id: O75351 gene_symbol: VPS4B product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: VPS4B is a conserved AAA-family ATPase that recognizes ESCRT-III assemblies through its MIT domain and uses ATP hydrolysis to remodel and disassemble ESCRT-III polymers. Direct biochemical evidence shows VPS4 binding to and disassembly of CHMP2A-CHMP3 helical tubes upon ATP hydrolysis. This core activity supports endosomal/MVB cargo sorting and related ESCRT membrane-remodeling outputs, including cytokinesis, viral budding, plasma membrane repair, and exosome secretion. The core function is ATP-dependent ESCRT-III remodeling/disassembly rather than generic protein binding or ESCRT-III complex membership. 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 VPS4B endosomal/MVB sorting and ESCRT-recycling function. action: ACCEPT reason: VPS4B ATPase activity recycles ESCRT-III assemblies, enabling MVB sorting, ILV formation, and late endosomal cargo transport. supported_by: - reference_id: UniProt:O75351 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their ATP-dependent disassembly - reference_id: UniProt:O75351 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:18687924 supporting_text: the AAA-type adenosine triphosphatase VPS4 could bind on the inside of the tubule and disassemble the tubes upon adenosine triphosphate hydrolysis. - reference_id: PMID:11563910 supporting_text: both human VPS4 proteins are involved in intracellular protein trafficking, presumably at a late endosomal protein transport step - reference_id: PMID:15024011 supporting_text: Agonist-induced proteolysis of DOR was significantly inhibited by dominant negative mutant versions of Vps4/Skd1 - term: id: GO:0016887 label: ATP hydrolysis activity evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables review: summary: 'Core VPS4B function: ATP-driven recognition, remodeling, and disassembly of ESCRT-III/protein assemblies.' action: ACCEPT reason: This is the central conserved molecular role of VPS4B and is directly supported by VPS4B biochemical and UniProt evidence. supported_by: - reference_id: UniProt:O75351 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their ATP-dependent disassembly - reference_id: UniProt:O75351 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:18687924 supporting_text: the AAA-type adenosine triphosphatase VPS4 could bind on the inside of the tubule and disassemble the tubes upon adenosine triphosphate hydrolysis. - 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 VPS4B endosomal/MVB sorting and ESCRT-recycling function. action: ACCEPT reason: VPS4B ATPase activity recycles ESCRT-III assemblies, enabling MVB sorting, ILV formation, and late endosomal cargo transport. supported_by: - reference_id: UniProt:O75351 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their ATP-dependent disassembly - reference_id: UniProt:O75351 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:18687924 supporting_text: the AAA-type adenosine triphosphatase VPS4 could bind on the inside of the tubule and disassemble the tubes upon adenosine triphosphate hydrolysis. - reference_id: PMID:11563910 supporting_text: both human VPS4 proteins are involved in intracellular protein trafficking, presumably at a late endosomal protein transport step - reference_id: PMID:15024011 supporting_text: Agonist-induced proteolysis of DOR was significantly inhibited by dominant negative mutant versions of Vps4/Skd1 - 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:11563910 supporting_text: both human VPS4 proteins are involved in intracellular protein trafficking, presumably at a late endosomal protein transport step - reference_id: PMID:15024011 supporting_text: Agonist-induced proteolysis of DOR was significantly inhibited by dominant negative mutant versions of Vps4/Skd1 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 centrosome/spindle context for VPS4B, downstream of its ESCRT ATPase function. action: KEEP_AS_NON_CORE reason: This is a bona fide VPS4B cellular context but is 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:20616062 supporting_text: VPS4 proteins concentrated at spindle poles during mitosis and then at midbodies during cytokinesis - term: id: GO:0005524 label: ATP binding evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: enables review: summary: Reviewed as peripheral or insufficiently specific relative to the core VPS4B ESCRT ATPase role. action: KEEP_AS_NON_CORE reason: No direct contradiction was found, but this annotation should not define VPS4B core function. supported_by: - reference_id: UniProt:O75351 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their ATP-dependent disassembly - reference_id: UniProt:O75351 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - term: id: GO:0005737 label: cytoplasm evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: located_in review: summary: Supported localization for a cytosolic AAA ATPase recruited to endosomal/late-endosomal membranes during ESCRT function. action: ACCEPT reason: These compartments match the core VPS4B endosomal/MVB sorting and ESCRT-disassembly role. supported_by: - reference_id: UniProt:O75351 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their ATP-dependent disassembly - reference_id: UniProt:O75351 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:11563910 supporting_text: both human VPS4 proteins are involved in intracellular protein trafficking, presumably at a late endosomal protein transport step - reference_id: PMID:15024011 supporting_text: Agonist-induced proteolysis of DOR was significantly inhibited by dominant negative mutant versions of Vps4/Skd1 - reference_id: PMID:16757520 supporting_text: SKD1(E235Q), a dominant-negative mutant of SKD1/Vps4 that inhibits disassembly of the endosomal sorting complex required for transport (ESCRT), caused an accumulation of ubiquitylated NPC1. - term: id: GO:0005813 label: centrosome evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: located_in review: summary: Supported cell-division or centrosome/spindle context for VPS4B, downstream of its ESCRT ATPase function. action: KEEP_AS_NON_CORE reason: This is a bona fide VPS4B cellular context but is 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:20616062 supporting_text: VPS4 proteins concentrated at spindle poles during mitosis and then at midbodies during cytokinesis - 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 VPS4B molecular role. action: KEEP_AS_NON_CORE reason: Keep as a non-core ESCRT membrane-sealing or nuclear-organization context; VPS4B 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 VPS4B late-endosomal/MVB trafficking function. action: MODIFY reason: A more specific late endosome-to-lysosome/MVB sorting pathway term better captures the supported role. supported_by: - reference_id: PMID:11563910 supporting_text: both human VPS4 proteins are involved in intracellular protein trafficking, presumably at a late endosomal protein transport step - reference_id: PMID:15024011 supporting_text: Agonist-induced proteolysis of DOR was significantly inhibited by dominant negative mutant versions of Vps4/Skd1 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: The cell-cycle/centriole annotation overstates downstream phenotypes from VPS4B/ESCRT depletion. action: MARK_AS_OVER_ANNOTATED reason: Available evidence supports ESCRT-mediated abscission and centrosome/spindle phenotypes, not direct control of this specific cell-cycle regulatory process as a core 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:20616062 supporting_text: VPS4 proteins concentrated at spindle poles during mitosis and then at midbodies during cytokinesis - 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 cell-cycle/centriole annotation overstates downstream phenotypes from VPS4B/ESCRT depletion. action: MARK_AS_OVER_ANNOTATED reason: Available evidence supports ESCRT-mediated abscission and centrosome/spindle phenotypes, not direct control of this specific cell-cycle regulatory process as a core 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:20616062 supporting_text: VPS4 proteins concentrated at spindle poles during mitosis and then at midbodies during cytokinesis - term: id: GO:0016887 label: ATP hydrolysis activity evidence_type: IEA original_reference_id: GO_REF:0000120 qualifier: enables review: summary: 'Core VPS4B function: ATP-driven recognition, remodeling, and disassembly of ESCRT-III/protein assemblies.' action: ACCEPT reason: This is the central conserved molecular role of VPS4B and is directly supported by VPS4B biochemical