Vcp

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0000153 cytoplasmic ubiquitin ligase complex	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA: Cytoplasmic ubiquitin ligase complex (ISO/IEA from mouse/human VCP), reflecting complexes of VCP with AMFR/gp78 or STUB1/UBXN2A. Reason: VCP is not an E3 ligase subunit but co-assembles with E3s such as AMFR and STUB1 in ERAD complexes; the membership claim is weak but not wrong, so kept as non-core. Supporting Evidence: file:rat/Vcp/Vcp-uniprot.txt Component of a VCP/p97-AMFR/gp78 complex that participates in the final step of the endoplasmic reticulum-associated degradation (ERAD) of HMGCR.
GO:0000153 cytoplasmic ubiquitin ligase complex	ISO GO_REF:0000121	KEEP AS NON CORE	Summary: ISO: Cytoplasmic ubiquitin ligase complex (ISO/IEA from mouse/human VCP), reflecting complexes of VCP with AMFR/gp78 or STUB1/UBXN2A. Reason: VCP is not an E3 ligase subunit but co-assembles with E3s such as AMFR and STUB1 in ERAD complexes; the membership claim is weak but not wrong, so kept as non-core. Supporting Evidence: file:rat/Vcp/Vcp-uniprot.txt Component of a VCP/p97-AMFR/gp78 complex that participates in the final step of the endoplasmic reticulum-associated degradation (ERAD) of HMGCR.
GO:0000423 mitophagy	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA: Mitophagy (ISO/IEA from human VCP): UBXD1 recruits p97 to damaged mitochondria and promotes Parkin-dependent mitophagy. Reason: VCP extracts ubiquitinated outer mitochondrial membrane proteins, a step that the mitophagy pathway depends on; supported for the ortholog and kept as a non-core process. Supporting Evidence: PMID:30120381 Once translocated, UBXD1 recruits p97 to mitochondria via a bipartite binding motif consisting of its N-terminal VIM and PUB domains. file:rat/Vcp/Vcp-uniprot.txt Required for cytoplasmic retrotranslocation of stressed/damaged mitochondrial outer-membrane proteins and their subsequent proteasomal degradation.
GO:0000423 mitophagy	ISO GO_REF:0000121	KEEP AS NON CORE	Summary: ISO: Mitophagy (ISO/IEA from human VCP): UBXD1 recruits p97 to damaged mitochondria and promotes Parkin-dependent mitophagy. Reason: VCP extracts ubiquitinated outer mitochondrial membrane proteins, a step that the mitophagy pathway depends on; supported for the ortholog and kept as a non-core process. Supporting Evidence: PMID:30120381 Once translocated, UBXD1 recruits p97 to mitochondria via a bipartite binding motif consisting of its N-terminal VIM and PUB domains. file:rat/Vcp/Vcp-uniprot.txt Required for cytoplasmic retrotranslocation of stressed/damaged mitochondrial outer-membrane proteins and their subsequent proteasomal degradation.
GO:0000502 proteasome complex	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: IEA: Proteasome complex (ISO/IEA from human VCP), based on co-purification of VCP with the 26S proteasome. Reason: VCP delivers substrates to the proteasome and co-purifies with it, but it is not a proteasome subunit; co-purification does not establish complex membership. Supporting Evidence: PMID:9452483 Further, VCP co-purifies with the 26 S proteasome on two-dimensional gels and co-immunoprecipitates with subunits of the 26 S proteasome.
GO:0000502 proteasome complex	ISO GO_REF:0000121	MARK AS OVER ANNOTATED	Summary: ISO: Proteasome complex (ISO/IEA from human VCP), based on co-purification of VCP with the 26S proteasome. Reason: VCP delivers substrates to the proteasome and co-purifies with it, but it is not a proteasome subunit; co-purification does not establish complex membership. Propagation Review Root cause: SOURCE BAD Failure modes: COMPARTMENT OR COMPLEX MISMATCH Sources checked: UniProtKB:P55072 SOURCE BAD The donor annotation rests on co-purification of VCP with the 26S proteasome (PMID:9452483); VCP is not a proteasome subunit. Supporting Evidence: PMID:9452483 Further, VCP co-purifies with the 26 S proteasome on two-dimensional gels and co-immunoprecipitates with subunits of the 26 S proteasome.
GO:0005515 protein binding	IPI PMID:10811609 A complex of mammalian ufd1 and npl4 links the AAA-ATPase, p...	REMOVE	Summary: IPI: IPI protein binding with rat p47 (Nsfl1c, O35987). The interaction is real and well characterised (one p47 trimer per p97 hexamer). Reason: Generic protein binding is uninformative under the protein-binding policy. The p47 interaction is already captured informatively by GO:1990730 VCP-NSFL1C complex (accepted from the same papers), and p47 is a cofactor, so no more specific MF of Vcp follows from this evidence. Removal does not dispute the interaction. Supporting Evidence: PMID:9214505 which forms a tight, stoichiometric complex with cytosolic p97 (one trimer of p47 per hexamer of p97)
GO:0005515 protein binding	IPI PMID:16601695 Conformational changes in the AAA ATPase p97-p47 adaptor com...	REMOVE	Summary: IPI: IPI protein binding with rat p47 (Nsfl1c, O35987). The interaction is real and well characterised (one p47 trimer per p97 hexamer). Reason: Generic protein binding is uninformative under the protein-binding policy. The p47 interaction is already captured informatively by GO:1990730 VCP-NSFL1C complex (accepted from the same papers), and p47 is a cofactor, so no more specific MF of Vcp follows from this evidence. Removal does not dispute the interaction. Supporting Evidence: PMID:9214505 which forms a tight, stoichiometric complex with cytosolic p97 (one trimer of p47 per hexamer of p97)
GO:0005515 protein binding	IPI PMID:20691684 Isolation of a point-mutated p47 lacking binding affinity to...	REMOVE	Summary: IPI: IPI protein binding with rat p47 (Nsfl1c, O35987). The interaction is real and well characterised (one p47 trimer per p97 hexamer). Reason: Generic protein binding is uninformative under the protein-binding policy. The p47 interaction is already captured informatively by GO:1990730 VCP-NSFL1C complex (accepted from the same papers), and p47 is a cofactor, so no more specific MF of Vcp follows from this evidence. Removal does not dispute the interaction. Supporting Evidence: PMID:9214505 which forms a tight, stoichiometric complex with cytosolic p97 (one trimer of p47 per hexamer of p97)
GO:0005515 protein binding	IPI PMID:9214505 p47 is a cofactor for p97-mediated membrane fusion.	REMOVE	Summary: IPI: IPI protein binding with rat p47 (Nsfl1c, O35987). The interaction is real and well characterised (one p47 trimer per p97 hexamer). Reason: Generic protein binding is uninformative under the protein-binding policy. The p47 interaction is already captured informatively by GO:1990730 VCP-NSFL1C complex (accepted from the same papers), and p47 is a cofactor, so no more specific MF of Vcp follows from this evidence. Removal does not dispute the interaction. Supporting Evidence: PMID:9214505 which forms a tight, stoichiometric complex with cytosolic p97 (one trimer of p47 per hexamer of p97)
GO:0005524 ATP binding	IDA PMID:7806566 Isolation and characterization of the principal ATPase assoc...	ACCEPT	Summary: IDA: ATP binding by rat p97 was measured directly; the ATP analogue ATPgammaS binds both D1 and D2 Walker A sites. Reason: Direct biochemical evidence on rat p97 (Walker A mutants K251A/K524A used to separate D1/D2 binding). Nucleotide binding is an intrinsic part of the ATPase cycle that powers the core function. Supporting Evidence: PMID:18332143 We report that adenosine 5'-O-(thiotriphosphate) (ATPgammaS) binds with similar affinity to D1 and D2, but ADP binds with higher affinity to D1 than D2 PMID:18332143 We sought to explore nucleotide binding to recombinant rat p97 by studying the D1 and D2 domains separately.
GO:0005524 ATP binding	IEA GO_REF:0000120	ACCEPT	Summary: IEA: ATP binding by rat p97 was measured directly; the ATP analogue ATPgammaS binds both D1 and D2 Walker A sites. Reason: Direct biochemical evidence on rat p97 (Walker A mutants K251A/K524A used to separate D1/D2 binding). Nucleotide binding is an intrinsic part of the ATPase cycle that powers the core function. Supporting Evidence: PMID:18332143 We report that adenosine 5'-O-(thiotriphosphate) (ATPgammaS) binds with similar affinity to D1 and D2, but ADP binds with higher affinity to D1 than D2 PMID:18332143 We sought to explore nucleotide binding to recombinant rat p97 by studying the D1 and D2 domains separately.
GO:0005524 ATP binding	IMP PMID:18332143 Analysis of nucleotide binding to P97 reveals the properties...	ACCEPT	Summary: IMP: ATP binding by rat p97 was measured directly; the ATP analogue ATPgammaS binds both D1 and D2 Walker A sites. Reason: Direct biochemical evidence on rat p97 (Walker A mutants K251A/K524A used to separate D1/D2 binding). Nucleotide binding is an intrinsic part of the ATPase cycle that powers the core function. Supporting Evidence: PMID:18332143 We report that adenosine 5'-O-(thiotriphosphate) (ATPgammaS) binds with similar affinity to D1 and D2, but ADP binds with higher affinity to D1 than D2 PMID:18332143 We sought to explore nucleotide binding to recombinant rat p97 by studying the D1 and D2 domains separately.
