949 ATPase complex	NAS PMID:19278657 Three-dimensional structure of AAA ATPase Vps4: advancing st...	ACCEPT	Summary: Core VPS4A function: ATP-driven recognition, remodeling, and disassembly of ESCRT-III/protein assemblies. Reason: This is the central conserved molecular role of VPS4A and directly supports ESCRT recycling and downstream membrane remodeling. Supporting Evidence: UniProt:Q9UN37 Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly UniProt:Q9UN37 Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. PMID:17928862 VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly PMID:18606141 Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding.
GO:0005829 cytosol	TAS Reactome:R-HSA-3159232	ACCEPT	Summary: Supported localization for a cytosolic AAA ATPase that is recruited to endosomal/vacuolar membranes during ESCRT function. Reason: VPS4A cycles between cytosol and membrane-associated ESCRT assemblies; these compartments are consistent with the core endosomal/MVB role. Supporting Evidence: UniProt:Q9UN37 Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly UniProt:Q9UN37 Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. PMID:10637304 The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking PMID:15075231 hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles
GO:0005829 cytosol	TAS Reactome:R-HSA-917693	ACCEPT	Summary: Supported localization for a cytosolic AAA ATPase that is recruited to endosomal/vacuolar membranes during ESCRT function. Reason: VPS4A cycles between cytosol and membrane-associated ESCRT assemblies; these compartments are consistent with the core endosomal/MVB role. Supporting Evidence: UniProt:Q9UN37 Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly UniProt:Q9UN37 Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. PMID:10637304 The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking PMID:15075231 hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles
GO:0005829 cytosol	TAS Reactome:R-HSA-9610942	ACCEPT	Summary: Supported localization for a cytosolic AAA ATPase that is recruited to endosomal/vacuolar membranes during ESCRT function. Reason: VPS4A cycles between cytosol and membrane-associated ESCRT assemblies; these compartments are consistent with the core endosomal/MVB role. Supporting Evidence: UniProt:Q9UN37 Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly UniProt:Q9UN37 Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. PMID:10637304 The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking PMID:15075231 hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles
GO:0005829 cytosol	TAS Reactome:R-HSA-9610954	ACCEPT	Summary: Supported localization for a cytosolic AAA ATPase that is recruited to endosomal/vacuolar membranes during ESCRT function. Reason: VPS4A cycles between cytosol and membrane-associated ESCRT assemblies; these compartments are consistent with the core endosomal/MVB role. Supporting Evidence: UniProt:Q9UN37 Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly UniProt:Q9UN37 Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. PMID:10637304 The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking PMID:15075231 hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles
GO:0005829 cytosol	TAS Reactome:R-HSA-9668389	ACCEPT	Summary: Supported localization for a cytosolic AAA ATPase that is recruited to endosomal/vacuolar membranes during ESCRT function. Reason: VPS4A cycles between cytosol and membrane-associated ESCRT assemblies; these compartments are consistent with the core endosomal/MVB role. Supporting Evidence: UniProt:Q9UN37 Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly UniProt:Q9UN37 Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. PMID:10637304 The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking PMID:15075231 hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles
GO:0005829 cytosol	TAS Reactome:R-HSA-9668415	ACCEPT	Summary: Supported localization for a cytosolic AAA ATPase that is recruited to endosomal/vacuolar membranes during ESCRT function. Reason: VPS4A cycles between cytosol and membrane-associated ESCRT assemblies; these compartments are consistent with the core endosomal/MVB role. Supporting Evidence: UniProt:Q9UN37 Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly UniProt:Q9UN37 Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. PMID:10637304 The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking PMID:15075231 hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles
GO:0016887 ATP hydrolysis activity	ISS GO_REF:0000024	ACCEPT	Summary: Core VPS4A function: ATP-driven recognition, remodeling, and disassembly of ESCRT-III/protein assemblies. Reason: This is the central conserved molecular role of VPS4A and directly supports ESCRT recycling and downstream membrane remodeling. Supporting Evidence: UniProt:Q9UN37 Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly UniProt:Q9UN37 Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. PMID:17928862 VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly PMID:18606141 Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding.
GO:0031902 late endosome membrane	ISS GO_REF:0000024	ACCEPT	Summary: Supported localization for a cytosolic AAA ATPase that is recruited to endosomal/vacuolar membranes during ESCRT function. Reason: VPS4A cycles between cytosol and membrane-associated ESCRT assemblies; these compartments are consistent with the core endosomal/MVB role. Supporting Evidence: UniProt:Q9UN37 Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly UniProt:Q9UN37 Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. PMID:10637304 The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking PMID:15075231 hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles
GO:0061952 midbody abscission	IMP PMID:24814515 ANCHR mediates Aurora-B-dependent abscission checkpoint cont...	KEEP AS NON CORE	Summary: Supported cell-division or midbody/spindle context for VPS4A, downstream of its ESCRT ATPase function. 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. Supporting Evidence: PMID:20616062 depletion of VPS4A, VPS4B, or any of the 11 different human ESCRT-III (CHMP) proteins inhibited abscission PMID:24814515 ANCHR associates with VPS4 at the midbody ring following DNA segregation defects to control abscission timing