and UniProt evidence. supported_by: - reference_id: UniProt:O75351 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their ATP-dependent disassembly - reference_id: UniProt:O75351 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:18687924 supporting_text: the AAA-type adenosine triphosphatase VPS4 could bind on the inside of the tubule and disassemble the tubes upon adenosine triphosphate hydrolysis. - 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: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Supported localization for a cytosolic AAA ATPase recruited to endosomal/late-endosomal membranes during ESCRT function. action: ACCEPT reason: These compartments match the core VPS4B endosomal/MVB sorting and ESCRT-disassembly role. supported_by: - reference_id: UniProt:O75351 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their ATP-dependent disassembly - reference_id: UniProt:O75351 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:11563910 supporting_text: both human VPS4 proteins are involved in intracellular protein trafficking, presumably at a late endosomal protein transport step - reference_id: PMID:15024011 supporting_text: Agonist-induced proteolysis of DOR was significantly inhibited by dominant negative mutant versions of Vps4/Skd1 - reference_id: PMID:16757520 supporting_text: SKD1(E235Q), a dominant-negative mutant of SKD1/Vps4 that inhibits disassembly of the endosomal sorting complex required for transport (ESCRT), caused an accumulation of ubiquitylated NPC1. - 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 VPS4B 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 VPS4B. supported_by: - reference_id: PMID:14505570 supporting_text: The protein network of HIV 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 VPS4B endosomal/MVB sorting and ESCRT-recycling function. action: ACCEPT reason: VPS4B ATPase activity recycles ESCRT-III assemblies, enabling MVB sorting, ILV formation, and late endosomal cargo transport. supported_by: - reference_id: UniProt:O75351 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their ATP-dependent disassembly - reference_id: UniProt:O75351 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:18687924 supporting_text: the AAA-type adenosine triphosphatase VPS4 could bind on the inside of the tubule and disassemble the tubes upon adenosine triphosphate hydrolysis. - reference_id: PMID:11563910 supporting_text: both human VPS4 proteins are involved in intracellular protein trafficking, presumably at a late endosomal protein transport step - reference_id: PMID:15024011 supporting_text: Agonist-induced proteolysis of DOR was significantly inhibited by dominant negative mutant versions of Vps4/Skd1 - term: id: GO:0051261 label: protein depolymerization evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in review: summary: VPS4B disassembles ESCRT-III assemblies rather than depolymerizing proteins generally. action: MODIFY reason: ESCRT III complex disassembly is the specific process supported by VPS4B biochemical evidence. supported_by: - reference_id: UniProt:O75351 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their ATP-dependent disassembly - reference_id: UniProt:O75351 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:18687924 supporting_text: the AAA-type adenosine triphosphatase VPS4 could bind on the inside of the tubule and disassemble the tubes upon adenosine triphosphate hydrolysis. 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 centrosome/spindle context for VPS4B, downstream of its ESCRT ATPase function. action: KEEP_AS_NON_CORE reason: This is a bona fide VPS4B cellular context but is 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:20616062 supporting_text: VPS4 proteins concentrated at spindle poles during mitosis and then at midbodies during cytokinesis - 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 centrosome/spindle context for VPS4B, downstream of its ESCRT ATPase function. action: KEEP_AS_NON_CORE reason: This is a bona fide VPS4B cellular context but is 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:20616062 supporting_text: VPS4 proteins concentrated at spindle poles during mitosis and then at midbodies during cytokinesis - 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:11563910 supporting_text: both human VPS4 proteins are involved in intracellular protein trafficking, presumably at a late endosomal protein transport step - reference_id: PMID:15024011 supporting_text: Agonist-induced proteolysis of DOR was significantly inhibited by dominant negative mutant versions of Vps4/Skd1 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 positive 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 VPS4B activity, so retain as non-core. supported_by: - reference_id: UniProt:O75351 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:17928862 qualifier: enables review: summary: The underlying interaction may be useful context, but GO:0005515 is too generic to describe VPS4B molecular function. action: MARK_AS_OVER_ANNOTATED reason: VPS4B function is better represented by ATP-dependent ESCRT-III remodeling/disassembly and protein-containing complex binding where supported. supported_by: - reference_id: file:human/VPS4B/VPS4B-notes.md supporting_text: Generic `GO:0005515 protein binding` rows should not be retained as informative molecular functions. - reference_id: PMID:18687924 supporting_text: the AAA-type adenosine triphosphatase VPS4 could bind on the inside of the tubule and disassemble the tubes upon adenosine triphosphate hydrolysis. - 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:25416956 qualifier: enables review: summary: The underlying interaction may be useful context, but GO:0005515 is too generic to describe VPS4B molecular function. action: MARK_AS_OVER_ANNOTATED reason: VPS4B function is better represented by ATP-dependent ESCRT-III remodeling/disassembly and protein-containing complex binding where supported. supported_by: - reference_id: file:human/VPS4B/VPS4B-notes.md supporting_text: Generic `GO:0005515 protein binding` rows should not be retained as informative molecular functions. - reference_id: PMID:18687924 supporting_text: the AAA-type adenosine triphosphatase VPS4 could bind on the inside of the tubule and disassemble the tubes upon adenosine triphosphate hydrolysis. - 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:31515488 qualifier: enables review: summary: The underlying interaction may be useful context, but GO:0005515 is too generic to describe VPS4B molecular function. action: MARK_AS_OVER_ANNOTATED reason: VPS4B function is better represented by ATP-dependent ESCRT-III remodeling/disassembly and protein-containing complex binding where supported. supported_by: - reference_id: file:human/VPS4B/VPS4B-notes.md supporting_text: Generic `GO:0005515 protein binding` rows should not be retained as informative molecular functions. - reference_id: PMID:18687924 supporting_text: the AAA-type adenosine triphosphatase VPS4 could bind on the inside of the tubule and disassemble the tubes upon adenosine triphosphate hydrolysis. - 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 may be useful context, but GO:0005515 is too generic to describe VPS4B molecular function. action: MARK_AS_OVER_ANNOTATED reason: VPS4B function is better represented by ATP-dependent ESCRT-III remodeling/disassembly and protein-containing complex binding where supported. supported_by: - reference_id: file:human/VPS4B/VPS4B-notes.md supporting_text: Generic `GO:0005515 protein binding` rows should not be retained as informative molecular functions. - reference_id: PMID:18687924 supporting_text: the AAA-type adenosine triphosphatase VPS4 could bind on the inside of the tubule and disassemble the tubes upon adenosine triphosphate hydrolysis. - 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:32814053 qualifier: enables review: summary: The underlying interaction may be useful context, but GO:0005515 is too generic to describe VPS4B molecular function. action: MARK_AS_OVER_ANNOTATED reason: VPS4B function is better represented by ATP-dependent ESCRT-III remodeling/disassembly and protein-containing complex binding where supported. supported_by: - reference_id: file:human/VPS4B/VPS4B-notes.md supporting_text: Generic `GO:0005515 protein binding` rows should not be retained as informative molecular functions. - reference_id: PMID:18687924 supporting_text: the AAA-type adenosine triphosphatase VPS4 could bind on the inside of the tubule and disassemble the tubes upon adenosine triphosphate hydrolysis. - 