GO:0005524 ATP binding	ISO GO_REF:0000121	ACCEPT	Summary: ISO: ATP binding by rat p97 was measured directly; the ATP analogue ATPgammaS binds both D1 and D2 Walker A sites. Reason: Direct biochemical evidence on rat p97 (Walker A mutants K251A/K524A used to separate D1/D2 binding). Nucleotide binding is an intrinsic part of the ATPase cycle that powers the core function. Supporting Evidence: PMID:18332143 We report that adenosine 5'-O-(thiotriphosphate) (ATPgammaS) binds with similar affinity to D1 and D2, but ADP binds with higher affinity to D1 than D2 PMID:18332143 We sought to explore nucleotide binding to recombinant rat p97 by studying the D1 and D2 domains separately.
GO:0005634 nucleus	EXP PMID:10811609 A complex of mammalian ufd1 and npl4 links the AAA-ATPase, p...	ACCEPT	Summary: EXP: p97 is found in the nucleus as well as the cytoplasm of rat (NRK) and monkey cells; nuclear VCP acts in DNA damage responses. Reason: Direct evidence (EXP, PMID:10811609) on rat cells and PAINT placement; nuclear pools of VCP extract proteins from chromatin. Accepted as a genuine location. Supporting Evidence: PMID:10811609 These data suggest that Ufd1 and Npl4 are mostly restricted to the nucleus whereas p97 is, in addition, found in the cytoplasm. file:rat/Vcp/Vcp-uniprot.txt Nucleus {ECO:0000269\|PubMed:10811609}
GO:0005634 nucleus	IBA GO_REF:0000033	ACCEPT	Summary: IBA: p97 is found in the nucleus as well as the cytoplasm of rat (NRK) and monkey cells; nuclear VCP acts in DNA damage responses. Reason: Direct evidence (EXP, PMID:10811609) on rat cells and PAINT placement; nuclear pools of VCP extract proteins from chromatin. Accepted as a genuine location. Supporting Evidence: PMID:10811609 These data suggest that Ufd1 and Npl4 are mostly restricted to the nucleus whereas p97 is, in addition, found in the cytoplasm. file:rat/Vcp/Vcp-uniprot.txt Nucleus {ECO:0000269\|PubMed:10811609}
GO:0005634 nucleus	IEA GO_REF:0000120	ACCEPT	Summary: IEA: p97 is found in the nucleus as well as the cytoplasm of rat (NRK) and monkey cells; nuclear VCP acts in DNA damage responses. Reason: Direct evidence (EXP, PMID:10811609) on rat cells and PAINT placement; nuclear pools of VCP extract proteins from chromatin. Accepted as a genuine location. Supporting Evidence: PMID:10811609 These data suggest that Ufd1 and Npl4 are mostly restricted to the nucleus whereas p97 is, in addition, found in the cytoplasm. file:rat/Vcp/Vcp-uniprot.txt Nucleus {ECO:0000269\|PubMed:10811609}
GO:0005634 nucleus	ISO GO_REF:0000121	ACCEPT	Summary: ISO: p97 is found in the nucleus as well as the cytoplasm of rat (NRK) and monkey cells; nuclear VCP acts in DNA damage responses. Reason: Direct evidence (EXP, PMID:10811609) on rat cells and PAINT placement; nuclear pools of VCP extract proteins from chromatin. Accepted as a genuine location. Supporting Evidence: PMID:10811609 These data suggest that Ufd1 and Npl4 are mostly restricted to the nucleus whereas p97 is, in addition, found in the cytoplasm. file:rat/Vcp/Vcp-uniprot.txt Nucleus {ECO:0000269\|PubMed:10811609}
GO:0005634 nucleus	ISO GO_REF:0000121	ACCEPT	Summary: ISO: p97 is found in the nucleus as well as the cytoplasm of rat (NRK) and monkey cells; nuclear VCP acts in DNA damage responses. Reason: Direct evidence (EXP, PMID:10811609) on rat cells and PAINT placement; nuclear pools of VCP extract proteins from chromatin. Accepted as a genuine location. Supporting Evidence: PMID:10811609 These data suggest that Ufd1 and Npl4 are mostly restricted to the nucleus whereas p97 is, in addition, found in the cytoplasm. file:rat/Vcp/Vcp-uniprot.txt Nucleus {ECO:0000269\|PubMed:10811609}
GO:0005654 nucleoplasm	IEA GO_REF:0000107	ACCEPT	Summary: IEA: Nucleoplasm transferred from human VCP (immunofluorescence, Reactome DNA repair events). Reason: Consistent with the directly shown nuclear location; nucleoplasm is the nuclear sub-compartment in which chromatin-associated VCP functions. Supporting Evidence: PMID:10811609 These data suggest that Ufd1 and Npl4 are mostly restricted to the nucleus whereas p97 is, in addition, found in the cytoplasm. file:rat/Vcp/Vcp-uniprot.txt Following DNA double-strand breaks, recruited to the sites of damage.
GO:0005654 nucleoplasm	ISO GO_REF:0000121	ACCEPT	Summary: ISO: Nucleoplasm transferred from human VCP (immunofluorescence, Reactome DNA repair events). Reason: Consistent with the directly shown nuclear location; nucleoplasm is the nuclear sub-compartment in which chromatin-associated VCP functions. Supporting Evidence: PMID:10811609 These data suggest that Ufd1 and Npl4 are mostly restricted to the nucleus whereas p97 is, in addition, found in the cytoplasm. file:rat/Vcp/Vcp-uniprot.txt Following DNA double-strand breaks, recruited to the sites of damage.
GO:0005737 cytoplasm	IEA GO_REF:0000107	TOO GENERAL	Summary: IEA: Cytoplasm (NAS, ISO, IEA). True, but entailed by the accepted cytosol (and stress granule, perinuclear) location terms. Reason: The specific location GO:0005829 cytosol is accepted on rat IDA evidence and entails this parent. Supporting Evidence: PMID:10811609 These data suggest that Ufd1 and Npl4 are mostly restricted to the nucleus whereas p97 is, in addition, found in the cytoplasm.
GO:0005737 cytoplasm	ISO GO_REF:0000121	TOO GENERAL	Summary: ISO: Cytoplasm (NAS, ISO, IEA). True, but entailed by the accepted cytosol (and stress granule, perinuclear) location terms. Reason: The specific location GO:0005829 cytosol is accepted on rat IDA evidence and entails this parent. Supporting Evidence: PMID:10811609 These data suggest that Ufd1 and Npl4 are mostly restricted to the nucleus whereas p97 is, in addition, found in the cytoplasm.
GO:0005737 cytoplasm	NAS PMID:16601695 Conformational changes in the AAA ATPase p97-p47 adaptor com...	TOO GENERAL	Summary: NAS: Cytoplasm (NAS, ISO, IEA). True, but entailed by the accepted cytosol (and stress granule, perinuclear) location terms. Reason: The specific location GO:0005829 cytosol is accepted on rat IDA evidence and entails this parent. Supporting Evidence: PMID:10811609 These data suggest that Ufd1 and Npl4 are mostly restricted to the nucleus whereas p97 is, in addition, found in the cytoplasm.
GO:0005783 endoplasmic reticulum	IEA GO_REF:0000120	ACCEPT	Summary: IEA: ER association: rat Vcp was isolated as the principal ATPase of rat liver transitional ER; VCP is recruited to the cytosolic face of the ER membrane. Reason: Organelle policy check: the claim holds - a rat ER-fraction purification (PMID:7806566) and ortholog recruitment via Derlin-1/VIMP/AMFR support ER association. The more precise ER membrane term is also present; the root term stays. Supporting Evidence: PMID:7806566 An ATPase with a monomer molecular weight of 100 kD by SDS-PAGE has been isolated from TER and designated as TER ATPase. file:rat/Vcp/Vcp-uniprot.txt Recruited to the cytoplasmic surface of the endoplasmic reticulum via interaction with AMFR/gp78.
GO:0005783 endoplasmic reticulum	ISO GO_REF:0000121	ACCEPT	Summary: ISO: ER association: rat Vcp was isolated as the principal ATPase of rat liver transitional ER; VCP is recruited to the cytosolic face of the ER membrane. Reason: Organelle policy check: the claim holds - a rat ER-fraction purification (PMID:7806566) and ortholog recruitment via Derlin-1/VIMP/AMFR support ER association. The more precise ER membrane term is also present; the root term stays. Supporting Evidence: PMID:7806566 An ATPase with a monomer molecular weight of 100 kD by SDS-PAGE has been isolated from TER and designated as TER ATPase. file:rat/Vcp/Vcp-uniprot.txt Recruited to the cytoplasmic surface of the endoplasmic reticulum via interaction with AMFR/gp78.
GO:0005783 endoplasmic reticulum	ISS GO_REF:0000024	ACCEPT	Summary: ISS: ER association: rat Vcp was isolated as the principal ATPase of rat liver transitional ER; VCP is recruited to the cytosolic face of the ER membrane. Reason: Organelle policy check: the claim holds - a rat ER-fraction purification (PMID:7806566) and ortholog recruitment via Derlin-1/VIMP/AMFR support ER association. The more precise ER membrane term is also present; the root term stays. Supporting Evidence: PMID:7806566 An ATPase with a monomer molecular weight of 100 kD by SDS-PAGE has been isolated from TER and designated as TER ATPase. file:rat/Vcp/Vcp-uniprot.txt Recruited to the cytoplasmic surface of the endoplasmic reticulum via interaction with AMFR/gp78.
GO:0005789 endoplasmic reticulum membrane	IEA GO_REF:0000120	ACCEPT	Summary: IEA: VCP is a peripheral protein on the cytosolic face of the ER membrane, docked via Derlin-1/VIMP and ER E3 ligases, where it extracts ERAD substrates. Reason: This is where the ERAD core function is executed; supported by ortholog experimental data and by rat ERAD work. Supporting Evidence: PMID:16186510 In higher eukaryotes, p97 is bound to the ER membrane by a membrane protein complex containing Derlin-1 and VCP-interacting membrane protein (VIMP). file:rat/Vcp/Vcp-uniprot.txt Recruited to the cytoplasmic surface of the endoplasmic reticulum via interaction with AMFR/gp78.