GO:0016887 ATP hydrolysis activity	TAS Reactome:R-HSA-9668415	ACCEPT	Summary: Core VPS4A function: ATP-driven recognition, remodeling, and disassembly of ESCRT-III/protein assemblies. Reason: This is the central conserved molecular role of VPS4A and directly supports ESCRT recycling and downstream membrane remodeling. Supporting Evidence: UniProt:Q9UN37 Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly UniProt:Q9UN37 Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. PMID:17928862 VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly PMID:18606141 Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding.
GO:0007084 mitotic nuclear membrane reassembly	TAS Reactome:R-HSA-2995410	KEEP AS NON CORE	Summary: Supported nuclear-envelope/nucleus-organization ESCRT context, but not the primary VPS4A molecular role. 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. Supporting Evidence: PMID:28242692 In mammals, VPS4 depletion induces nuclear morphology defects
GO:0005515 protein binding	IPI PMID:18606141 Two distinct modes of ESCRT-III recognition are required for...	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: file:human/VPS4A/VPS4A-notes.md Plain `GO:0005515 protein binding` rows should not be retained as informative functions. PMID:17928862 VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly PMID:18606141 Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding.
GO:0000916 actomyosin contractile ring contraction	TAS PMID:28242692 LEM2 recruits CHMP7 for ESCRT-mediated nuclear envelope clos...	MODIFY	Summary: The evidence supports cytokinetic abscission rather than the broader or less accurate cell-division term currently used. Reason: VPS4A acts in the ESCRT-mediated abscission stage of cytokinesis, so midbody abscission is the better term. Proposed replacements: midbody abscission Supporting Evidence: PMID:20616062 depletion of VPS4A, VPS4B, or any of the 11 different human ESCRT-III (CHMP) proteins inhibited abscission PMID:24814515 ANCHR associates with VPS4 at the midbody ring following DNA segregation defects to control abscission timing
GO:0140545 ATP-dependent protein disaggregase activity	NAS PMID:28242692 LEM2 recruits CHMP7 for ESCRT-mediated nuclear envelope clos...	ACCEPT	Summary: Core VPS4A function: ATP-driven recognition, remodeling, and disassembly of ESCRT-III/protein assemblies. Reason: This is the central conserved molecular role of VPS4A and directly supports ESCRT recycling and downstream membrane remodeling. Supporting Evidence: UniProt:Q9UN37 Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly UniProt:Q9UN37 Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. PMID:17928862 VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly PMID:18606141 Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding.
GO:0005515 protein binding	IPI PMID:16174732 Structure and ESCRT-III protein interactions of the MIT doma...	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: file:human/VPS4A/VPS4A-notes.md Plain `GO:0005515 protein binding` rows should not be retained as informative functions. PMID:17928862 VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly PMID:18606141 Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding.
GO:0046761 viral budding from plasma membrane	IMP PMID:17940959 Involvement of vacuolar protein sorting pathway in Ebola vir...	KEEP AS NON CORE	Summary: Directly supported viral/plasma-membrane ESCRT context, but this is host-pathogen exploitation of VPS4A machinery rather than the core cellular function. Reason: Keep as a real non-core ESCRT output; do not use it to define the primary function of VPS4A. Supporting Evidence: PMID:11595185 Dominant negative mutant Vps4 proteins that inhibit vacuolar protein sorting also arrest HIV-1 and MLV budding. PMID:17940959 A lack of VPS4 adenosine triphosphatase activity reduced budding by up to 80%
GO:0032880 regulation of protein localization	IMP PMID:18005716 Identification of human MVB12 proteins as ESCRT-I subunits t...	KEEP AS NON CORE	Summary: Reviewed as a peripheral or insufficiently specific VPS4A annotation relative to the core ESCRT ATPase role. Reason: The annotation is not central enough to define VPS4A core function, but no direct contradiction was found in the local evidence. Supporting Evidence: UniProt:Q9UN37 Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly UniProt:Q9UN37 Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting.
GO:0010008 endosome membrane	IMP PMID:18606141 Two distinct modes of ESCRT-III recognition are required for...	ACCEPT	Summary: Supported localization for a cytosolic AAA ATPase that is recruited to endosomal/vacuolar membranes during ESCRT function. Reason: VPS4A cycles between cytosol and membrane-associated ESCRT assemblies; these compartments are consistent with the core endosomal/MVB role. Supporting Evidence: UniProt:Q9UN37 Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly UniProt:Q9UN37 Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. PMID:10637304 The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking PMID:15075231 hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles
GO:0044877 protein-containing complex binding	IPI PMID:18606141 Two distinct modes of ESCRT-III recognition are required for...	ACCEPT	Summary: Core VPS4A function: ATP-driven recognition, remodeling, and disassembly of ESCRT-III/protein assemblies. Reason: This is the central conserved molecular role of VPS4A and directly supports ESCRT recycling and downstream membrane remodeling. Supporting Evidence: UniProt:Q9UN37 Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly UniProt:Q9UN37 Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. PMID:17928862 VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly PMID:18606141 Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding.
GO:0061952 midbody abscission	IMP PMID:20616062 Human ESCRT-III and VPS4 proteins are required for centrosom...	KEEP AS NON CORE	Summary: Supported cell-division or midbody/spindle context for VPS4A, downstream of its ESCRT ATPase function. 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. Supporting Evidence: PMID:20616062 depletion of VPS4A, VPS4B, or any of the 11 different human ESCRT-III (CHMP) proteins inhibited abscission PMID:24814515 ANCHR associates with VPS4 at the midbody ring following DNA segregation defects to control abscission timing