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: IEA original_reference_id: GO_REF:0000107 qualifier: located_in review: summary: Supported localization for a cytosolic AAA ATPase recruited to endosomal/late-endosomal membranes during ESCRT function. action: ACCEPT reason: These compartments match the core VPS4B endosomal/MVB sorting and ESCRT-disassembly role. supported_by: - reference_id: UniProt:O75351 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their ATP-dependent disassembly - reference_id: UniProt:O75351 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:11563910 supporting_text: both human VPS4 proteins are involved in intracellular protein trafficking, presumably at a late endosomal protein transport step - reference_id: PMID:15024011 supporting_text: Agonist-induced proteolysis of DOR was significantly inhibited by dominant negative mutant versions of Vps4/Skd1 - reference_id: PMID:16757520 supporting_text: SKD1(E235Q), a dominant-negative mutant of SKD1/Vps4 that inhibits disassembly of the endosomal sorting complex required for transport (ESCRT), caused an accumulation of ubiquitylated NPC1. - 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 VPS4B endosomal/MVB sorting and ESCRT-recycling function. action: ACCEPT reason: VPS4B ATPase activity recycles ESCRT-III assemblies, enabling MVB sorting, ILV formation, and late endosomal cargo transport. supported_by: - reference_id: UniProt:O75351 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their ATP-dependent disassembly - reference_id: UniProt:O75351 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:18687924 supporting_text: the AAA-type adenosine triphosphatase VPS4 could bind on the inside of the tubule and disassemble the tubes upon adenosine triphosphate hydrolysis. - reference_id: PMID:11563910 supporting_text: both human VPS4 proteins are involved in intracellular protein trafficking, presumably at a late endosomal protein transport step - reference_id: PMID:15024011 supporting_text: Agonist-induced proteolysis of DOR was significantly inhibited by dominant negative mutant versions of Vps4/Skd1 - 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 VPS4B 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 VPS4B. supported_by: - reference_id: PMID:14505570 supporting_text: The protein network of HIV budding. - reference_id: PMID:17940959 supporting_text: A lack of VPS4 adenosine triphosphatase activity reduced budding by up to 80% - 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 plausible for ESCRT machinery, but this specific human VPS4B row is automated/transferred in the local files. action: UNDECIDED reason: Retain uncertainty pending direct human evidence or a reviewed source tying VPS4B 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: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 VPS4B 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 VPS4B molecular role. action: KEEP_AS_NON_CORE reason: Keep as a non-core ESCRT membrane-sealing or nuclear-organization context; VPS4B 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 VPS4B 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 VPS4B. supported_by: - reference_id: PMID:14505570 supporting_text: The protein network of HIV 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 VPS4B annotation is yeast-only or review-level rather than direct human VPS4B evidence. action: MARK_AS_OVER_ANNOTATED reason: The annotation overstates direct evidence for human VPS4B 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 VPS4B molecular role. action: KEEP_AS_NON_CORE reason: Keep as a non-core ESCRT membrane-sealing or nuclear-organization context; VPS4B 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 centrosome/spindle context for VPS4B, downstream of its ESCRT ATPase function. action: KEEP_AS_NON_CORE reason: This is a bona fide VPS4B cellular context but is 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:20616062 supporting_text: VPS4 proteins concentrated at spindle poles during mitosis and then at midbodies during cytokinesis - 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 VPS4B molecular role. action: KEEP_AS_NON_CORE reason: Keep as a non-core ESCRT membrane-sealing or nuclear-organization context; VPS4B 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 VPS4B endosomal/MVB sorting and ESCRT-recycling function. action: ACCEPT reason: VPS4B ATPase activity recycles ESCRT-III assemblies, enabling MVB sorting, ILV formation, and late endosomal cargo transport. supported_by: - reference_id: UniProt:O75351 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their ATP-dependent disassembly - reference_id: UniProt:O75351 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:18687924 supporting_text: the AAA-type adenosine triphosphatase VPS4 could bind on the inside of the tubule and disassemble the tubes upon adenosine triphosphate hydrolysis. - reference_id: PMID:11563910 supporting_text: both human VPS4 proteins are involved in intracellular protein trafficking, presumably at a late endosomal protein transport step - reference_id: PMID:15024011 supporting_text: Agonist-induced proteolysis of DOR was significantly inhibited by dominant negative mutant versions of Vps4/Skd1 - 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 VPS4B 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 VPS4B. supported_by: - reference_id: PMID:14505570 supporting_text: The protein network of HIV 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 VPS4B endosomal/MVB sorting and ESCRT-recycling function. action: ACCEPT reason: VPS4B ATPase activity recycles ESCRT-III assemblies, enabling MVB sorting, ILV formation, and late endosomal cargo transport. supported_by: - reference_id: UniProt:O75351 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their ATP-dependent disassembly - reference_id: UniProt:O75351 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:18687924 supporting_text: the AAA-type adenosine triphosphatase VPS4 could bind on the inside of the tubule and disassemble the tubes upon adenosine triphosphate hydrolysis. - reference_id: PMID:11563910 supporting_text: both human VPS4 proteins are involved in intracellular protein trafficking, presumably at a late endosomal protein transport step - reference_id: PMID:15024011 supporting_text: Agonist-induced proteolysis of DOR was significantly inhibited by dominant negative mutant versions of Vps4/Skd1 - term: id: GO:0061952 label: midbody abscission evidence_type: NAS original_reference_id: PMID:20616062 qualifier: involved_in review: summary: Supported cell-division or centrosome/spindle context for VPS4B, downstream of its ESCRT ATPase function. action: KEEP_AS_NON_CORE reason: This is a bona fide VPS4B cellular context but is 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:20616062 supporting_text: VPS4 proteins concentrated at spindle poles during mitosis and then at midbodies during cytokinesis - 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 VPS4B endosomal/MVB sorting and ESCRT-recycling function. action: ACCEPT reason: VPS4B ATPase activity recycles ESCRT-III assemblies, enabling MVB sorting, ILV formation, and late endosomal cargo transport. supported_by: - reference_id: UniProt:O75351 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their ATP-dependent disassembly - reference_id: UniProt:O75351 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:18687924 supporting_text: the AAA-type adenosine triphosphatase VPS4 could bind on the inside of the tubule and disassemble the tubes upon adenosine triphosphate hydrolysis. - reference_id: PMID:11563910 supporting_text: both human VPS4 proteins are involved in intracellular protein trafficking, presumably at a late endosomal protein transport step - reference_id: PMID:15024011 supporting_text: Agonist-induced proteolysis of DOR was significantly inhibited by dominant negative mutant versions of Vps4/Skd1 - term: id: GO:0090148 label: membrane fission evidence_type: NAS original_reference_id: PMID:19234443 qualifier: involved_in review: summary: Supported as an ESCRT/VPS4 membrane-remodeling output, with direct VPS4B disassembly evidence and broader ESCRT membrane-fission support. action: ACCEPT reason: VPS4B-controlled ESCRT-III polymer remodeling supports membrane-neck constriction/fission in MVB and related pathways. supported_by: - reference_id: PMID:18687924 supporting_text: the AAA-type adenosine triphosphatase VPS4 could bind on the inside of the tubule and disassemble the tubes upon adenosine triphosphate hydrolysis. - reference_id: UniProt:O75351 