GO:0005789 endoplasmic reticulum membrane	ISO GO_REF:0000121	ACCEPT	Summary: ISO: VCP is a peripheral protein on the cytosolic face of the ER membrane, docked via Derlin-1/VIMP and ER E3 ligases, where it extracts ERAD substrates. Reason: This is where the ERAD core function is executed; supported by ortholog experimental data and by rat ERAD work. Supporting Evidence: PMID:16186510 In higher eukaryotes, p97 is bound to the ER membrane by a membrane protein complex containing Derlin-1 and VCP-interacting membrane protein (VIMP). file:rat/Vcp/Vcp-uniprot.txt Recruited to the cytoplasmic surface of the endoplasmic reticulum via interaction with AMFR/gp78.
GO:0005789 endoplasmic reticulum membrane	ISO GO_REF:0000121	ACCEPT	Summary: ISO: VCP is a peripheral protein on the cytosolic face of the ER membrane, docked via Derlin-1/VIMP and ER E3 ligases, where it extracts ERAD substrates. Reason: This is where the ERAD core function is executed; supported by ortholog experimental data and by rat ERAD work. Supporting Evidence: PMID:16186510 In higher eukaryotes, p97 is bound to the ER membrane by a membrane protein complex containing Derlin-1 and VCP-interacting membrane protein (VIMP). file:rat/Vcp/Vcp-uniprot.txt Recruited to the cytoplasmic surface of the endoplasmic reticulum via interaction with AMFR/gp78.
GO:0005789 endoplasmic reticulum membrane	ISO GO_REF:0000121	ACCEPT	Summary: ISO: VCP is a peripheral protein on the cytosolic face of the ER membrane, docked via Derlin-1/VIMP and ER E3 ligases, where it extracts ERAD substrates. Reason: This is where the ERAD core function is executed; supported by ortholog experimental data and by rat ERAD work. Supporting Evidence: PMID:16186510 In higher eukaryotes, p97 is bound to the ER membrane by a membrane protein complex containing Derlin-1 and VCP-interacting membrane protein (VIMP). file:rat/Vcp/Vcp-uniprot.txt Recruited to the cytoplasmic surface of the endoplasmic reticulum via interaction with AMFR/gp78.
GO:0005811 lipid droplet	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA: Lipid droplet localisation transferred from human VCP: UBXD8 recruits p97 to lipid droplets where it regulates ATGL. Reason: Supported in human cells; a specialised, cofactor-dependent location that is peripheral to the main functions. Supporting Evidence: PMID:23297223 UBXD8-mediated recruitment of p97/VCP to LDs increases LD size by inhibiting the activity of adipose triglyceride lipase (ATGL)
GO:0005811 lipid droplet	ISO GO_REF:0000121	KEEP AS NON CORE	Summary: ISO: Lipid droplet localisation transferred from human VCP: UBXD8 recruits p97 to lipid droplets where it regulates ATGL. Reason: Supported in human cells; a specialised, cofactor-dependent location that is peripheral to the main functions. Supporting Evidence: PMID:23297223 UBXD8-mediated recruitment of p97/VCP to LDs increases LD size by inhibiting the activity of adipose triglyceride lipase (ATGL)
GO:0005829 cytosol	IBA GO_REF:0000033	ACCEPT	Summary: IBA: Vcp is a soluble, abundant cytosolic protein; p97 complexes were purified from rat liver cytosol and Vcp is cytosolic in rat beta cells. Reason: Direct evidence from rat tissue (IDA) and PAINT placement (IBA); the cytosol is where the ATPase engages ubiquitinated substrates extracted from membranes and complexes. Supporting Evidence: PMID:10811609 Cytosolic p97 therefore comprises at least two alternative complexes: p97/p47 and p97/Ufd1/Npl4. file:rat/Vcp/Vcp-uniprot.txt Cytoplasm, cytosol {ECO:0000269\|PubMed:10811609}
GO:0005829 cytosol	IDA PMID:23444373 SDF2L1 interacts with the ER-associated degradation machiner...	ACCEPT	Summary: IDA: Vcp is a soluble, abundant cytosolic protein; p97 complexes were purified from rat liver cytosol and Vcp is cytosolic in rat beta cells. Reason: Direct evidence from rat tissue (IDA) and PAINT placement (IBA); the cytosol is where the ATPase engages ubiquitinated substrates extracted from membranes and complexes. Supporting Evidence: PMID:10811609 Cytosolic p97 therefore comprises at least two alternative complexes: p97/p47 and p97/Ufd1/Npl4. file:rat/Vcp/Vcp-uniprot.txt Cytoplasm, cytosol {ECO:0000269\|PubMed:10811609}
GO:0005829 cytosol	IDA PMID:9214505 p47 is a cofactor for p97-mediated membrane fusion.	ACCEPT	Summary: IDA: Vcp is a soluble, abundant cytosolic protein; p97 complexes were purified from rat liver cytosol and Vcp is cytosolic in rat beta cells. Reason: Direct evidence from rat tissue (IDA) and PAINT placement (IBA); the cytosol is where the ATPase engages ubiquitinated substrates extracted from membranes and complexes. Supporting Evidence: PMID:10811609 Cytosolic p97 therefore comprises at least two alternative complexes: p97/p47 and p97/Ufd1/Npl4. file:rat/Vcp/Vcp-uniprot.txt Cytoplasm, cytosol {ECO:0000269\|PubMed:10811609}
GO:0005829 cytosol	IEA GO_REF:0000120	ACCEPT	Summary: IEA: Vcp is a soluble, abundant cytosolic protein; p97 complexes were purified from rat liver cytosol and Vcp is cytosolic in rat beta cells. Reason: Direct evidence from rat tissue (IDA) and PAINT placement (IBA); the cytosol is where the ATPase engages ubiquitinated substrates extracted from membranes and complexes. Supporting Evidence: PMID:10811609 Cytosolic p97 therefore comprises at least two alternative complexes: p97/p47 and p97/Ufd1/Npl4. file:rat/Vcp/Vcp-uniprot.txt Cytoplasm, cytosol {ECO:0000269\|PubMed:10811609}
GO:0005829 cytosol	ISO GO_REF:0000121	ACCEPT	Summary: ISO: Vcp is a soluble, abundant cytosolic protein; p97 complexes were purified from rat liver cytosol and Vcp is cytosolic in rat beta cells. Reason: Direct evidence from rat tissue (IDA) and PAINT placement (IBA); the cytosol is where the ATPase engages ubiquitinated substrates extracted from membranes and complexes. Supporting Evidence: PMID:10811609 Cytosolic p97 therefore comprises at least two alternative complexes: p97/p47 and p97/Ufd1/Npl4. file:rat/Vcp/Vcp-uniprot.txt Cytoplasm, cytosol {ECO:0000269\|PubMed:10811609}
GO:0005829 cytosol	ISO GO_REF:0000121	ACCEPT	Summary: ISO: Vcp is a soluble, abundant cytosolic protein; p97 complexes were purified from rat liver cytosol and Vcp is cytosolic in rat beta cells. Reason: Direct evidence from rat tissue (IDA) and PAINT placement (IBA); the cytosol is where the ATPase engages ubiquitinated substrates extracted from membranes and complexes. Supporting Evidence: PMID:10811609 Cytosolic p97 therefore comprises at least two alternative complexes: p97/p47 and p97/Ufd1/Npl4. file:rat/Vcp/Vcp-uniprot.txt Cytoplasm, cytosol {ECO:0000269\|PubMed:10811609}
GO:0006281 DNA repair	ISS GO_REF:0000024	TOO GENERAL	Summary: ISS: DNA repair (ISS from Xenopus p97). True, but entailed by the specific repair terms kept here. Reason: GO:0006302, GO:0106300 and GO:0036297 are kept and are descendants of DNA repair. Supporting Evidence: file:rat/Vcp/Vcp-uniprot.txt Involved in interstrand cross-link repair in response to replication stress by mediating unloading of the ubiquitinated CMG helicase complex.
GO:0006302 double-strand break repair	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA: Double-strand break repair (ISS/ISO/IEA from human VCP): VCP-NPL4 is recruited to DSBs and extracts L3MBTL1 from chromatin to allow 53BP1 recruitment. Reason: Supported by human experimental data; VCP's ATPase performs the extraction step. A real but non-core role relative to ERAD/proteostasis. Supporting Evidence: PMID:22120668 The ATPase activity of VCP promotes the release of the Polycomb protein L3MBTL1 from chromatin PMID:22120668 Here we show that RNF8-mediated ubiquitylation facilitates the recruitment of the AAA-ATPase valosin-containing protein (VCP, also known as p97) and its cofactor NPL4 to sites of double-strand breaks.
GO:0006302 double-strand break repair	ISO GO_REF:0000121	KEEP AS NON CORE	Summary: ISO: Double-strand break repair (ISS/ISO/IEA from human VCP): VCP-NPL4 is recruited to DSBs and extracts L3MBTL1 from chromatin to allow 53BP1 recruitment. Reason: Supported by human experimental data; VCP's ATPase performs the extraction step. A real but non-core role relative to ERAD/proteostasis. Supporting Evidence: PMID:22120668 The ATPase activity of VCP promotes the release of the Polycomb protein L3MBTL1 from chromatin PMID:22120668 Here we show that RNF8-mediated ubiquitylation facilitates the recruitment of the AAA-ATPase valosin-containing protein (VCP, also known as p97) and its cofactor NPL4 to sites of double-strand breaks.