GO:0006998 nuclear envelope organization	TAS PMID:28242692 LEM2 recruits CHMP7 for ESCRT-mediated nuclear envelope clos...	KEEP AS NON CORE	Summary: Supported nuclear-envelope/nucleus-organization ESCRT context, but not the primary VPS4A molecular role. 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. Supporting Evidence: PMID:28242692 In mammals, VPS4 depletion induces nuclear morphology defects
GO:0031468 nuclear membrane reassembly	TAS PMID:28242692 LEM2 recruits CHMP7 for ESCRT-mediated nuclear envelope clos...	KEEP AS NON CORE	Summary: Supported nuclear-envelope/nucleus-organization ESCRT context, but not the primary VPS4A molecular role. 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. Supporting Evidence: PMID:28242692 In mammals, VPS4 depletion induces nuclear morphology defects
GO:1904903 ESCRT III complex disassembly	NAS PMID:28242692 LEM2 recruits CHMP7 for ESCRT-mediated nuclear envelope clos...	ACCEPT	Summary: Core VPS4A function: ATP-driven recognition, remodeling, and disassembly of ESCRT-III/protein assemblies. Reason: This is the central conserved molecular role of VPS4A and directly supports ESCRT recycling and downstream membrane remodeling. Supporting Evidence: UniProt:Q9UN37 Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly UniProt:Q9UN37 Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. PMID:17928862 VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly PMID:18606141 Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding.
GO:0006622 protein targeting to lysosome	IMP PMID:16973552 Human ESCRT-II complex and its role in human immunodeficienc...	ACCEPT	Summary: Supported as part of the core VPS4A endosomal/MVB sorting and ESCRT-recycling function. Reason: VPS4A ATPase activity recycles ESCRT-III assemblies, enabling MVB sorting, ILV formation, and late endosomal cargo transport. Supporting Evidence: UniProt:Q9UN37 Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly UniProt:Q9UN37 Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. PMID:10637304 The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking PMID:15075231 hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles
GO:0044878 mitotic cytokinesis checkpoint signaling	IMP PMID:24814515 ANCHR mediates Aurora-B-dependent abscission checkpoint cont...	KEEP AS NON CORE	Summary: Supported cell-division or midbody/spindle context for VPS4A, downstream of its ESCRT ATPase function. 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. Supporting Evidence: PMID:20616062 depletion of VPS4A, VPS4B, or any of the 11 different human ESCRT-III (CHMP) proteins inhibited abscission PMID:24814515 ANCHR associates with VPS4 at the midbody ring following DNA segregation defects to control abscission timing
GO:0030496 midbody	TAS PMID:28242692 LEM2 recruits CHMP7 for ESCRT-mediated nuclear envelope clos...	KEEP AS NON CORE	Summary: Supported cell-division or midbody/spindle context for VPS4A, downstream of its ESCRT ATPase function. 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. Supporting Evidence: PMID:20616062 depletion of VPS4A, VPS4B, or any of the 11 different human ESCRT-III (CHMP) proteins inhibited abscission PMID:24814515 ANCHR associates with VPS4 at the midbody ring following DNA segregation defects to control abscission timing
GO:0061640 cytoskeleton-dependent cytokinesis	TAS PMID:28242692 LEM2 recruits CHMP7 for ESCRT-mediated nuclear envelope clos...	KEEP AS NON CORE	Summary: Supported cell-division or midbody/spindle context for VPS4A, downstream of its ESCRT ATPase function. 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. Supporting Evidence: PMID:20616062 depletion of VPS4A, VPS4B, or any of the 11 different human ESCRT-III (CHMP) proteins inhibited abscission PMID:24814515 ANCHR associates with VPS4 at the midbody ring following DNA segregation defects to control abscission timing
GO:0016236 macroautophagy	NAS PMID:20588296 Membrane budding and scission by the ESCRT machinery: it's a...	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: PMID:17428789 deletion of VPS4 and VPS36 caused impaired maturation of the vacuolar proaminopeptidase I (pAPI) via autophagy or the cytosol to vacuole targeting pathway PMID:20588296 ESCRT-III-mediated membrane neck cleavage is crucial for many processes, including the biogenesis of multivesicular bodies, viral budding, cytokinesis, and probably autophagy.
GO:0036258 multivesicular body assembly	NAS PMID:20588296 Membrane budding and scission by the ESCRT machinery: it's a...	ACCEPT	Summary: Supported as part of the core VPS4A endosomal/MVB sorting and ESCRT-recycling function. Reason: VPS4A ATPase activity recycles ESCRT-III assemblies, enabling MVB sorting, ILV formation, and late endosomal cargo transport. Supporting Evidence: UniProt:Q9UN37 Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly UniProt:Q9UN37 Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. PMID:10637304 The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking PMID:15075231 hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles
GO:1904903 ESCRT III complex disassembly	NAS PMID:20588296 Membrane budding and scission by the ESCRT machinery: it's a...	ACCEPT	Summary: Core VPS4A function: ATP-driven recognition, remodeling, and disassembly of ESCRT-III/protein assemblies. Reason: This is the central conserved molecular role of VPS4A and directly supports ESCRT recycling and downstream membrane remodeling. Supporting Evidence: UniProt:Q9UN37 Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly UniProt:Q9UN37 Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. PMID:17928862 VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly PMID:18606141 Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding.
GO:1904896 ESCRT complex disassembly	NAS PMID:21118109 The role of ESCRT proteins in fusion events involving lysoso...	ACCEPT	Summary: Core VPS4A function: ATP-driven recognition, remodeling, and disassembly of ESCRT-III/protein assemblies. Reason: This is the central conserved molecular role of VPS4A and directly supports ESCRT recycling and downstream membrane remodeling. Supporting Evidence: UniProt:Q9UN37 Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly UniProt:Q9UN37 Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. PMID:17928862 VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly PMID:18606141 Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding.