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their ATP-dependent disassembly - reference_id: UniProt:O75351 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 VPS4B annotation is yeast-only or review-level rather than direct human VPS4B evidence. action: MARK_AS_OVER_ANNOTATED reason: The annotation overstates direct evidence for human VPS4B 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 VPS4B function: ATP-driven recognition, remodeling, and disassembly of ESCRT-III/protein assemblies.' action: ACCEPT reason: This is the central conserved molecular role of VPS4B and is directly supported by VPS4B biochemical and UniProt evidence. supported_by: - reference_id: UniProt:O75351 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their ATP-dependent disassembly - reference_id: UniProt:O75351 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:18687924 supporting_text: the AAA-type adenosine triphosphatase VPS4 could bind on the inside of the tubule and disassemble the tubes upon adenosine triphosphate hydrolysis. - 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 recruited to endosomal/late-endosomal membranes during ESCRT function. action: ACCEPT reason: These compartments match the core VPS4B endosomal/MVB sorting and ESCRT-disassembly role. supported_by: - reference_id: UniProt:O75351 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their ATP-dependent disassembly - reference_id: UniProt:O75351 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:11563910 supporting_text: both human VPS4 proteins are involved in intracellular protein trafficking, presumably at a late endosomal protein transport step - reference_id: PMID:15024011 supporting_text: Agonist-induced proteolysis of DOR was significantly inhibited by dominant negative mutant versions of Vps4/Skd1 - reference_id: PMID:16757520 supporting_text: SKD1(E235Q), a dominant-negative mutant of SKD1/Vps4 that inhibits disassembly of the endosomal sorting complex required for transport (ESCRT), caused an accumulation of ubiquitylated NPC1. - term: id: GO:0046761 label: viral budding from plasma membrane evidence_type: IMP original_reference_id: PMID:14505570 qualifier: involved_in review: summary: Directly supported viral/plasma-membrane ESCRT context, but this is host-pathogen exploitation of VPS4B 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 VPS4B. supported_by: - reference_id: PMID:14505570 supporting_text: The protein network of HIV budding. - reference_id: PMID:17940959 supporting_text: A lack of VPS4 adenosine triphosphatase activity reduced budding by up to 80% - 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 VPS4B 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 VPS4B. supported_by: - reference_id: PMID:14505570 supporting_text: The protein network of HIV budding. - reference_id: PMID:17940959 supporting_text: A lack of VPS4 adenosine triphosphatase activity reduced budding by up to 80% - term: id: GO:0016887 label: ATP hydrolysis activity evidence_type: IDA original_reference_id: PMID:18687924 qualifier: enables review: summary: 'Core VPS4B function: ATP-driven recognition, remodeling, and disassembly of ESCRT-III/protein assemblies.' action: ACCEPT reason: This is the central conserved molecular role of VPS4B and is directly supported by VPS4B biochemical and UniProt evidence. supported_by: - reference_id: UniProt:O75351 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their ATP-dependent disassembly - reference_id: UniProt:O75351 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:18687924 supporting_text: the AAA-type adenosine triphosphatase VPS4 could bind on the inside of the tubule and disassemble the tubes upon adenosine triphosphate hydrolysis. - 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:18687924 qualifier: enables review: summary: The underlying interaction may be useful context, but GO:0005515 is too generic to describe VPS4B molecular function. action: MARK_AS_OVER_ANNOTATED reason: VPS4B function is better represented by ATP-dependent ESCRT-III remodeling/disassembly and protein-containing complex binding where supported. supported_by: - reference_id: file:human/VPS4B/VPS4B-notes.md supporting_text: Generic `GO:0005515 protein binding` rows should not be retained as informative molecular functions. - reference_id: PMID:18687924 supporting_text: the AAA-type adenosine triphosphatase VPS4 could bind on the inside of the tubule and disassemble the tubes upon adenosine triphosphate hydrolysis. - 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:0044877 label: protein-containing complex binding evidence_type: IDA original_reference_id: PMID:18687924 qualifier: enables review: summary: 'Core VPS4B function: ATP-driven recognition, remodeling, and disassembly of ESCRT-III/protein assemblies.' action: ACCEPT reason: This is the central conserved molecular role of VPS4B and is directly supported by VPS4B biochemical and UniProt evidence. supported_by: - reference_id: UniProt:O75351 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their ATP-dependent disassembly - reference_id: UniProt:O75351 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:18687924 supporting_text: the AAA-type adenosine triphosphatase VPS4 could bind on the inside of the tubule and disassemble the tubes upon adenosine triphosphate hydrolysis. - 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:1904903 label: ESCRT III complex disassembly evidence_type: IDA original_reference_id: PMID:18687924 qualifier: involved_in review: summary: 'Core VPS4B function: ATP-driven recognition, remodeling, and disassembly of ESCRT-III/protein assemblies.' action: ACCEPT reason: This is the central conserved molecular role of VPS4B and is directly supported by VPS4B biochemical and UniProt evidence. supported_by: - reference_id: UniProt:O75351 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their ATP-dependent disassembly - reference_id: UniProt:O75351 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:18687924 supporting_text: the AAA-type adenosine triphosphatase VPS4 could bind on the inside of the tubule and disassemble the tubes upon adenosine triphosphate hydrolysis. - 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 centrosome/spindle context for VPS4B, downstream of its ESCRT ATPase function. action: KEEP_AS_NON_CORE reason: This is a bona fide VPS4B cellular context but is 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:20616062 supporting_text: VPS4 proteins concentrated at spindle poles during mitosis and then at midbodies during cytokinesis - 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 VPS4B annotation is yeast-only or review-level rather than direct human VPS4B evidence. action: MARK_AS_OVER_ANNOTATED reason: The annotation overstates direct evidence for human VPS4B 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 VPS4B endosomal/MVB sorting and ESCRT-recycling function. action: ACCEPT reason: VPS4B ATPase activity recycles ESCRT-III assemblies, enabling MVB sorting, ILV formation, and late endosomal cargo transport. supported_by: - reference_id: UniProt:O75351 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their ATP-dependent disassembly - reference_id: UniProt:O75351 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:18687924 supporting_text: the AAA-type adenosine triphosphatase VPS4 could bind on the inside of the tubule and disassemble the tubes upon adenosine triphosphate hydrolysis. - reference_id: PMID:11563910 supporting_text: both human VPS4 proteins are involved in intracellular protein trafficking, presumably at a late endosomal protein transport step - reference_id: PMID:15024011 supporting_text: Agonist-induced proteolysis of DOR was significantly inhibited by dominant negative mutant versions of Vps4/Skd1 - term: id: GO:1904903 label: ESCRT III complex disassembly evidence_type: NAS original_reference_id: PMID:20588296 qualifier: involved_in review: summary: 'Core VPS4B function: ATP-driven recognition, remodeling, and disassembly of ESCRT-III/protein assemblies.' action: ACCEPT reason: This is the central conserved molecular role of VPS4B and is directly supported by VPS4B biochemical and UniProt evidence. supported_by: - reference_id: UniProt:O75351 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their ATP-dependent disassembly - reference_id: UniProt:O75351 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:18687924 supporting_text: the AAA-type adenosine triphosphatase VPS4 could bind on the inside of the tubule and disassemble the tubes upon adenosine triphosphate hydrolysis. - 