GO:0006302 double-strand break repair	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS: Double-strand break repair (ISS/ISO/IEA from human VCP): VCP-NPL4 is recruited to DSBs and extracts L3MBTL1 from chromatin to allow 53BP1 recruitment. Reason: Supported by human experimental data; VCP's ATPase performs the extraction step. A real but non-core role relative to ERAD/proteostasis. Supporting Evidence: PMID:22120668 The ATPase activity of VCP promotes the release of the Polycomb protein L3MBTL1 from chromatin PMID:22120668 Here we show that RNF8-mediated ubiquitylation facilitates the recruitment of the AAA-ATPase valosin-containing protein (VCP, also known as p97) and its cofactor NPL4 to sites of double-strand breaks.
GO:0006511 ubiquitin-dependent protein catabolic process	ISO GO_REF:0000121	TOO GENERAL	Summary: ISO: Ubiquitin-dependent protein catabolic process (ISO, acts upstream of or within). True, but entailed by the accepted GO:0043161. Reason: GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process is accepted and is a descendant of this term. Supporting Evidence: PMID:11483959 VCP associates with ubiquitinated proteins through the direct binding of its amino-terminal domain to the multi-ubiquitin chains of substrates.
GO:0006888 endoplasmic reticulum to Golgi vesicle-mediated transport	IMP PMID:7806566 Isolation and characterization of the principal ATPase assoc...	KEEP AS NON CORE	Summary: IMP: IMP: antisera against the rat TER ATPase reduced ATP-dependent transition-vesicle formation from rat liver transitional ER and ER-to-Golgi transfer in vitro. Reason: Experimental rat evidence (abstract only for us). Later work places p97 in tER/Golgi membrane assembly through p47-dependent fusion rather than in vesicle budding per se, so the role in ER-to-Golgi transport is kept as non-core rather than accepted as core; the curator's call is respected. Supporting Evidence: PMID:7806566 These antisera reduced the ATP-dependent cell-free formation of transition vesicles from isolated TER of rat liver.
GO:0006914 autophagy	IEA GO_REF:0000107	TOO GENERAL	Summary: IEA: Autophagy (ISS/ISO/IEA). True, but entailed by the accepted autophagosome maturation term. Reason: GO:0097352 autophagosome maturation is accepted and is a descendant of autophagy. Supporting Evidence: file:rat/Vcp/Vcp-uniprot.txt Essential for the maturation of ubiquitin-containing autophagosomes and the clearance of ubiquitinated protein by autophagy.
GO:0006914 autophagy	ISO GO_REF:0000121	TOO GENERAL	Summary: ISO: Autophagy (ISS/ISO/IEA). True, but entailed by the accepted autophagosome maturation term. Reason: GO:0097352 autophagosome maturation is accepted and is a descendant of autophagy. Supporting Evidence: file:rat/Vcp/Vcp-uniprot.txt Essential for the maturation of ubiquitin-containing autophagosomes and the clearance of ubiquitinated protein by autophagy.
GO:0006914 autophagy	ISS GO_REF:0000024	TOO GENERAL	Summary: ISS: Autophagy (ISS/ISO/IEA). True, but entailed by the accepted autophagosome maturation term. Reason: GO:0097352 autophagosome maturation is accepted and is a descendant of autophagy. Supporting Evidence: file:rat/Vcp/Vcp-uniprot.txt Essential for the maturation of ubiquitin-containing autophagosomes and the clearance of ubiquitinated protein by autophagy.
GO:0006974 DNA damage response	IEA GO_REF:0000107	TOO GENERAL	Summary: IEA: DNA damage response (ISS/ISO/IEA). True, but entailed by the more specific DNA repair terms kept here. Reason: Double-strand break repair, DNA-protein cross-link repair, interstrand cross-link repair and translesion synthesis are kept and are descendants of this term. Supporting Evidence: file:rat/Vcp/Vcp-uniprot.txt Following DNA double-strand breaks, recruited to the sites of damage.
GO:0006974 DNA damage response	ISO GO_REF:0000121	TOO GENERAL	Summary: ISO: DNA damage response (ISS/ISO/IEA). True, but entailed by the more specific DNA repair terms kept here. Reason: Double-strand break repair, DNA-protein cross-link repair, interstrand cross-link repair and translesion synthesis are kept and are descendants of this term. Supporting Evidence: file:rat/Vcp/Vcp-uniprot.txt Following DNA double-strand breaks, recruited to the sites of damage.
GO:0006974 DNA damage response	ISS GO_REF:0000024	TOO GENERAL	Summary: ISS: DNA damage response (ISS/ISO/IEA). True, but entailed by the more specific DNA repair terms kept here. Reason: Double-strand break repair, DNA-protein cross-link repair, interstrand cross-link repair and translesion synthesis are kept and are descendants of this term. Supporting Evidence: file:rat/Vcp/Vcp-uniprot.txt Following DNA double-strand breaks, recruited to the sites of damage.
GO:0010494 cytoplasmic stress granule	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: IEA: Stress granule localisation (ISS/ISO/IEA from human VCP): ZFAND1 recruits p97 to arsenite-induced stress granules. Reason: Well supported for the ortholog and reflects where VCP acts in stress granule clearance; a stress-induced location, kept as non-core. Supporting Evidence: PMID:29804830 ZFAND1 interacts with two key factors of protein degradation, the 26S proteasome and the ubiquitin-selective segregase p97, and recruits them to arsenite-induced SGs. file:rat/Vcp/Vcp-uniprot.txt Colocalizes with TIA1, ZFAND1 and G3BP1 in cytoplasmic stress granules (SGs) in response to arsenite-induced stress treatment
GO:0010494 cytoplasmic stress granule	ISO GO_REF:0000121	KEEP AS NON CORE	Summary: ISO: Stress granule localisation (ISS/ISO/IEA from human VCP): ZFAND1 recruits p97 to arsenite-induced stress granules. Reason: Well supported for the ortholog and reflects where VCP acts in stress granule clearance; a stress-induced location, kept as non-core. Supporting Evidence: PMID:29804830 ZFAND1 interacts with two key factors of protein degradation, the 26S proteasome and the ubiquitin-selective segregase p97, and recruits them to arsenite-induced SGs. file:rat/Vcp/Vcp-uniprot.txt Colocalizes with TIA1, ZFAND1 and G3BP1 in cytoplasmic stress granules (SGs) in response to arsenite-induced stress treatment
GO:0010494 cytoplasmic stress granule	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS: Stress granule localisation (ISS/ISO/IEA from human VCP): ZFAND1 recruits p97 to arsenite-induced stress granules. Reason: Well supported for the ortholog and reflects where VCP acts in stress granule clearance; a stress-induced location, kept as non-core. Supporting Evidence: PMID:29804830 ZFAND1 interacts with two key factors of protein degradation, the 26S proteasome and the ubiquitin-selective segregase p97, and recruits them to arsenite-induced SGs. file:rat/Vcp/Vcp-uniprot.txt Colocalizes with TIA1, ZFAND1 and G3BP1 in cytoplasmic stress granules (SGs) in response to arsenite-induced stress treatment
GO:0010498 proteasomal protein catabolic process	IEA GO_REF:0000107	TOO GENERAL	Summary: IEA: Proteasomal protein catabolic process (ISS/ISO/IEA). True, but entailed by the accepted proteasome-mediated ubiquitin-dependent protein catabolic process and ERAD terms. Reason: GO:0043161 and GO:0036503, both accepted, are descendants of this term. Supporting Evidence: file:rat/Vcp/Vcp-uniprot.txt The ternary complex containing UFD1, VCP and NPLOC4 binds ubiquitinated proteins and is necessary for the export of misfolded proteins from the ER to the cytoplasm, where they are degraded by the proteasome
GO:0010498 proteasomal protein catabolic process	ISO GO_REF:0000121	TOO GENERAL	Summary: ISO: Proteasomal protein catabolic process (ISS/ISO/IEA). True, but entailed by the accepted proteasome-mediated ubiquitin-dependent protein catabolic process and ERAD terms. Reason: GO:0043161 and GO:0036503, both accepted, are descendants of this term. Supporting Evidence: file:rat/Vcp/Vcp-uniprot.txt The ternary complex containing UFD1, VCP and NPLOC4 binds ubiquitinated proteins and is necessary for the export of misfolded proteins from the ER to the cytoplasm, where they are degraded by the proteasome
GO:0010498 proteasomal protein catabolic process	ISS GO_REF:0000024	TOO GENERAL	Summary: ISS: Proteasomal protein catabolic process (ISS/ISO/IEA). True, but entailed by the accepted proteasome-mediated ubiquitin-dependent protein catabolic process and ERAD terms. Reason: GO:0043161 and GO:0036503, both accepted, are descendants of this term. Supporting Evidence: file:rat/Vcp/Vcp-uniprot.txt The ternary complex containing UFD1, VCP and NPLOC4 binds ubiquitinated proteins and is necessary for the export of misfolded proteins from the ER to the cytoplasm, where they are degraded by the proteasome
GO:0010918 positive regulation of mitochondrial membrane potential	IEA GO_REF:0000120	MARK AS OVER ANNOTATED	Summary: IEA: Positive regulation of mitochondrial membrane potential (ISO/IEA from human VCP): patient VCP-mutant fibroblasts show uncoupling and reduced membrane potential. Reason: A downstream phenotype of VCP deficiency; no mechanism by which VCP itself regulates membrane potential is shown. Over-annotation from phenotype data. Supporting Evidence: PMID:23498975 we show that VCP deficiency causes profound mitochondrial uncoupling leading to decreased mitochondrial membrane potential and increased mitochondrial oxygen consumption.
GO:0010918 positive regulation of mitochondrial membrane potential	ISO GO_REF:0000121	MARK AS OVER ANNOTATED	Summary: ISO: Positive regulation of mitochondrial membrane potential (ISO/IEA from human VCP): patient VCP-mutant fibroblasts show uncoupling and reduced membrane potential. Reason: A downstream phenotype of VCP deficiency; no mechanism by which VCP itself regulates membrane potential is shown. Over-annotation from phenotype data. Propagation Review Root cause: SOURCE BAD Failure modes: ROLE CONFLATION SOURCE EVIDENCE WEAK Sources checked: MGI:MGI:99919 SOURCE BAD The donor annotation rests on a phenotype of VCP-deficient human fibroblasts (mitochondrial uncoupling, PMID:23498975), not on an activity of VCP; the transfer is faithful but the source over-reaches. Supporting Evidence: PMID:23498975 we show that VCP deficiency causes profound mitochondrial uncoupling leading to decreased mitochondrial membrane potential and increased mitochondrial oxygen consumption.