GO:0036258 multivesicular body assembly	ISS GO_REF:0000024	ACCEPT	Summary: Supported as part of the core VPS4A endosomal/MVB sorting and ESCRT-recycling function. Reason: VPS4A ATPase activity recycles ESCRT-III assemblies, enabling MVB sorting, ILV formation, and late endosomal cargo transport. Supporting Evidence: UniProt:Q9UN37 Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly UniProt:Q9UN37 Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. PMID:10637304 The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking PMID:15075231 hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles
GO:0061738 late endosomal microautophagy	ISS GO_REF:0000024	UNDECIDED	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. Reason: Retain uncertainty pending direct human evidence or a reviewed source tying VPS4A specifically to late endosomal microautophagy. Supporting Evidence: PMID:17428789 deletion of VPS4 and VPS36 caused impaired maturation of the vacuolar proaminopeptidase I (pAPI) via autophagy or the cytosol to vacuole targeting pathway PMID:20588296 ESCRT-III-mediated membrane neck cleavage is crucial for many processes, including the biogenesis of multivesicular bodies, viral budding, cytokinesis, and probably autophagy.
GO:0005524 ATP binding	IMP PMID:10637304 ATPase-defective mammalian VPS4 localizes to aberrant endoso...	ACCEPT	Summary: Accept ATP binding as part of the core AAA ATPase mechanism that enables VPS4A ATP hydrolysis and ESCRT-III remodeling. 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. Supporting Evidence: UniProt:Q9UN37 Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly UniProt:Q9UN37 Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. PMID:17928862 VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly
GO:0005764 lysosome	IDA PMID:10637304 ATPase-defective mammalian VPS4 localizes to aberrant endoso...	KEEP AS NON CORE	Summary: Supported localization or pathway context, but not central enough to define VPS4A core function. Reason: Keep as a non-core context attached to the broader ESCRT ATPase role. Supporting Evidence: PMID:10637304 The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking PMID:15075231 hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles
GO:0005769 early endosome	IDA PMID:10637304 ATPase-defective mammalian VPS4 localizes to aberrant endoso...	ACCEPT	Summary: Supported localization for a cytosolic AAA ATPase that is recruited to endosomal/vacuolar membranes during ESCRT function. Reason: VPS4A cycles between cytosol and membrane-associated ESCRT assemblies; these compartments are consistent with the core endosomal/MVB role. Supporting Evidence: UniProt:Q9UN37 Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly UniProt:Q9UN37 Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. PMID:10637304 The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking PMID:15075231 hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles
GO:0005770 late endosome	IDA PMID:10637304 ATPase-defective mammalian VPS4 localizes to aberrant endoso...	ACCEPT	Summary: Supported localization for a cytosolic AAA ATPase that is recruited to endosomal/vacuolar membranes during ESCRT function. Reason: VPS4A cycles between cytosol and membrane-associated ESCRT assemblies; these compartments are consistent with the core endosomal/MVB role. Supporting Evidence: UniProt:Q9UN37 Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly UniProt:Q9UN37 Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. PMID:10637304 The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking PMID:15075231 hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles
GO:0005774 vacuolar membrane	IDA PMID:10637304 ATPase-defective mammalian VPS4 localizes to aberrant endoso...	ACCEPT	Summary: Supported localization for a cytosolic AAA ATPase that is recruited to endosomal/vacuolar membranes during ESCRT function. Reason: VPS4A cycles between cytosol and membrane-associated ESCRT assemblies; these compartments are consistent with the core endosomal/MVB role. Supporting Evidence: UniProt:Q9UN37 Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly UniProt:Q9UN37 Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. PMID:10637304 The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking PMID:15075231 hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles
GO:0005829 cytosol	IDA PMID:10637304 ATPase-defective mammalian VPS4 localizes to aberrant endoso...	ACCEPT	Summary: Supported localization for a cytosolic AAA ATPase that is recruited to endosomal/vacuolar membranes during ESCRT function. Reason: VPS4A cycles between cytosol and membrane-associated ESCRT assemblies; these compartments are consistent with the core endosomal/MVB role. Supporting Evidence: UniProt:Q9UN37 Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly UniProt:Q9UN37 Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. PMID:10637304 The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking PMID:15075231 hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles
GO:0016197 endosomal transport	IMP PMID:10637304 ATPase-defective mammalian VPS4 localizes to aberrant endoso...	ACCEPT	Summary: Supported as part of the core VPS4A endosomal/MVB sorting and ESCRT-recycling function. Reason: VPS4A ATPase activity recycles ESCRT-III assemblies, enabling MVB sorting, ILV formation, and late endosomal cargo transport. Supporting Evidence: UniProt:Q9UN37 Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly UniProt:Q9UN37 Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. PMID:10637304 The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking PMID:15075231 hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles
GO:0016887 ATP hydrolysis activity	IMP PMID:10637304 ATPase-defective mammalian VPS4 localizes to aberrant endoso...	ACCEPT	Summary: Core VPS4A function: ATP-driven recognition, remodeling, and disassembly of ESCRT-III/protein assemblies. Reason: This is the central conserved molecular role of VPS4A and directly supports ESCRT recycling and downstream membrane remodeling. Supporting Evidence: UniProt:Q9UN37 Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly UniProt:Q9UN37 Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. PMID:17928862 VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly PMID:18606141 Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding.