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:18385515 qualifier: enables review: summary: The underlying interaction may be useful context, but GO:0005515 is too generic to describe VPS4B molecular function. action: MARK_AS_OVER_ANNOTATED reason: VPS4B function is better represented by ATP-dependent ESCRT-III remodeling/disassembly and protein-containing complex binding where supported. supported_by: - reference_id: file:human/VPS4B/VPS4B-notes.md supporting_text: Generic `GO:0005515 protein binding` rows should not be retained as informative molecular functions. - reference_id: PMID:18687924 supporting_text: the AAA-type adenosine triphosphatase VPS4 could bind on the inside of the tubule and disassemble the tubes upon adenosine triphosphate hydrolysis. - 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 may be useful context, but GO:0005515 is too generic to describe VPS4B molecular function. action: MARK_AS_OVER_ANNOTATED reason: VPS4B function is better represented by ATP-dependent ESCRT-III remodeling/disassembly and protein-containing complex binding where supported. supported_by: - reference_id: file:human/VPS4B/VPS4B-notes.md supporting_text: Generic `GO:0005515 protein binding` rows should not be retained as informative molecular functions. - reference_id: PMID:18687924 supporting_text: the AAA-type adenosine triphosphatase VPS4 could bind on the inside of the tubule and disassemble the tubes upon adenosine triphosphate hydrolysis. - 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:16193069 qualifier: enables review: summary: The underlying interaction may be useful context, but GO:0005515 is too generic to describe VPS4B molecular function. action: MARK_AS_OVER_ANNOTATED reason: VPS4B function is better represented by ATP-dependent ESCRT-III remodeling/disassembly and protein-containing complex binding where supported. supported_by: - reference_id: file:human/VPS4B/VPS4B-notes.md supporting_text: Generic `GO:0005515 protein binding` rows should not be retained as informative molecular functions. - reference_id: PMID:18687924 supporting_text: the AAA-type adenosine triphosphatase VPS4 could bind on the inside of the tubule and disassemble the tubes upon adenosine triphosphate hydrolysis. - 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:0042802 label: identical protein binding evidence_type: IDA original_reference_id: PMID:16193069 qualifier: enables review: summary: Identical protein binding is too generic and does not capture the VPS4B oligomeric ATPase mechanism. action: MARK_AS_OVER_ANNOTATED reason: VPS4B oligomerization is better discussed as part of ATPase assembly and ESCRT-III disassembly, not as a standalone identical-protein-binding function. supported_by: - reference_id: UniProt:O75351 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their ATP-dependent disassembly - reference_id: UniProt:O75351 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - term: id: GO:0042803 label: protein homodimerization activity evidence_type: IDA original_reference_id: PMID:16193069 qualifier: enables review: summary: VPS4B oligomerization is a real mechanistic property of the ATPase but not an informative core molecular function by itself. action: KEEP_AS_NON_CORE reason: Retain as non-core because VPS4B forms ATP-dependent oligomeric assemblies, while the core function is ATP-dependent ESCRT-III disassembly. supported_by: - reference_id: UniProt:O75351 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their ATP-dependent disassembly - reference_id: UniProt:O75351 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - term: id: GO:0051261 label: protein depolymerization evidence_type: IDA original_reference_id: PMID:18687924 qualifier: involved_in review: summary: VPS4B disassembles ESCRT-III assemblies rather than depolymerizing proteins generally. action: MODIFY reason: ESCRT III complex disassembly is the specific process supported by VPS4B biochemical evidence. supported_by: - reference_id: UniProt:O75351 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their ATP-dependent disassembly - reference_id: UniProt:O75351 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:18687924 supporting_text: the AAA-type adenosine triphosphatase VPS4 could bind on the inside of the tubule and disassemble the tubes upon adenosine triphosphate hydrolysis. proposed_replacement_terms: - id: GO:1904903 label: ESCRT III complex disassembly - term: id: GO:0000922 label: spindle pole evidence_type: IDA original_reference_id: PMID:20616062 qualifier: located_in review: summary: Supported cell-division or centrosome/spindle context for VPS4B, downstream of its ESCRT ATPase function. action: KEEP_AS_NON_CORE reason: This is a bona fide VPS4B cellular context but is 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:20616062 supporting_text: VPS4 proteins concentrated at spindle poles during mitosis and then at midbodies during cytokinesis - 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 VPS4B molecular role. action: KEEP_AS_NON_CORE reason: Keep as a non-core ESCRT membrane-sealing or nuclear-organization context; VPS4B 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 recruited to endosomal/late-endosomal membranes during ESCRT function. action: ACCEPT reason: These compartments match the core VPS4B endosomal/MVB sorting and ESCRT-disassembly role. supported_by: - reference_id: UniProt:O75351 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their ATP-dependent disassembly - reference_id: UniProt:O75351 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:11563910 supporting_text: both human VPS4 proteins are involved in intracellular protein trafficking, presumably at a late endosomal protein transport step - reference_id: PMID:15024011 supporting_text: Agonist-induced proteolysis of DOR was significantly inhibited by dominant negative mutant versions of Vps4/Skd1 - reference_id: PMID:16757520 supporting_text: SKD1(E235Q), a dominant-negative mutant of SKD1/Vps4 that inhibits disassembly of the endosomal sorting complex required for transport (ESCRT), caused an accumulation of ubiquitylated NPC1. - term: id: GO:0005813 label: centrosome evidence_type: IDA original_reference_id: PMID:20616062 qualifier: located_in review: summary: Supported cell-division or centrosome/spindle context for VPS4B, downstream of its ESCRT ATPase function. action: KEEP_AS_NON_CORE reason: This is a bona fide VPS4B cellular context but is 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:20616062 supporting_text: VPS4 proteins concentrated at spindle poles during mitosis and then at midbodies during cytokinesis - 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 VPS4B molecular role. action: KEEP_AS_NON_CORE reason: Keep as a non-core ESCRT membrane-sealing or nuclear-organization context; VPS4B 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: The cell-cycle/centriole annotation overstates downstream phenotypes from VPS4B/ESCRT depletion. action: MARK_AS_OVER_ANNOTATED reason: Available evidence supports ESCRT-mediated abscission and centrosome/spindle phenotypes, not direct control of this specific cell-cycle regulatory process as a core 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:20616062 supporting_text: VPS4 proteins concentrated at spindle poles during mitosis and then at midbodies during cytokinesis - term: id: GO:0010824 label: regulation of centrosome duplication evidence_type: IMP original_reference_id: PMID:20616062 qualifier: involved_in review: summary: Supported cell-division or centrosome/spindle context for VPS4B, downstream of its ESCRT ATPase function. action: KEEP_AS_NON_CORE reason: This is a bona fide VPS4B cellular context but is 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:20616062 supporting_text: VPS4 proteins concentrated at spindle poles during mitosis and then at midbodies during cytokinesis - term: id: GO:0010971 label: positive regulation of G2/M transition of mitotic cell cycle evidence_type: IMP original_reference_id: PMID:20616062 qualifier: involved_in review: summary: The cell-cycle/centriole annotation overstates downstream phenotypes from VPS4B/ESCRT depletion. action: MARK_AS_OVER_ANNOTATED reason: Available evidence supports ESCRT-mediated abscission and centrosome/spindle phenotypes, not direct control of this specific cell-cycle regulatory process as a core 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:20616062 supporting_text: VPS4 proteins concentrated at spindle poles during mitosis and then at midbodies during cytokinesis - term: id: GO:0090543 label: Flemming