GO:0010918 positive regulation of mitochondrial membrane potential	ISO GO_REF:0000121	MARK AS OVER ANNOTATED	Summary: ISO: Positive regulation of mitochondrial membrane potential (ISO/IEA from human VCP): patient VCP-mutant fibroblasts show uncoupling and reduced membrane potential. Reason: A downstream phenotype of VCP deficiency; no mechanism by which VCP itself regulates membrane potential is shown. Over-annotation from phenotype data. Propagation Review Root cause: SOURCE BAD Failure modes: ROLE CONFLATION SOURCE EVIDENCE WEAK Sources checked: UniProtKB:P55072 SOURCE BAD The donor annotation rests on a phenotype of VCP-deficient human fibroblasts (mitochondrial uncoupling, PMID:23498975), not on an activity of VCP; the transfer is faithful but the source over-reaches. Supporting Evidence: PMID:23498975 we show that VCP deficiency causes profound mitochondrial uncoupling leading to decreased mitochondrial membrane potential and increased mitochondrial oxygen consumption.
GO:0016236 macroautophagy	IEA GO_REF:0000107	TOO GENERAL	Summary: IEA: Macroautophagy (ISS/ISO/IEA). True, but entailed by the accepted autophagosome maturation term. Reason: GO:0097352 autophagosome maturation (accepted) and GO:0000423 mitophagy (kept) are descendants of macroautophagy. Supporting Evidence: file:rat/Vcp/Vcp-uniprot.txt Essential for the maturation of ubiquitin-containing autophagosomes and the clearance of ubiquitinated protein by autophagy.
GO:0016236 macroautophagy	ISO GO_REF:0000121	TOO GENERAL	Summary: ISO: Macroautophagy (ISS/ISO/IEA). True, but entailed by the accepted autophagosome maturation term. Reason: GO:0097352 autophagosome maturation (accepted) and GO:0000423 mitophagy (kept) are descendants of macroautophagy. Supporting Evidence: file:rat/Vcp/Vcp-uniprot.txt Essential for the maturation of ubiquitin-containing autophagosomes and the clearance of ubiquitinated protein by autophagy.
GO:0016236 macroautophagy	ISS GO_REF:0000024	TOO GENERAL	Summary: ISS: Macroautophagy (ISS/ISO/IEA). True, but entailed by the accepted autophagosome maturation term. Reason: GO:0097352 autophagosome maturation (accepted) and GO:0000423 mitophagy (kept) are descendants of macroautophagy. Supporting Evidence: file:rat/Vcp/Vcp-uniprot.txt Essential for the maturation of ubiquitin-containing autophagosomes and the clearance of ubiquitinated protein by autophagy.
GO:0016567 protein ubiquitination	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: IEA: Protein ubiquitination (ISS/ISO/IEA from human VCP; Derlin-1 complex and L3MBTL1 papers). Reason: Vcp has no ubiquitin ligase activity; it binds E3s and processes ubiquitinated substrates downstream of ubiquitination. Changes in substrate ubiquitination after VCP perturbation are indirect, so this process term over-annotates Vcp. Supporting Evidence: PMID:16186510 Here, we report that p97 interacts directly with several ubiquitin ligases and facilitates their recruitment to Derlin-1.
GO:0016567 protein ubiquitination	ISO GO_REF:0000121	MARK AS OVER ANNOTATED	Summary: ISO: Protein ubiquitination (ISS/ISO/IEA from human VCP; Derlin-1 complex and L3MBTL1 papers). Reason: Vcp has no ubiquitin ligase activity; it binds E3s and processes ubiquitinated substrates downstream of ubiquitination. Changes in substrate ubiquitination after VCP perturbation are indirect, so this process term over-annotates Vcp. Propagation Review Root cause: SOURCE BAD Failure modes: ROLE CONFLATION Sources checked: UniProtKB:P55072 SOURCE BAD VCP has no ubiquitin ligase activity; the donor annotations (Derlin-1 complex and L3MBTL1 papers) record effects on substrate ubiquitination downstream of VCP. Supporting Evidence: PMID:16186510 Here, we report that p97 interacts directly with several ubiquitin ligases and facilitates their recruitment to Derlin-1.
GO:0016567 protein ubiquitination	ISS GO_REF:0000024	MARK AS OVER ANNOTATED	Summary: ISS: Protein ubiquitination (ISS/ISO/IEA from human VCP; Derlin-1 complex and L3MBTL1 papers). Reason: Vcp has no ubiquitin ligase activity; it binds E3s and processes ubiquitinated substrates downstream of ubiquitination. Changes in substrate ubiquitination after VCP perturbation are indirect, so this process term over-annotates Vcp. Supporting Evidence: PMID:16186510 Here, we report that p97 interacts directly with several ubiquitin ligases and facilitates their recruitment to Derlin-1.
GO:0016787 hydrolase activity	IEA GO_REF:0000002	TOO GENERAL	Summary: IEA: InterPro-based hydrolase activity. True, but entailed by the accepted ATP hydrolysis activity (GO:0016887). Reason: Vcp is a hydrolase only as an ATPase; the specific term GO:0016887 is accepted on direct rat evidence and already entails this parent. Supporting Evidence: file:rat/Vcp/Vcp-uniprot.txt Belongs to the AAA ATPase family.
GO:0016887 ATP hydrolysis activity	IBA GO_REF:0000033	ACCEPT	Summary: IBA: Rat Vcp is a hexameric type II AAA ATPase. ATP hydrolysis was measured on the native rat liver TER ATPase and on recombinant rat p97, with D2 as the main catalytic ring. Reason: Core molecular function, directly measured on the rat protein (IDA, IMP) and consistent with the conserved Walker A/B motifs of both AAA domains, PAINT placement (IBA) and the human/mouse orthologs (ISS/ISO/IEA). The hydrolysis cycle drives substrate extraction and unfolding. Supporting Evidence: PMID:7806566 The native TER ATPase has been characterized as a hexamer of six 100-kD subunits by gel filtration. The protein catalyzes the hydrolysis of [gamma 32-P]ATP PMID:18332143 p97 carrying the Walker A mutation to the D1 domain alone (K251A) showed a moderate decrease in ATPase activity, whereas p97 carrying mutations in the D2 domain (K524A, K251A,K524A, R359A,R635A) showed little ATPase activity when compared with wild type PMID:12847084 ATP hydrolysis by the D2 domain, and probably also the D1 domain, are needed to move the polypeptide chain into the cytosol.
GO:0016887 ATP hydrolysis activity	IDA PMID:7806566 Isolation and characterization of the principal ATPase assoc...	ACCEPT	Summary: IDA: Rat Vcp is a hexameric type II AAA ATPase. ATP hydrolysis was measured on the native rat liver TER ATPase and on recombinant rat p97, with D2 as the main catalytic ring. Reason: Core molecular function, directly measured on the rat protein (IDA, IMP) and consistent with the conserved Walker A/B motifs of both AAA domains, PAINT placement (IBA) and the human/mouse orthologs (ISS/ISO/IEA). The hydrolysis cycle drives substrate extraction and unfolding. Supporting Evidence: PMID:7806566 The native TER ATPase has been characterized as a hexamer of six 100-kD subunits by gel filtration. The protein catalyzes the hydrolysis of [gamma 32-P]ATP PMID:18332143 p97 carrying the Walker A mutation to the D1 domain alone (K251A) showed a moderate decrease in ATPase activity, whereas p97 carrying mutations in the D2 domain (K524A, K251A,K524A, R359A,R635A) showed little ATPase activity when compared with wild type PMID:12847084 ATP hydrolysis by the D2 domain, and probably also the D1 domain, are needed to move the polypeptide chain into the cytosol.
GO:0016887 ATP hydrolysis activity	IEA GO_REF:0000120	ACCEPT	Summary: IEA: Rat Vcp is a hexameric type II AAA ATPase. ATP hydrolysis was measured on the native rat liver TER ATPase and on recombinant rat p97, with D2 as the main catalytic ring. Reason: Core molecular function, directly measured on the rat protein (IDA, IMP) and consistent with the conserved Walker A/B motifs of both AAA domains, PAINT placement (IBA) and the human/mouse orthologs (ISS/ISO/IEA). The hydrolysis cycle drives substrate extraction and unfolding. Supporting Evidence: PMID:7806566 The native TER ATPase has been characterized as a hexamer of six 100-kD subunits by gel filtration. The protein catalyzes the hydrolysis of [gamma 32-P]ATP PMID:18332143 p97 carrying the Walker A mutation to the D1 domain alone (K251A) showed a moderate decrease in ATPase activity, whereas p97 carrying mutations in the D2 domain (K524A, K251A,K524A, R359A,R635A) showed little ATPase activity when compared with wild type PMID:12847084 ATP hydrolysis by the D2 domain, and probably also the D1 domain, are needed to move the polypeptide chain into the cytosol.