GO:0032367 intracellular cholesterol transport	IMP PMID:10637304 ATPase-defective mammalian VPS4 localizes to aberrant endoso...	MODIFY	Summary: ATPase-defective hVPS4 produces cholesterol-enriched endosomal compartments, but VPS4A is not a cholesterol transporter. Reason: The cholesterol phenotype is a consequence of disrupted postendosomal trafficking; endosomal transport better captures the supported role. Proposed replacements: endosomal transport Supporting Evidence: PMID:10637304 The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking PMID:15075231 hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles
GO:0005515 protein binding	IPI PMID:18385515 Novel interactions of ESCRT-III with LIP5 and VPS4 and their...	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: file:human/VPS4A/VPS4A-notes.md Plain `GO:0005515 protein binding` rows should not be retained as informative functions. PMID:17928862 VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly PMID:18606141 Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding.
GO:0005515 protein binding	IPI PMID:23105106 Interactions of the human LIP5 regulatory protein with endos...	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: file:human/VPS4A/VPS4A-notes.md Plain `GO:0005515 protein binding` rows should not be retained as informative functions. PMID:17928862 VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly PMID:18606141 Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding.
GO:0034058 endosomal vesicle fusion	IMP PMID:15075231 ATPase-deficient hVPS4 impairs formation of internal endosom...	MODIFY	Summary: The hVPS4(EQ) evidence supports ILV formation and coat disassembly on endosomal vacuoles, not endosomal vesicle fusion. Reason: The biological effect is MVB/ILV biogenesis; fusion is the wrong process for this evidence. Proposed replacements: multivesicular body assembly Supporting Evidence: PMID:10637304 The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking PMID:15075231 hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles
GO:0005737 cytoplasm	IDA PMID:15075231 ATPase-deficient hVPS4 impairs formation of internal endosom...	ACCEPT	Summary: Supported localization for a cytosolic AAA ATPase that is recruited to endosomal/vacuolar membranes during ESCRT function. Reason: VPS4A cycles between cytosol and membrane-associated ESCRT assemblies; these compartments are consistent with the core endosomal/MVB role. Supporting Evidence: UniProt:Q9UN37 Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly UniProt:Q9UN37 Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. PMID:10637304 The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking PMID:15075231 hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles
GO:0005769 early endosome	IDA PMID:15075231 ATPase-deficient hVPS4 impairs formation of internal endosom...	ACCEPT	Summary: Supported localization for a cytosolic AAA ATPase that is recruited to endosomal/vacuolar membranes during ESCRT function. Reason: VPS4A cycles between cytosol and membrane-associated ESCRT assemblies; these compartments are consistent with the core endosomal/MVB role. Supporting Evidence: UniProt:Q9UN37 Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly UniProt:Q9UN37 Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. PMID:10637304 The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking PMID:15075231 hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles
GO:0005770 late endosome	IDA PMID:15075231 ATPase-deficient hVPS4 impairs formation of internal endosom...	ACCEPT	Summary: Supported localization for a cytosolic AAA ATPase that is recruited to endosomal/vacuolar membranes during ESCRT function. Reason: VPS4A cycles between cytosol and membrane-associated ESCRT assemblies; these compartments are consistent with the core endosomal/MVB role. Supporting Evidence: UniProt:Q9UN37 Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly UniProt:Q9UN37 Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. PMID:10637304 The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking PMID:15075231 hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles
GO:0006900 vesicle budding from membrane	IMP PMID:15075231 ATPase-deficient hVPS4 impairs formation of internal endosom...	ACCEPT	Summary: Supported endosomal ILV formation/coat-disassembly role downstream of VPS4A ATPase activity. Reason: ATPase-deficient hVPS4 reduces internal endosomal vesicles and stabilizes coats, consistent with this MVB biogenesis function. Supporting Evidence: PMID:10637304 The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking PMID:15075231 hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles
GO:0072319 vesicle uncoating	IMP PMID:15075231 ATPase-deficient hVPS4 impairs formation of internal endosom...	ACCEPT	Summary: Supported endosomal ILV formation/coat-disassembly role downstream of VPS4A ATPase activity. Reason: ATPase-deficient hVPS4 reduces internal endosomal vesicles and stabilizes coats, consistent with this MVB biogenesis function. Supporting Evidence: PMID:10637304 The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking PMID:15075231 hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles
GO:0005515 protein binding	IPI PMID:18997780 Structural basis for midbody targeting of spastin by the ESC...	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: file:human/VPS4A/VPS4A-notes.md Plain `GO:0005515 protein binding` rows should not be retained as informative functions. PMID:17928862 VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly PMID:18606141 Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding.
GO:0019076 viral release from host cell	IMP PMID:11595185 Tsg101 and the vacuolar protein sorting pathway are essentia...	KEEP AS NON CORE	Summary: Directly supported viral/plasma-membrane ESCRT context, but this is host-pathogen exploitation of VPS4A machinery rather than the core cellular function. Reason: Keep as a real non-core ESCRT output; do not use it to define the primary function of VPS4A. Supporting Evidence: PMID:11595185 Dominant negative mutant Vps4 proteins that inhibit vacuolar protein sorting also arrest HIV-1 and MLV budding. PMID:17940959 A lack of VPS4 adenosine triphosphatase activity reduced budding by up to 80%