body evidence_type: IDA original_reference_id: PMID:20616062 qualifier: located_in review: summary: Supported cell-division or centrosome/spindle context for VPS4B, downstream of its ESCRT ATPase function. action: KEEP_AS_NON_CORE reason: This is a bona fide VPS4B cellular context but is 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:20616062 supporting_text: VPS4 proteins concentrated at spindle poles during mitosis and then at midbodies during cytokinesis - term: id: GO:1901673 label: regulation of mitotic spindle assembly evidence_type: IMP original_reference_id: PMID:20616062 qualifier: involved_in review: summary: Supported cell-division or centrosome/spindle context for VPS4B, downstream of its ESCRT ATPase function. action: KEEP_AS_NON_CORE reason: This is a bona fide VPS4B cellular context but is 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:20616062 supporting_text: VPS4 proteins concentrated at spindle poles during mitosis and then at midbodies during cytokinesis - term: id: GO:1903724 label: positive regulation of centriole elongation evidence_type: IMP original_reference_id: PMID:20616062 qualifier: involved_in review: summary: The cell-cycle/centriole annotation overstates downstream phenotypes from VPS4B/ESCRT depletion. action: MARK_AS_OVER_ANNOTATED reason: Available evidence supports ESCRT-mediated abscission and centrosome/spindle phenotypes, not direct control of this specific cell-cycle regulatory process as a core 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:20616062 supporting_text: VPS4 proteins concentrated at spindle poles during mitosis and then at midbodies during cytokinesis - 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:11563910 supporting_text: both human VPS4 proteins are involved in intracellular protein trafficking, presumably at a late endosomal protein transport step - reference_id: PMID:15024011 supporting_text: Agonist-induced proteolysis of DOR was significantly inhibited by dominant negative mutant versions of Vps4/Skd1 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 positive 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 VPS4B activity, so retain as non-core. supported_by: - reference_id: UniProt:O75351 supporting_text: VPS4A/B are required for the exosomal release of SDCBP, CD63 and syndecan - term: id: GO:1903542 label: negative regulation of exosomal secretion evidence_type: IMP original_reference_id: PMID:24105262 qualifier: involved_in review: summary: Supported context-dependent negative regulation of EV secretion in a HeLa-CIITA RNAi screen. action: KEEP_AS_NON_CORE reason: This exosome phenotype is cell/cargo-context dependent and non-core relative to ATP-dependent ESCRT-III disassembly. supported_by: - reference_id: PMID:24105262 supporting_text: depletion of VPS4B augmented this secretion while not altering the features of EVs. - 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 VPS4B endosomal/MVB sorting and ESCRT-recycling function. action: ACCEPT reason: VPS4B ATPase activity recycles ESCRT-III assemblies, enabling MVB sorting, ILV formation, and late endosomal cargo transport. supported_by: - reference_id: UniProt:O75351 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their ATP-dependent disassembly - reference_id: UniProt:O75351 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:18687924 supporting_text: the AAA-type adenosine triphosphatase VPS4 could bind on the inside of the tubule and disassemble the tubes upon adenosine triphosphate hydrolysis. - reference_id: PMID:11563910 supporting_text: both human VPS4 proteins are involved in intracellular protein trafficking, presumably at a late endosomal protein transport step - reference_id: PMID:15024011 supporting_text: Agonist-induced proteolysis of DOR was significantly inhibited by dominant negative mutant versions of Vps4/Skd1 - 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 VPS4B 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 VPS4B. supported_by: - reference_id: PMID:14505570 supporting_text: The protein network of HIV budding. - reference_id: PMID:17940959 supporting_text: A lack of VPS4 adenosine triphosphatase activity reduced budding by up to 80% - 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 VPS4B localization. action: MARK_AS_OVER_ANNOTATED reason: VPS4B 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:O75351 supporting_text: VPS4A/B are required for the exosomal release of SDCBP, CD63 and syndecan - reference_id: PMID:24105262 supporting_text: depletion of VPS4B augmented this secretion while not altering the features of EVs. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:14505570 qualifier: enables review: summary: The underlying interaction may be useful context, but GO:0005515 is too generic to describe VPS4B molecular function. action: MARK_AS_OVER_ANNOTATED reason: VPS4B function is better represented by ATP-dependent ESCRT-III remodeling/disassembly and protein-containing complex binding where supported. supported_by: - reference_id: file:human/VPS4B/VPS4B-notes.md supporting_text: Generic `GO:0005515 protein binding` rows should not be retained as informative molecular functions. - reference_id: PMID:18687924 supporting_text: the AAA-type adenosine triphosphatase VPS4 could bind on the inside of the tubule and disassemble the tubes upon adenosine triphosphate hydrolysis. - 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:19056867 qualifier: located_in review: summary: High-throughput exosome proteomics does not establish extracellular exosome as a core VPS4B localization. action: MARK_AS_OVER_ANNOTATED reason: VPS4B 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:O75351 supporting_text: VPS4A/B are required for the exosomal release of SDCBP, CD63 and syndecan - reference_id: PMID:24105262 supporting_text: depletion of VPS4B augmented this secretion while not altering the features of EVs. - 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 recruited to endosomal/late-endosomal membranes during ESCRT function. action: ACCEPT reason: These compartments match the core VPS4B endosomal/MVB sorting and ESCRT-disassembly role. supported_by: - reference_id: UniProt:O75351 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their ATP-dependent disassembly - reference_id: UniProt:O75351 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:11563910 supporting_text: both human VPS4 proteins are involved in intracellular protein trafficking, presumably at a late endosomal protein transport step - reference_id: PMID:15024011 supporting_text: Agonist-induced proteolysis of DOR was significantly inhibited by dominant negative mutant versions of Vps4/Skd1 - reference_id: PMID:16757520 supporting_text: SKD1(E235Q), a dominant-negative mutant of SKD1/Vps4 that inhibits disassembly of the endosomal sorting complex required for transport (ESCRT), caused an accumulation of ubiquitylated NPC1. - 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 recruited to endosomal/late-endosomal membranes during ESCRT function. action: ACCEPT reason: These compartments match the core VPS4B endosomal/MVB sorting and ESCRT-disassembly role. supported_by: - reference_id: UniProt:O75351 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their ATP-dependent disassembly - reference_id: UniProt:O75351 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:11563910 supporting_text: both human VPS4 proteins are involved in intracellular protein trafficking, presumably at a late endosomal protein transport step - reference_id: PMID:15024011 supporting_text: Agonist-induced proteolysis of DOR was significantly inhibited by dominant negative mutant versions of Vps4/Skd1 - reference_id: PMID:16757520 supporting_text: SKD1(E235Q), a dominant-negative mutant of SKD1/Vps4 that inhibits disassembly of the endosomal sorting complex required for transport (ESCRT), caused an accumulation of ubiquitylated NPC1. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:19129479 qualifier: enables review: summary: The underlying interaction may be useful context, but GO:0005515 is too generic to describe VPS4B molecular function. action: MARK_AS_OVER_ANNOTATED reason: VPS4B function is better represented by ATP-dependent ESCRT-III remodeling/disassembly and protein-containing complex binding where supported. supported_by: - reference_id: file:human/VPS4B/VPS4B-notes.md supporting_text: Generic `GO:0005515 protein binding` rows should not be retained as informative molecular functions. - reference_id: PMID:18687924 supporting_text: the AAA-type adenosine triphosphatase VPS4 could bind on the inside of the tubule and disassemble the tubes upon adenosine triphosphate hydrolysis. - 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:0005768 label: endosome evidence_type: IDA original_reference_id: PMID:11563910 qualifier: located_in review: summary: Supported localization for a cytosolic AAA ATPase recruited to endosomal/late-endosomal membranes during ESCRT function. action: ACCEPT reason: These compartments match the core VPS4B endosomal/MVB sorting and ESCRT-disassembly role. supported_by: - reference_id: UniProt:O75351 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their ATP-dependent disassembly - reference_id: UniProt:O75351 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:11563910 supporting_text: both human VPS4 proteins are involved in intracellular protein trafficking, presumably at a late endosomal protein transport step - reference_id: PMID:15024011 supporting_text: Agonist-induced proteolysis of DOR was significantly inhibited by dominant negative mutant versions of Vps4/Skd1 - reference_id: PMID:16757520 supporting_text: SKD1(E235Q), a dominant-negative mutant of SKD1/Vps4 that inhibits disassembly of the endosomal sorting complex required for transport (ESCRT), caused an accumulation of ubiquitylated NPC1. - term: id: GO:0016197 label: endosomal transport evidence_type: IDA original_reference_id: PMID:11563910 qualifier: acts_upstream_of_or_within review: summary: Supported as part of the core VPS4B endosomal/MVB sorting and ESCRT-recycling function. action: ACCEPT reason: VPS4B ATPase activity recycles ESCRT-III assemblies, enabling MVB sorting, ILV formation, and late endosomal cargo transport. supported_by: - reference_id: UniProt:O75351 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their ATP-dependent disassembly - reference_id: UniProt:O75351 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:18687924 supporting_text: the AAA-type adenosine triphosphatase VPS4 could bind on the inside of the tubule and disassemble the tubes upon adenosine triphosphate hydrolysis. - reference_id: PMID:11563910 supporting_text: both human VPS4 proteins are involved in intracellular protein trafficking, presumably at a late endosomal protein transport step - reference_id: PMID:15024011 supporting_text: Agonist-induced proteolysis of DOR was significantly inhibited by dominant negative mutant versions of Vps4/Skd1 - term: id: GO:0016887 label: ATP hydrolysis activity evidence_type: IDA original_reference_id: PMID:11563910 qualifier: enables review: summary: 'Core VPS4B function: ATP-driven recognition, remodeling, and disassembly of ESCRT-III/protein assemblies.' action: ACCEPT reason: This is the central conserved molecular role of VPS4B and is directly supported by VPS4B biochemical and UniProt evidence. supported_by: - reference_id: UniProt:O75351 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their ATP-dependent disassembly - reference_id: UniProt:O75351 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:18687924 supporting_text: the AAA-type adenosine triphosphatase VPS4 could bind on the inside of the tubule and disassemble the tubes upon adenosine triphosphate hydrolysis. - 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:16757520 qualifier: enables review: summary: The underlying interaction may be useful context, but GO:0005515 is too generic to describe VPS4B molecular function. action: MARK_AS_OVER_ANNOTATED reason: VPS4B function is better represented by ATP-dependent ESCRT-III remodeling/disassembly and protein-containing complex binding where supported. supported_by: - reference_id: file:human/VPS4B/VPS4B-notes.md supporting_text: Generic `GO:0005515 protein binding` rows should not be retained as informative molecular functions. - reference_id: PMID:18687924 supporting_text: the AAA-type adenosine triphosphatase VPS4 could bind on the inside of the tubule and disassemble the tubes upon adenosine triphosphate hydrolysis. - 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:0005634 label: nucleus evidence_type: IDA original_reference_id: PMID:16757520 qualifier: located_in review: summary: Supported nuclear-envelope/nucleus-organization ESCRT context, but not the primary VPS4B molecular role. action: KEEP_AS_NON_CORE reason: Keep as a non-core ESCRT membrane-sealing or nuclear-organization context; VPS4B 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:16757520 qualifier: located_in review: summary: Supported localization for a cytosolic AAA ATPase recruited to endosomal/late-endosomal membranes during ESCRT function. action: ACCEPT reason: These compartments match the core VPS4B endosomal/MVB sorting and ESCRT-disassembly role. supported_by: - reference_id: UniProt:O75351 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their ATP-dependent disassembly - reference_id: UniProt:O75351 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:11563910 supporting_text: both human VPS4 proteins are involved in intracellular protein trafficking, presumably at a late endosomal protein transport step - reference_id: PMID:15024011 supporting_text: Agonist-induced proteolysis of DOR was significantly inhibited by dominant negative mutant versions of Vps4/Skd1 - reference_id: PMID:16757520 supporting_text: SKD1(E235Q), a dominant-negative mutant of SKD1/Vps4 that inhibits disassembly of the endosomal sorting complex required for transport (ESCRT), caused an accumulation of ubiquitylated NPC1. - term: id: GO:0010008 label: endosome membrane evidence_type: IDA original_reference_id: PMID:16757520 qualifier: located_in review: summary: Supported localization for a cytosolic AAA ATPase recruited to endosomal/late-endosomal membranes during ESCRT function. action: ACCEPT reason: These compartments match the core VPS4B endosomal/MVB sorting and ESCRT-disassembly role. supported_by: - reference_id: UniProt:O75351 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their ATP-dependent disassembly - reference_id: UniProt:O75351 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:11563910 supporting_text: both human VPS4 proteins are involved in intracellular protein trafficking, presumably at a late endosomal protein transport step - reference_id: PMID:15024011 supporting_text: Agonist-induced proteolysis of DOR was significantly inhibited by dominant negative mutant versions of Vps4/Skd1 - reference_id: PMID:16757520 supporting_text: SKD1(E235Q), a dominant-negative mutant of SKD1/Vps4 that inhibits disassembly of the endosomal sorting complex required for transport (ESCRT), caused an accumulation of ubiquitylated NPC1. - term: id: GO:0032510 label: endosome to lysosome transport via multivesicular body sorting pathway evidence_type: IMP original_reference_id: PMID:15024011 qualifier: involved_in review: summary: Supported as part of the core VPS4B endosomal/MVB sorting and ESCRT-recycling function. action: ACCEPT reason: VPS4B ATPase activity recycles ESCRT-III assemblies, enabling MVB sorting, ILV formation, and late endosomal cargo transport. supported_by: - reference_id: UniProt:O75351 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their ATP-dependent disassembly - reference_id: UniProt:O75351 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:18687924 supporting_text: the AAA-type adenosine triphosphatase VPS4 could bind on the inside of the tubule and disassemble the tubes upon adenosine triphosphate hydrolysis. - reference_id: PMID:11563910 supporting_text: both human VPS4 proteins are involved in intracellular protein trafficking, presumably at a late endosomal protein transport step - reference_id: PMID:15024011 supporting_text: Agonist-induced proteolysis of DOR was significantly inhibited by dominant negative mutant versions of Vps4/Skd1 - term: id: GO:0033993 label: response to lipid evidence_type: IDA original_reference_id: PMID:16757520 qualifier: involved_in review: summary: NPC1/SKD1 response to cholesterol depletion supports ESCRT-endosome involvement, not a core lipid-response function for VPS4B. action: MARK_AS_OVER_ANNOTATED reason: The lipid/cholesterol effect is cargo and context dependent; VPS4B core activity is ESCRT-III disassembly. supported_by: - reference_id: PMID:16757520 supporting_text: SKD1(E235Q), a dominant-negative mutant of SKD1/Vps4 that inhibits disassembly of the endosomal sorting complex required for transport (ESCRT), caused an accumulation of ubiquitylated NPC1. - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:11563910 qualifier: enables review: summary: The underlying interaction may be useful context, but GO:0005515 is too generic to describe VPS4B