GO:0016887 ATP hydrolysis activity	IMP PMID:18332143 Analysis of nucleotide binding to P97 reveals the properties...	ACCEPT	Summary: IMP: Rat Vcp is a hexameric type II AAA ATPase. ATP hydrolysis was measured on the native rat liver TER ATPase and on recombinant rat p97, with D2 as the main catalytic ring. Reason: Core molecular function, directly measured on the rat protein (IDA, IMP) and consistent with the conserved Walker A/B motifs of both AAA domains, PAINT placement (IBA) and the human/mouse orthologs (ISS/ISO/IEA). The hydrolysis cycle drives substrate extraction and unfolding. Supporting Evidence: PMID:7806566 The native TER ATPase has been characterized as a hexamer of six 100-kD subunits by gel filtration. The protein catalyzes the hydrolysis of [gamma 32-P]ATP PMID:18332143 p97 carrying the Walker A mutation to the D1 domain alone (K251A) showed a moderate decrease in ATPase activity, whereas p97 carrying mutations in the D2 domain (K524A, K251A,K524A, R359A,R635A) showed little ATPase activity when compared with wild type PMID:12847084 ATP hydrolysis by the D2 domain, and probably also the D1 domain, are needed to move the polypeptide chain into the cytosol.
GO:0016887 ATP hydrolysis activity	ISO GO_REF:0000121	ACCEPT	Summary: ISO: Rat Vcp is a hexameric type II AAA ATPase. ATP hydrolysis was measured on the native rat liver TER ATPase and on recombinant rat p97, with D2 as the main catalytic ring. Reason: Core molecular function, directly measured on the rat protein (IDA, IMP) and consistent with the conserved Walker A/B motifs of both AAA domains, PAINT placement (IBA) and the human/mouse orthologs (ISS/ISO/IEA). The hydrolysis cycle drives substrate extraction and unfolding. Supporting Evidence: PMID:7806566 The native TER ATPase has been characterized as a hexamer of six 100-kD subunits by gel filtration. The protein catalyzes the hydrolysis of [gamma 32-P]ATP PMID:18332143 p97 carrying the Walker A mutation to the D1 domain alone (K251A) showed a moderate decrease in ATPase activity, whereas p97 carrying mutations in the D2 domain (K524A, K251A,K524A, R359A,R635A) showed little ATPase activity when compared with wild type PMID:12847084 ATP hydrolysis by the D2 domain, and probably also the D1 domain, are needed to move the polypeptide chain into the cytosol.
GO:0016887 ATP hydrolysis activity	ISO GO_REF:0000121	ACCEPT	Summary: ISO: Rat Vcp is a hexameric type II AAA ATPase. ATP hydrolysis was measured on the native rat liver TER ATPase and on recombinant rat p97, with D2 as the main catalytic ring. Reason: Core molecular function, directly measured on the rat protein (IDA, IMP) and consistent with the conserved Walker A/B motifs of both AAA domains, PAINT placement (IBA) and the human/mouse orthologs (ISS/ISO/IEA). The hydrolysis cycle drives substrate extraction and unfolding. Supporting Evidence: PMID:7806566 The native TER ATPase has been characterized as a hexamer of six 100-kD subunits by gel filtration. The protein catalyzes the hydrolysis of [gamma 32-P]ATP PMID:18332143 p97 carrying the Walker A mutation to the D1 domain alone (K251A) showed a moderate decrease in ATPase activity, whereas p97 carrying mutations in the D2 domain (K524A, K251A,K524A, R359A,R635A) showed little ATPase activity when compared with wild type PMID:12847084 ATP hydrolysis by the D2 domain, and probably also the D1 domain, are needed to move the polypeptide chain into the cytosol.
GO:0016887 ATP hydrolysis activity	ISS GO_REF:0000024	ACCEPT	Summary: ISS: Rat Vcp is a hexameric type II AAA ATPase. ATP hydrolysis was measured on the native rat liver TER ATPase and on recombinant rat p97, with D2 as the main catalytic ring. Reason: Core molecular function, directly measured on the rat protein (IDA, IMP) and consistent with the conserved Walker A/B motifs of both AAA domains, PAINT placement (IBA) and the human/mouse orthologs (ISS/ISO/IEA). The hydrolysis cycle drives substrate extraction and unfolding. Supporting Evidence: PMID:7806566 The native TER ATPase has been characterized as a hexamer of six 100-kD subunits by gel filtration. The protein catalyzes the hydrolysis of [gamma 32-P]ATP PMID:18332143 p97 carrying the Walker A mutation to the D1 domain alone (K251A) showed a moderate decrease in ATPase activity, whereas p97 carrying mutations in the D2 domain (K524A, K251A,K524A, R359A,R635A) showed little ATPase activity when compared with wild type PMID:12847084 ATP hydrolysis by the D2 domain, and probably also the D1 domain, are needed to move the polypeptide chain into the cytosol.
GO:0019079 viral genome replication	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: IEA: Viral genome replication (ISO/IEA from human VCP): VCP is a host factor required for poliovirus RNA replication. Reason: This is host-dependency (necessity) evidence: the virus exploits VCP. VCP does not perform viral genome replication, and the finding is specific to poliovirus in human cells. Supporting Evidence: PMID:22379090 We identified valosin-containing protein (VCP/p97) as a host factor of PV replication required after viral protein synthesis, and its ATPase activity was essential for PV replication.
GO:0019079 viral genome replication	ISO GO_REF:0000121	MARK AS OVER ANNOTATED	Summary: ISO: Viral genome replication (ISO/IEA from human VCP): VCP is a host factor required for poliovirus RNA replication. Reason: This is host-dependency (necessity) evidence: the virus exploits VCP. VCP does not perform viral genome replication, and the finding is specific to poliovirus in human cells. Propagation Review Root cause: SOURCE BAD Failure modes: ROLE CONFLATION Sources checked: UniProtKB:P55072 SOURCE BAD The donor annotation records host-factor dependency of poliovirus replication on VCP (PMID:22379090); VCP does not perform viral genome replication. Supporting Evidence: PMID:22379090 We identified valosin-containing protein (VCP/p97) as a host factor of PV replication required after viral protein synthesis, and its ATPase activity was essential for PV replication.
GO:0019674 NAD+ metabolic process	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: IEA: NAD+ metabolic process (ISO/IEA from the human fibroblast study PMID:23498975). Reason: The study reports mitochondrial uncoupling in VCP-deficient cells; any change in NAD+ is an indirect metabolic phenotype. VCP has no NAD+-metabolising activity. Supporting Evidence: PMID:23498975 we show that VCP deficiency causes profound mitochondrial uncoupling leading to decreased mitochondrial membrane potential and increased mitochondrial oxygen consumption.
GO:0019674 NAD+ metabolic process	ISO GO_REF:0000121	MARK AS OVER ANNOTATED	Summary: ISO: NAD+ metabolic process (ISO/IEA from the human fibroblast study PMID:23498975). Reason: The study reports mitochondrial uncoupling in VCP-deficient cells; any change in NAD+ is an indirect metabolic phenotype. VCP has no NAD+-metabolising activity. Propagation Review Root cause: SOURCE BAD Failure modes: ROLE CONFLATION SOURCE EVIDENCE WEAK Sources checked: UniProtKB:P55072 SOURCE BAD The donor annotation rests on a phenotype of VCP-deficient human fibroblasts (mitochondrial uncoupling, PMID:23498975), not on an activity of VCP; the transfer is faithful but the source over-reaches. Supporting Evidence: PMID:23498975 we show that VCP deficiency causes profound mitochondrial uncoupling leading to decreased mitochondrial membrane potential and increased mitochondrial oxygen consumption.
GO:0019903 protein phosphatase binding	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA: Protein phosphatase binding transferred from human VCP: the tyrosine phosphatase PTPH1 traps and dephosphorylates VCP C-terminal tyrosines. Reason: The interaction is real but VCP is the phosphatase substrate here; this is a regulatory interaction peripheral to the core function. Supporting Evidence: PMID:10364224 Furthermore, this double mutant specifically trapped VCP in vivo and recognized the C-terminal tyrosines of VCP
GO:0019903 protein phosphatase binding	ISO GO_REF:0000121	KEEP AS NON CORE	Summary: ISO: Protein phosphatase binding transferred from human VCP: the tyrosine phosphatase PTPH1 traps and dephosphorylates VCP C-terminal tyrosines. Reason: The interaction is real but VCP is the phosphatase substrate here; this is a regulatory interaction peripheral to the core function. Supporting Evidence: PMID:10364224 Furthermore, this double mutant specifically trapped VCP in vivo and recognized the C-terminal tyrosines of VCP
GO:0019904 protein domain specific binding	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA: Protein domain specific binding transferred from human VCP: the VCP N domain binds UBX domains of cofactors such as SAKS1/UBXN1. Reason: Cofactor recruitment via UBX/VIM/SHP motifs is well established and important for targeting, but it is an adaptor-binding property rather than the catalytic function; kept as non-core. Supporting Evidence: PMID:15362974 SAKS1 bound ubiquitin tetramers and VCP (valosin-containing protein) in vitro via the UBA and UBX domains respectively. file:rat/Vcp/Vcp-uniprot.txt Interacts (via N-terminus) with UBXN7, UBXN8, and probably several other UBX domain-containing proteins (via UBX domains)
GO:0019904 protein domain specific binding	ISO GO_REF:0000121	KEEP AS NON CORE	Summary: ISO: Protein domain specific binding transferred from human VCP: the VCP N domain binds UBX domains of cofactors such as SAKS1/UBXN1. Reason: Cofactor recruitment via UBX/VIM/SHP motifs is well established and important for targeting, but it is an adaptor-binding property rather than the catalytic function; kept as non-core. Supporting Evidence: PMID:15362974 SAKS1 bound ubiquitin tetramers and VCP (valosin-containing protein) in vitro via the UBA and UBX domains respectively. file:rat/Vcp/Vcp-uniprot.txt Interacts (via N-terminus) with UBXN7, UBXN8, and probably several other UBX domain-containing proteins (via UBX domains)
GO:0019985 translesion synthesis	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA: Translesion synthesis (ISS/ISO/IEA from human VCP): VCP, recruited by SPRTN, extracts DNA polymerase eta to limit TLS. Reason: VCP acts within TLS by removing the TLS polymerase; supported for the ortholog and kept as non-core. Supporting Evidence: file:rat/Vcp/Vcp-uniprot.txt may act by mediating extraction of DNA polymerase eta (POLH) to prevent excessive translesion DNA synthesis
GO:0019985 translesion synthesis	ISO GO_REF:0000121	KEEP AS NON CORE	Summary: ISO: Translesion synthesis (ISS/ISO/IEA from human VCP): VCP, recruited by SPRTN, extracts DNA polymerase eta to limit TLS. Reason: VCP acts within TLS by removing the TLS polymerase; supported for the ortholog and kept as non-core. Supporting Evidence: file:rat/Vcp/Vcp-uniprot.txt may act by mediating extraction of DNA polymerase eta (POLH) to prevent excessive translesion DNA synthesis
GO:0019985 translesion synthesis	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS: Translesion synthesis (ISS/ISO/IEA from human VCP): VCP, recruited by SPRTN, extracts DNA polymerase eta to limit TLS. Reason: VCP acts within TLS by removing the TLS polymerase; supported for the ortholog and kept as non-core. Supporting Evidence: file:rat/Vcp/Vcp-uniprot.txt may act by mediating extraction of DNA polymerase eta (POLH) to prevent excessive translesion DNA synthesis
GO:0030970 retrograde protein transport, ER to cytosol	EXP PMID:12847084 Function of the p97-Ufd1-Npl4 complex in retrotranslocation ...	ACCEPT	Summary: EXP: p97-Ufd1-Npl4 uses ATP hydrolysis to move polyubiquitinated ERAD substrates (MHC class I heavy chains) out of the ER membrane into the cytosol. Reason: Core process. Direct experimental support (EXP, PMID:12847084; the assays used rat liver cytosol for cofactor binding) and PAINT placement; Vcp performs the extraction step itself. Supporting Evidence: PMID:12847084 Thus, both ubiquitin binding and ATP hydrolysis by p97–Ufd1–Npl4 complex are required for the release of polyubiquitinated substrates into the cytosol. PMID:12847084 ATP hydrolysis by the D2 domain, and probably also the D1 domain, are needed to move the polypeptide chain into the cytosol. PMID:11740563 We propose that the Cdc48/p97-Ufd1-Npl4 complex extracts proteins from the ER membrane for cytosolic degradation.