GO:0005768 endosome	IDA PMID:17940959 Involvement of vacuolar protein sorting pathway in Ebola vir...	ACCEPT	Summary: Supported localization for a cytosolic AAA ATPase that is recruited to endosomal/vacuolar membranes during ESCRT function. Reason: VPS4A cycles between cytosol and membrane-associated ESCRT assemblies; these compartments are consistent with the core endosomal/MVB role. Supporting Evidence: UniProt:Q9UN37 Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly UniProt:Q9UN37 Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. PMID:10637304 The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking PMID:15075231 hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles
GO:0005886 plasma membrane	IDA PMID:17940959 Involvement of vacuolar protein sorting pathway in Ebola vir...	KEEP AS NON CORE	Summary: Directly supported viral/plasma-membrane ESCRT context, but this is host-pathogen exploitation of VPS4A machinery rather than the core cellular function. Reason: Keep as a real non-core ESCRT output; do not use it to define the primary function of VPS4A. Supporting Evidence: PMID:11595185 Dominant negative mutant Vps4 proteins that inhibit vacuolar protein sorting also arrest HIV-1 and MLV budding. PMID:17940959 A lack of VPS4 adenosine triphosphatase activity reduced budding by up to 80%
GO:0051301 cell division	IDA PMID:17853893 Human ESCRT and ALIX proteins interact with proteins of the ...	MODIFY	Summary: The evidence supports cytokinetic abscission rather than the broader or less accurate cell-division term currently used. Reason: VPS4A acts in the ESCRT-mediated abscission stage of cytokinesis, so midbody abscission is the better term. Proposed replacements: midbody abscission Supporting Evidence: PMID:20616062 depletion of VPS4A, VPS4B, or any of the 11 different human ESCRT-III (CHMP) proteins inhibited abscission PMID:24814515 ANCHR associates with VPS4 at the midbody ring following DNA segregation defects to control abscission timing
GO:1903076 regulation of protein localization to plasma membrane	IMP PMID:24878737 Structure of cellular ESCRT-III spirals and their relationsh...	KEEP AS NON CORE	Summary: Directly supported viral/plasma-membrane ESCRT context, but this is host-pathogen exploitation of VPS4A machinery rather than the core cellular function. Reason: Keep as a real non-core ESCRT output; do not use it to define the primary function of VPS4A. Supporting Evidence: PMID:11595185 Dominant negative mutant Vps4 proteins that inhibit vacuolar protein sorting also arrest HIV-1 and MLV budding. PMID:17940959 A lack of VPS4 adenosine triphosphatase activity reduced budding by up to 80%
GO:1903774 positive regulation of viral budding via host ESCRT complex	IMP PMID:24878737 Structure of cellular ESCRT-III spirals and their relationsh...	KEEP AS NON CORE	Summary: Directly supported viral/plasma-membrane ESCRT context, but this is host-pathogen exploitation of VPS4A machinery rather than the core cellular function. Reason: Keep as a real non-core ESCRT output; do not use it to define the primary function of VPS4A. Supporting Evidence: PMID:11595185 Dominant negative mutant Vps4 proteins that inhibit vacuolar protein sorting also arrest HIV-1 and MLV budding. PMID:17940959 A lack of VPS4 adenosine triphosphatase activity reduced budding by up to 80%
GO:0000922 spindle pole	IDA PMID:20616062 Human ESCRT-III and VPS4 proteins are required for centrosom...	KEEP AS NON CORE	Summary: Supported cell-division or midbody/spindle context for VPS4A, downstream of its ESCRT ATPase function. 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. Supporting Evidence: PMID:20616062 depletion of VPS4A, VPS4B, or any of the 11 different human ESCRT-III (CHMP) proteins inhibited abscission PMID:24814515 ANCHR associates with VPS4 at the midbody ring following DNA segregation defects to control abscission timing
GO:0005634 nucleus	IDA PMID:20616062 Human ESCRT-III and VPS4 proteins are required for centrosom...	KEEP AS NON CORE	Summary: Supported nuclear-envelope/nucleus-organization ESCRT context, but not the primary VPS4A molecular role. 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. Supporting Evidence: PMID:28242692 In mammals, VPS4 depletion induces nuclear morphology defects
GO:0005737 cytoplasm	IDA PMID:20616062 Human ESCRT-III and VPS4 proteins are required for centrosom...	ACCEPT	Summary: Supported localization for a cytosolic AAA ATPase that is recruited to endosomal/vacuolar membranes during ESCRT function. Reason: VPS4A cycles between cytosol and membrane-associated ESCRT assemblies; these compartments are consistent with the core endosomal/MVB role. Supporting Evidence: UniProt:Q9UN37 Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly UniProt:Q9UN37 Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. PMID:10637304 The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking PMID:15075231 hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles
GO:0005813 centrosome	IDA PMID:20616062 Human ESCRT-III and VPS4 proteins are required for centrosom...	KEEP AS NON CORE	Summary: Supported cell-division or midbody/spindle context for VPS4A, downstream of its ESCRT ATPase function. 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. Supporting Evidence: PMID:20616062 depletion of VPS4A, VPS4B, or any of the 11 different human ESCRT-III (CHMP) proteins inhibited abscission PMID:24814515 ANCHR associates with VPS4 at the midbody ring following DNA segregation defects to control abscission timing
GO:0006997 nucleus organization	IMP PMID:20616062 Human ESCRT-III and VPS4 proteins are required for centrosom...	KEEP AS NON CORE	Summary: Supported nuclear-envelope/nucleus-organization ESCRT context, but not the primary VPS4A molecular role. 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. Supporting Evidence: PMID:28242692 In mammals, VPS4 depletion induces nuclear morphology defects
GO:0007080 mitotic metaphase chromosome alignment	IMP PMID:20616062 Human ESCRT-III and VPS4 proteins are required for centrosom...	MARK AS OVER ANNOTATED	Summary: VPS4A/ESCRT depletion can perturb spindle and chromosome phenotypes, but this does not show VPS4A is a metaphase chromosome-alignment factor. Reason: The term overstates a downstream cell-division phenotype relative to the direct ESCRT/VPS4 mechanism. Supporting Evidence: PMID:20616062 depletion of VPS4A, VPS4B, or any of the 11 different human ESCRT-III (CHMP) proteins inhibited abscission PMID:24814515 ANCHR associates with VPS4 at the midbody ring following DNA segregation defects to control abscission timing