molecular function. action: MARK_AS_OVER_ANNOTATED reason: VPS4B function is better represented by ATP-dependent ESCRT-III remodeling/disassembly and protein-containing complex binding where supported. supported_by: - reference_id: file:human/VPS4B/VPS4B-notes.md supporting_text: Generic `GO:0005515 protein binding` rows should not be retained as informative molecular functions. - reference_id: PMID:18687924 supporting_text: the AAA-type adenosine triphosphatase VPS4 could bind on the inside of the tubule and disassemble the tubes upon adenosine triphosphate hydrolysis. - 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:0140545 label: ATP-dependent protein disaggregase activity evidence_type: IDA original_reference_id: PMID:18687924 qualifier: enables review: summary: Added because direct VPS4B biochemical evidence shows ATP-dependent disassembly of CHMP2A-CHMP3 ESCRT-III tubes, which is more specific than generic ATP hydrolysis activity. action: NEW reason: PMID:18687924 directly supports an ATP-dependent protein-complex disassembly activity for VPS4B; this term captures the core molecular function more precisely than protein binding or generic ATP hydrolysis alone. supported_by: - reference_id: PMID:18687924 supporting_text: the AAA-type adenosine triphosphatase VPS4 could bind on the inside of the tubule and disassemble the tubes upon adenosine triphosphate hydrolysis. - reference_id: UniProt:O75351 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their ATP-dependent disassembly - reference_id: UniProt:O75351 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. 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: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:11563910 title: Mammalian cells express two VPS4 proteins both of which are involved in intracellular protein trafficking. findings: - statement: Human VPS4A and VPS4B are involved in late endosomal protein transport; ATPase-domain mutants cause dominant-negative sorting defects. - id: PMID:14505570 title: The protein network of HIV budding. findings: [] - id: PMID:15024011 title: Role of mammalian vacuolar protein-sorting proteins in endocytic trafficking of a non-ubiquitinated G protein-coupled receptor to lysosomes. findings: - statement: Dominant-negative Vps4/Skd1 inhibits lysosomal trafficking of a non-ubiquitinated GPCR, supporting endosome-to-lysosome/MVB sorting. - 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:16757520 title: Cholesterol depletion facilitates ubiquitylation of NPC1 and its association with SKD1/Vps4. findings: - statement: NPC1 ubiquitylation and association with SKD1/Vps4 respond to cholesterol depletion, supporting endosomal ESCRT context but not a core lipid-response function. - 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:17928862 title: ESCRT-III recognition by VPS4 ATPases. findings: [] - id: PMID:17940959 title: Involvement of vacuolar protein sorting pathway in Ebola virus release independent of TSG101 interaction. 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: VPS4 MIT-domain interactions with ESCRT-III MIM motifs support VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding. - id: PMID:18687924 title: Helical structures of ESCRT-III are disassembled by VPS4. findings: - statement: VPS4 binds and ATP-dependently disassembles CHMP2A-CHMP3 helical ESCRT-III tubes, directly supporting VPS4B ESCRT-III disassembly activity. - id: PMID:19056867 title: Large-scale proteomics and phosphoproteomics of urinary exosomes. findings: [] - id: PMID:19129479 title: Biochemical analyses of human IST1 and its function in cytokinesis. 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 VPS4B 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 depletion affects abscission, centrosomes, and spindle poles; these are retained as non-core cell-division contexts. - 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:24105262 title: Analysis of ESCRT functions in exosome biogenesis, composition and secretion highlights the heterogeneity of extracellular vesicles. findings: - statement: VPS4B depletion increased EV-associated CD63 and MHC II secretion in a HeLa-CIITA screen, supporting a context-dependent exosome phenotype. - 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:25416956 title: A proteome-scale map of the human interactome network. 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:28242692 title: LEM2 recruits CHMP7 for ESCRT-mediated nuclear envelope closure in fission yeast and human cells. findings: - statement: ESCRT-III/VPS4 activity is linked to nuclear-envelope repair and morphology; this supports a non-core nuclear-envelope context for VPS4B. - id: PMID:31515488 title: Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations. findings: [] - id: PMID:32296183 title: A reference map of the human binary protein interactome. findings: [] - id: PMID:32814053 title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains. findings: [] - 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-3159232 title: Recruitment Of HIV Virion Budding Machinery findings: [] - id: Reactome:R-HSA-917693 title: ESCRT Disassembly findings: [] - id: UniProt:O75351 title: UniProt entry for VPS4B (O75351) findings: - statement: VPS4B is an AAA ATPase that recognizes and ATP-dependently disassembles ESCRT-III assemblies for further rounds of MVB sorting. - id: file:human/VPS4B/VPS4B-notes.md title: Local curation notes for VPS4B findings: - statement: Local synthesis identifies ATP-dependent ESCRT-III remodeling/disassembly as the core VPS4B 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:O75351 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their ATP-dependent disassembly - reference_id: UniProt:O75351 supporting_text: Redistributes the ESCRT-III components to the cytoplasm for further rounds of MVB sorting. - reference_id: PMID:18687924 supporting_text: the AAA-type adenosine triphosphatase VPS4 could bind on the inside of the tubule and disassemble the tubes upon adenosine triphosphate hydrolysis. - reference_id: PMID:18606141 supporting_text: Mutations that block VPS4 MIT-MIM2 interactions inhibit VPS4 recruitment, lysosomal protein targeting, and HIV-1 budding. molecular_function: id: GO:0140545 label: ATP-dependent protein disaggregase activity directly_involved_in: - id: GO:1904903 label: ESCRT III 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:11563910 supporting_text: both human VPS4 proteins are involved in intracellular protein trafficking, presumably at a late endosomal protein transport step - reference_id: PMID:15024011 supporting_text: Agonist-induced proteolysis of DOR was significantly inhibited by dominant negative mutant versions of Vps4/Skd1 - reference_id: UniProt:O75351 supporting_text: Recognizes membrane-associated ESCRT-III assemblies and catalyzes their ATP-dependent disassembly - reference_id: UniProt:O75351 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:0032510 label: endosome to lysosome transport via 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:0005829 label: cytosol - id: GO:0031902 label: late endosome membrane suggested_questions: - question: Which ESCRT-dependent contexts require VPS4B specifically rather than VPS4A or mixed VPS4A/VPS4B assemblies? - question: Does VPS4B have direct human-cell roles in phagophore closure or late endosomal microautophagy beyond its generic ESCRT-III disassembly function? - question: How do VPS4B-specific regulators such as VTA1 and ZFYVE19/ANCHR tune ATPase assembly, ESCRT-III turnover, and context-specific membrane remodeling? suggested_experiments: - description: Use rescue assays after VPS4A/VPS4B depletion with VPS4B wild-type, ATPase-dead, MIT-interface, and VTA1-binding mutants across MVB sorting, cytokinesis, exosome, and autophagy assays. hypothesis: VPS4B ATPase activity, ESCRT-III recognition, and VTA1-dependent regulation make separable contributions to different ESCRT-dependent cellular contexts. - description: Measure endogenous VPS4B recruitment and ESCRT-III turnover during phagophore closure or late endosomal microautophagy with live imaging and acute VPS4B-specific perturbation. hypothesis: If VPS4B has a direct autophagy role, it should be transiently recruited to the relevant membrane and required for ESCRT-III turnover there. - description: Compare VPS4A and VPS4B ATP-dependent disassembly kinetics on defined CHMP2A-CHMP3 and mixed ESCRT-III polymers in vitro. hypothesis: VPS4B shares the conserved ESCRT-III disassembly mechanism but may differ from VPS4A in substrate preference, VTA1 response, or assembly kinetics.