GO:0030970 retrograde protein transport, ER to cytosol	IBA GO_REF:0000033	ACCEPT	Summary: IBA: p97-Ufd1-Npl4 uses ATP hydrolysis to move polyubiquitinated ERAD substrates (MHC class I heavy chains) out of the ER membrane into the cytosol. Reason: Core process. Direct experimental support (EXP, PMID:12847084; the assays used rat liver cytosol for cofactor binding) and PAINT placement; Vcp performs the extraction step itself. Supporting Evidence: PMID:12847084 Thus, both ubiquitin binding and ATP hydrolysis by p97–Ufd1–Npl4 complex are required for the release of polyubiquitinated substrates into the cytosol. PMID:12847084 ATP hydrolysis by the D2 domain, and probably also the D1 domain, are needed to move the polypeptide chain into the cytosol. PMID:11740563 We propose that the Cdc48/p97-Ufd1-Npl4 complex extracts proteins from the ER membrane for cytosolic degradation.
GO:0030970 retrograde protein transport, ER to cytosol	IEA GO_REF:0000120	ACCEPT	Summary: IEA: p97-Ufd1-Npl4 uses ATP hydrolysis to move polyubiquitinated ERAD substrates (MHC class I heavy chains) out of the ER membrane into the cytosol. Reason: Core process. Direct experimental support (EXP, PMID:12847084; the assays used rat liver cytosol for cofactor binding) and PAINT placement; Vcp performs the extraction step itself. Supporting Evidence: PMID:12847084 Thus, both ubiquitin binding and ATP hydrolysis by p97–Ufd1–Npl4 complex are required for the release of polyubiquitinated substrates into the cytosol. PMID:12847084 ATP hydrolysis by the D2 domain, and probably also the D1 domain, are needed to move the polypeptide chain into the cytosol. PMID:11740563 We propose that the Cdc48/p97-Ufd1-Npl4 complex extracts proteins from the ER membrane for cytosolic degradation.
GO:0030970 retrograde protein transport, ER to cytosol	ISO GO_REF:0000121	ACCEPT	Summary: ISO: p97-Ufd1-Npl4 uses ATP hydrolysis to move polyubiquitinated ERAD substrates (MHC class I heavy chains) out of the ER membrane into the cytosol. Reason: Core process. Direct experimental support (EXP, PMID:12847084; the assays used rat liver cytosol for cofactor binding) and PAINT placement; Vcp performs the extraction step itself. Supporting Evidence: PMID:12847084 Thus, both ubiquitin binding and ATP hydrolysis by p97–Ufd1–Npl4 complex are required for the release of polyubiquitinated substrates into the cytosol. PMID:12847084 ATP hydrolysis by the D2 domain, and probably also the D1 domain, are needed to move the polypeptide chain into the cytosol. PMID:11740563 We propose that the Cdc48/p97-Ufd1-Npl4 complex extracts proteins from the ER membrane for cytosolic degradation.
GO:0030970 retrograde protein transport, ER to cytosol	ISO GO_REF:0000121	ACCEPT	Summary: ISO: p97-Ufd1-Npl4 uses ATP hydrolysis to move polyubiquitinated ERAD substrates (MHC class I heavy chains) out of the ER membrane into the cytosol. Reason: Core process. Direct experimental support (EXP, PMID:12847084; the assays used rat liver cytosol for cofactor binding) and PAINT placement; Vcp performs the extraction step itself. Supporting Evidence: PMID:12847084 Thus, both ubiquitin binding and ATP hydrolysis by p97–Ufd1–Npl4 complex are required for the release of polyubiquitinated substrates into the cytosol. PMID:12847084 ATP hydrolysis by the D2 domain, and probably also the D1 domain, are needed to move the polypeptide chain into the cytosol. PMID:11740563 We propose that the Cdc48/p97-Ufd1-Npl4 complex extracts proteins from the ER membrane for cytosolic degradation.
GO:0031334 positive regulation of protein-containing complex assembly	IEA GO_REF:0000107	UNDECIDED	Summary: IEA: Positive regulation of protein-containing complex assembly (ISO/IEA from human VCP; source PMID:18775313, UBXD7/HIF1alpha network proteomics). Reason: The cited abstract describes p97-UBX protein assemblies and HIF1alpha turnover but does not state that VCP promotes the assembly of a protein complex; we cannot see which observation the curator used, so the row is left undecided. Supporting Evidence: PMID:18775313 We employed "network proteomics" to show that p97 assembles with all of the 13 mammalian UBX-domain proteins.
GO:0031334 positive regulation of protein-containing complex assembly	ISO GO_REF:0000121	UNDECIDED	Summary: ISO: Positive regulation of protein-containing complex assembly (ISO/IEA from human VCP; source PMID:18775313, UBXD7/HIF1alpha network proteomics). Reason: The cited abstract describes p97-UBX protein assemblies and HIF1alpha turnover but does not state that VCP promotes the assembly of a protein complex; we cannot see which observation the curator used, so the row is left undecided. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:P55072 UNRESOLVED The donor annotation cites PMID:18775313; the abstract does not show which observation supports promotion of complex assembly. Supporting Evidence: PMID:18775313 We employed "network proteomics" to show that p97 assembles with all of the 13 mammalian UBX-domain proteins.
GO:0031593 polyubiquitin modification-dependent protein binding	IBA GO_REF:0000033	ACCEPT	Summary: IBA: p97 itself binds polyubiquitin chains (as well as via the Ufd1-Npl4 and p47 cofactors), which is required for release of ERAD substrates into the cytosol. Reason: Supported by Ye et al. 2003 (which used rat liver cytosol for cofactor binding) and orthologs; PAINT placement is consistent. Ubiquitin recognition is part of the core mechanism of substrate selection. Supporting Evidence: PMID:12847084 Together, these data suggest that both p97 and Ufd1 can bind polyubiquitin chains. PMID:11483959 VCP associates with ubiquitinated proteins through the direct binding of its amino-terminal domain to the multi-ubiquitin chains of substrates.
GO:0031593 polyubiquitin modification-dependent protein binding	IEA GO_REF:0000120	ACCEPT	Summary: IEA: p97 itself binds polyubiquitin chains (as well as via the Ufd1-Npl4 and p47 cofactors), which is required for release of ERAD substrates into the cytosol. Reason: Supported by Ye et al. 2003 (which used rat liver cytosol for cofactor binding) and orthologs; PAINT placement is consistent. Ubiquitin recognition is part of the core mechanism of substrate selection. Supporting Evidence: PMID:12847084 Together, these data suggest that both p97 and Ufd1 can bind polyubiquitin chains. PMID:11483959 VCP associates with ubiquitinated proteins through the direct binding of its amino-terminal domain to the multi-ubiquitin chains of substrates.
GO:0031593 polyubiquitin modification-dependent protein binding	ISO GO_REF:0000121	ACCEPT	Summary: ISO: p97 itself binds polyubiquitin chains (as well as via the Ufd1-Npl4 and p47 cofactors), which is required for release of ERAD substrates into the cytosol. Reason: Supported by Ye et al. 2003 (which used rat liver cytosol for cofactor binding) and orthologs; PAINT placement is consistent. Ubiquitin recognition is part of the core mechanism of substrate selection. Supporting Evidence: PMID:12847084 Together, these data suggest that both p97 and Ufd1 can bind polyubiquitin chains. PMID:11483959 VCP associates with ubiquitinated proteins through the direct binding of its amino-terminal domain to the multi-ubiquitin chains of substrates.