GO:0090543 Flemming body	IDA PMID:20616062 Human ESCRT-III and VPS4 proteins are required for centrosom...	KEEP AS NON CORE	Summary: Supported cell-division or midbody/spindle context for VPS4A, downstream of its ESCRT ATPase function. 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. Supporting Evidence: PMID:20616062 depletion of VPS4A, VPS4B, or any of the 11 different human ESCRT-III (CHMP) proteins inhibited abscission PMID:24814515 ANCHR associates with VPS4 at the midbody ring following DNA segregation defects to control abscission timing
GO:0090611 obsolete ubiquitin-independent protein catabolic process via the multivesicular body sorting pathway	IMP PMID:22547407 ALIX binds a YPX(3)L motif of the GPCR PAR1 and mediates ubi...	MODIFY	Summary: The annotation captures a real ubiquitin-independent MVB-sorting context, but the current GO term is obsolete. Reason: Use a current MVB sorting pathway term rather than retaining an obsolete ubiquitin-independent protein catabolic process term. Proposed replacements: multivesicular body sorting pathway Supporting Evidence: PMID:10637304 The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking PMID:15075231 hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles
GO:1903543 positive regulation of exosomal secretion	IMP PMID:22660413 Syndecan-syntenin-ALIX regulates the biogenesis of exosomes.	KEEP AS NON CORE	Summary: Supported exosome-release context for VPS4A/B but not the primary cellular function. Reason: Exosome secretion is one downstream ESCRT-dependent output of VPS4A activity, so retain as non-core. Supporting Evidence: UniProt:Q9UN37 VPS4A/B are required for the exosomal release of SDCBP, CD63 and syndecan
GO:0039702 viral budding via host ESCRT complex	IGI PMID:24107264 ESCRT requirements for EIAV budding.	KEEP AS NON CORE	Summary: Directly supported viral/plasma-membrane ESCRT context, but this is host-pathogen exploitation of VPS4A machinery rather than the core cellular function. Reason: Keep as a real non-core ESCRT output; do not use it to define the primary function of VPS4A. Supporting Evidence: PMID:11595185 Dominant negative mutant Vps4 proteins that inhibit vacuolar protein sorting also arrest HIV-1 and MLV budding. PMID:17940959 A lack of VPS4 adenosine triphosphatase activity reduced budding by up to 80%
GO:0043162 ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway	IMP PMID:22547407 ALIX binds a YPX(3)L motif of the GPCR PAR1 and mediates ubi...	ACCEPT	Summary: Supported as part of the core VPS4A endosomal/MVB sorting and ESCRT-recycling function. Reason: VPS4A ATPase activity recycles ESCRT-III assemblies, enabling MVB sorting, ILV formation, and late endosomal cargo transport. Supporting Evidence: UniProt:Q9UN37 Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly UniProt:Q9UN37 Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. PMID:10637304 The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking PMID:15075231 hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles
GO:0070062 extracellular exosome	HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres...	MARK AS OVER ANNOTATED	Summary: High-throughput exosome proteomics does not establish extracellular exosome as a core VPS4A localization. Reason: VPS4A is a cytosolic/endosomal ESCRT ATPase involved in exosome biogenesis; HDA exosome detection is not an informative localization for its core function. Supporting Evidence: UniProt:Q9UN37 VPS4A/B are required for the exosomal release of SDCBP, CD63 and syndecan
GO:0030496 midbody	IDA PMID:24814515 ANCHR mediates Aurora-B-dependent abscission checkpoint cont...	KEEP AS NON CORE	Summary: Supported cell-division or midbody/spindle context for VPS4A, downstream of its ESCRT ATPase function. 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. Supporting Evidence: PMID:20616062 depletion of VPS4A, VPS4B, or any of the 11 different human ESCRT-III (CHMP) proteins inhibited abscission PMID:24814515 ANCHR associates with VPS4 at the midbody ring following DNA segregation defects to control abscission timing
GO:0032466 negative regulation of cytokinesis	IMP PMID:24814515 ANCHR mediates Aurora-B-dependent abscission checkpoint cont...	KEEP AS NON CORE	Summary: Supported cell-division or midbody/spindle context for VPS4A, downstream of its ESCRT ATPase function. 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. Supporting Evidence: PMID:20616062 depletion of VPS4A, VPS4B, or any of the 11 different human ESCRT-III (CHMP) proteins inhibited abscission PMID:24814515 ANCHR associates with VPS4 at the midbody ring following DNA segregation defects to control abscission timing
GO:0005515 protein binding	IPI PMID:14519844 Divergent retroviral late-budding domains recruit vacuolar p...	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: file:human/VPS4A/VPS4A-notes.md Plain `GO:0005515 protein binding` rows should not be retained as informative functions. PMID:17928862 VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly PMID:18606141 Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding.
GO:0005515 protein binding	IPI PMID:14505570 The protein network of HIV budding.	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: file:human/VPS4A/VPS4A-notes.md Plain `GO:0005515 protein binding` rows should not be retained as informative functions. PMID:17928862 VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly PMID:18606141 Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding.
GO:0070062 extracellular exosome	HDA PMID:19199708 Proteomic analysis of human parotid gland exosomes by multid...	MARK AS OVER ANNOTATED	Summary: High-throughput exosome proteomics does not establish extracellular exosome as a core VPS4A localization. Reason: VPS4A is a cytosolic/endosomal ESCRT ATPase involved in exosome biogenesis; HDA exosome detection is not an informative localization for its core function. Supporting Evidence: UniProt:Q9UN37 VPS4A/B are required for the exosomal release of SDCBP, CD63 and syndecan
GO:0005515 protein binding	IPI PMID:21543490 Mechanism of inhibition of retrovirus release from cells by ...	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: file:human/VPS4A/VPS4A-notes.md Plain `GO:0005515 protein binding` rows should not be retained as informative functions. PMID:17928862 VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly PMID:18606141 Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding.
GO:0005515 protein binding	IPI PMID:19129480 Essential role of hIST1 in cytokinesis.	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: file:human/VPS4A/VPS4A-notes.md Plain `GO:0005515 protein binding` rows should not be retained as informative functions. PMID:17928862 VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly PMID:18606141 Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding.
GO:0030496 midbody	IDA PMID:19129479 Biochemical analyses of human IST1 and its function in cytok...	KEEP AS NON CORE	Summary: Supported cell-division or midbody/spindle context for VPS4A, downstream of its ESCRT ATPase function. 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. Supporting Evidence: PMID:20616062 depletion of VPS4A, VPS4B, or any of the 11 different human ESCRT-III (CHMP) proteins inhibited abscission PMID:24814515 ANCHR associates with VPS4 at the midbody ring following DNA segregation defects to control abscission timing
GO:0005515 protein binding	IPI PMID:19129479 Biochemical analyses of human IST1 and its function in cytok...	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: file:human/VPS4A/VPS4A-notes.md Plain `GO:0005515 protein binding` rows should not be retained as informative functions. PMID:17928862 VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly PMID:18606141 Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding.
GO:0030496 midbody	IDA PMID:17853893 Human ESCRT and ALIX proteins interact with proteins of the ...	KEEP AS NON CORE	Summary: Supported cell-division or midbody/spindle context for VPS4A, downstream of its ESCRT ATPase function. 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. Supporting Evidence: PMID:20616062 depletion of VPS4A, VPS4B, or any of the 11 different human ESCRT-III (CHMP) proteins inhibited abscission PMID:24814515 ANCHR associates with VPS4 at the midbody ring following DNA segregation defects to control abscission timing
GO:0016197 endosomal transport	IMP PMID:11559748 CHMP1 functions as a member of a newly defined family of ves...	ACCEPT	Summary: Supported as part of the core VPS4A endosomal/MVB sorting and ESCRT-recycling function. Reason: VPS4A ATPase activity recycles ESCRT-III assemblies, enabling MVB sorting, ILV formation, and late endosomal cargo transport. Supporting Evidence: UniProt:Q9UN37 Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly UniProt:Q9UN37 Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. PMID:10637304 The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking PMID:15075231 hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles
GO:0005515 protein binding	IPI PMID:11559748 CHMP1 functions as a member of a newly defined family of ves...	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: file:human/VPS4A/VPS4A-notes.md Plain `GO:0005515 protein binding` rows should not be retained as informative functions. PMID:17928862 VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly PMID:18606141 Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding.
GO:0005515 protein binding	IPI PMID:11563910 Mammalian cells express two VPS4 proteins both of which are ...	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: file:human/VPS4A/VPS4A-notes.md Plain `GO:0005515 protein binding` rows should not be retained as informative functions. PMID:17928862 VPS4 ATPases perform a key function in this pathway by recognizing membrane-associated ESCRT-III assemblies and catalysing their disassembly PMID:18606141 Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding.
GO:0005737 cytoplasm	IDA PMID:11563910 Mammalian cells express two VPS4 proteins both of which are ...	ACCEPT	Summary: Supported localization for a cytosolic AAA ATPase that is recruited to endosomal/vacuolar membranes during ESCRT function. Reason: VPS4A cycles between cytosol and membrane-associated ESCRT assemblies; these compartments are consistent with the core endosomal/MVB role. Supporting Evidence: UniProt:Q9UN37 Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly UniProt:Q9UN37 Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. PMID:10637304 The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking PMID:15075231 hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles
GO:0016192 vesicle-mediated transport	IDA PMID:11563910 Mammalian cells express two VPS4 proteins both of which are ...	ACCEPT	Summary: Supported as part of the core VPS4A endosomal/MVB sorting and ESCRT-recycling function. Reason: VPS4A ATPase activity recycles ESCRT-III assemblies, enabling MVB sorting, ILV formation, and late endosomal cargo transport. Supporting Evidence: UniProt:Q9UN37 Recognizes membrane-associated ESCRT-III assemblies and catalyzes their disassembly UniProt:Q9UN37 Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. PMID:10637304 The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking PMID:15075231 hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles
GO:0048471 perinuclear region of cytoplasm	IDA PMID:11563910 Mammalian cells express two VPS4 proteins both of which are ...	KEEP AS NON CORE	Summary: Supported localization or pathway context, but not central enough to define VPS4A core function. Reason: Keep as a non-core context attached to the broader ESCRT ATPase role. Supporting Evidence: PMID:10637304 The yeast vacuolar sorting protein Vps4p is an ATPase required for endosomal trafficking PMID:15075231 hVPS4(EQ) leads to a reduction in the number of internal vesicles in early and late endosomal vacuoles

📄 View Raw YAML

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.

Gene Description

Existing Annotations Review

Core Functions

ATP-dependent remodeling and disassembly of ESCRT-III assemblies during endosomal/MVB sorting and related ESCRT membrane-remodeling events.

ESCRT-dependent endosomal cargo sorting and multivesicular-body/intralumenal-vesicle biogenesis.

References

Suggested Questions for Experts

Suggested Experiments

📚 Additional Documentation

Notes

VPS4A notes

Local evidence reviewed

Curation synthesis

Pn Notes

VPS4A PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

PN row 1: Autophagy-Lysosome Pathway | Autophagosome closure maturation and lysosome fusion | Sealing of autophagophore membrane | ESCRT-III complex activity modulator

PN row 2: Autophagy-Lysosome Pathway | Microautophagy | General microautophagy machinery | ESCRT-III complex component

Projected GO annotations (2)

Note

📄 View Raw YAML