GO:0031593 polyubiquitin modification-dependent protein binding	ISO GO_REF:0000121	ACCEPT	Summary: ISO: p97 itself binds polyubiquitin chains (as well as via the Ufd1-Npl4 and p47 cofactors), which is required for release of ERAD substrates into the cytosol. Reason: Supported by Ye et al. 2003 (which used rat liver cytosol for cofactor binding) and orthologs; PAINT placement is consistent. Ubiquitin recognition is part of the core mechanism of substrate selection. Supporting Evidence: PMID:12847084 Together, these data suggest that both p97 and Ufd1 can bind polyubiquitin chains. PMID:11483959 VCP associates with ubiquitinated proteins through the direct binding of its amino-terminal domain to the multi-ubiquitin chains of substrates.
GO:0031625 ubiquitin protein ligase binding	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA: Ubiquitin protein ligase binding transferred from human/mouse VCP (e.g. HRD1/SYVN1, AMFR/gp78, RNF19A). Reason: VCP binds several ERAD E3 ligases directly and helps recruit them to Derlin-1; real but auxiliary to the ATPase function. Supporting Evidence: PMID:16186510 Here, we report that p97 interacts directly with several ubiquitin ligases and facilitates their recruitment to Derlin-1. file:rat/Vcp/Vcp-uniprot.txt Directly interacts with UBXN4 and RNF19A.
GO:0031625 ubiquitin protein ligase binding	ISO GO_REF:0000121	KEEP AS NON CORE	Summary: ISO: Ubiquitin protein ligase binding transferred from human/mouse VCP (e.g. HRD1/SYVN1, AMFR/gp78, RNF19A). Reason: VCP binds several ERAD E3 ligases directly and helps recruit them to Derlin-1; real but auxiliary to the ATPase function. Supporting Evidence: PMID:16186510 Here, we report that p97 interacts directly with several ubiquitin ligases and facilitates their recruitment to Derlin-1. file:rat/Vcp/Vcp-uniprot.txt Directly interacts with UBXN4 and RNF19A.
GO:0032436 positive regulation of proteasomal ubiquitin-dependent protein catabolic process	IEA GO_REF:0000107	MODIFY	Summary: IEA: Positive regulation of proteasomal ubiquitin-dependent catabolism (ISO/IEA from human VCP; IkappaBalpha study). Reason: The source shows VCP physically linking ubiquitinated IkappaBalpha to the proteasome, i.e. participation in the degradation itself. The direct-participation term GO:0043161 (already accepted) fits better than a positive-regulation term. Proposed replacements: proteasome-mediated ubiquitin-dependent protein catabolic process Supporting Evidence: PMID:9452483 Further, VCP co-purifies with the 26 S proteasome on two-dimensional gels and co-immunoprecipitates with subunits of the 26 S proteasome. PMID:11483959 VCP associates with ubiquitinated proteins through the direct binding of its amino-terminal domain to the multi-ubiquitin chains of substrates.
GO:0032436 positive regulation of proteasomal ubiquitin-dependent protein catabolic process	ISO GO_REF:0000121	MODIFY	Summary: ISO: Positive regulation of proteasomal ubiquitin-dependent catabolism (ISO/IEA from human VCP; IkappaBalpha study). Reason: The source shows VCP physically linking ubiquitinated IkappaBalpha to the proteasome, i.e. participation in the degradation itself. The direct-participation term GO:0043161 (already accepted) fits better than a positive-regulation term. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: UniProtKB:P55072 SUPPORTS TRANSFER The donor evidence (PMID:9452483) is sound and transfers to rat, but shows participation in proteasomal degradation rather than its positive regulation. Proposed replacements: proteasome-mediated ubiquitin-dependent protein catabolic process Supporting Evidence: PMID:9452483 Further, VCP co-purifies with the 26 S proteasome on two-dimensional gels and co-immunoprecipitates with subunits of the 26 S proteasome. PMID:11483959 VCP associates with ubiquitinated proteins through the direct binding of its amino-terminal domain to the multi-ubiquitin chains of substrates.
GO:0032510 endosome to lysosome transport via multivesicular body sorting pathway	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA: Endosome-to-lysosome transport via MVB sorting (ISS/ISO/IEA from human VCP): VCP-UBXD1 handles ubiquitylated caveolin-1 on endosomes. Reason: Supported in human cells; a specialised cofactor-dependent role, kept as non-core. Supporting Evidence: PMID:21822278 We show that VCP-UBXD1 targets mono-ubiquitylated CAV1 in SDS-resistant high-molecular-weight complexes on endosomes, which are en route to degradation in endolysosomes. file:rat/Vcp/Vcp-uniprot.txt May play a role in the ubiquitin-dependent sorting of membrane proteins to lysosomes where they undergo degradation
GO:0032510 endosome to lysosome transport via multivesicular body sorting pathway	ISO GO_REF:0000121	KEEP AS NON CORE	Summary: ISO: Endosome-to-lysosome transport via MVB sorting (ISS/ISO/IEA from human VCP): VCP-UBXD1 handles ubiquitylated caveolin-1 on endosomes. Reason: Supported in human cells; a specialised cofactor-dependent role, kept as non-core. Supporting Evidence: PMID:21822278 We show that VCP-UBXD1 targets mono-ubiquitylated CAV1 in SDS-resistant high-molecular-weight complexes on endosomes, which are en route to degradation in endolysosomes. file:rat/Vcp/Vcp-uniprot.txt May play a role in the ubiquitin-dependent sorting of membrane proteins to lysosomes where they undergo degradation
GO:0032510 endosome to lysosome transport via multivesicular body sorting pathway	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS: Endosome-to-lysosome transport via MVB sorting (ISS/ISO/IEA from human VCP): VCP-UBXD1 handles ubiquitylated caveolin-1 on endosomes. Reason: Supported in human cells; a specialised cofactor-dependent role, kept as non-core. Supporting Evidence: PMID:21822278 We show that VCP-UBXD1 targets mono-ubiquitylated CAV1 in SDS-resistant high-molecular-weight complexes on endosomes, which are en route to degradation in endolysosomes. file:rat/Vcp/Vcp-uniprot.txt May play a role in the ubiquitin-dependent sorting of membrane proteins to lysosomes where they undergo degradation
GO:0032991 protein-containing complex	IEA GO_REF:0000120	TOO GENERAL	Summary: IEA: Protein-containing complex (ISO/IEA). True, but entailed by the specific complexes accepted here. Reason: GO:0034098 VCP-NPL4-UFD1 AAA ATPase complex and GO:1990730 VCP-NSFL1C complex are accepted and are both is_a descendants of this term. Supporting Evidence: PMID:10811609 Cytosolic p97 therefore comprises at least two alternative complexes: p97/p47 and p97/Ufd1/Npl4.
GO:0032991 protein-containing complex	ISO GO_REF:0000121	TOO GENERAL	Summary: ISO: Protein-containing complex (ISO/IEA). True, but entailed by the specific complexes accepted here. Reason: GO:0034098 VCP-NPL4-UFD1 AAA ATPase complex and GO:1990730 VCP-NSFL1C complex are accepted and are both is_a descendants of this term. Supporting Evidence: PMID:10811609 Cytosolic p97 therefore comprises at least two alternative complexes: p97/p47 and p97/Ufd1/Npl4.
GO:0032991 protein-containing complex	ISO GO_REF:0000121	TOO GENERAL	Summary: ISO: Protein-containing complex (ISO/IEA). True, but entailed by the specific complexes accepted here. Reason: GO:0034098 VCP-NPL4-UFD1 AAA ATPase complex and GO:1990730 VCP-NSFL1C complex are accepted and are both is_a descendants of this term. Supporting Evidence: PMID:10811609 Cytosolic p97 therefore comprises at least two alternative complexes: p97/p47 and p97/Ufd1/Npl4.
GO:0034098 VCP-NPL4-UFD1 AAA ATPase complex	EXP PMID:22232657 Distinct conformations of the protein complex p97-Ufd1-Npl4 ...	ACCEPT	Summary: EXP: Vcp forms the VCP-NPL4-UFD1 complex: shown in rat liver cytosol and with recombinant rat proteins, and visualised by cryo-EM. Reason: Direct rat evidence (IDA, EXP) plus PAINT placement and ortholog data. This is the principal ERAD/proteasome-targeting complex of Vcp. Supporting Evidence: PMID:10811609 Binding experiments with recombinant proteins revealed that Npl4 and Ufd1 form a binary complex on their own that can bind p97 to form a ternary complex. PMID:10811609 Cytosolic p97 therefore comprises at least two alternative complexes: p97/p47 and p97/Ufd1/Npl4. PMID:22232657 Our reconstructions show that p97-Ufd1-Npl4 is highly dynamic and that Ufd1-Npl4 assumes distinct positions relative to the p97 ring upon addition of nucleotide.
GO:0034098 VCP-NPL4-UFD1 AAA ATPase complex	IBA GO_REF:0000033	ACCEPT	Summary: IBA: Vcp forms the VCP-NPL4-UFD1 complex: shown in rat liver cytosol and with recombinant rat proteins, and visualised by cryo-EM. Reason: Direct rat evidence (IDA, EXP) plus PAINT placement and ortholog data. This is the principal ERAD/proteasome-targeting complex of Vcp. Supporting Evidence: PMID:10811609 Binding experiments with recombinant proteins revealed that Npl4 and Ufd1 form a binary complex on their own that can bind p97 to form a ternary complex. PMID:10811609 Cytosolic p97 therefore comprises at least two alternative complexes: p97/p47 and p97/Ufd1/Npl4. PMID:22232657 Our reconstructions show that p97-Ufd1-Npl4 is highly dynamic and that Ufd1-Npl4 assumes distinct positions relative to the p97 ring upon addition of nucleotide.
GO:0034098 VCP-NPL4-UFD1 AAA ATPase complex	IDA PMID:10811609 A complex of mammalian ufd1 and npl4 links the AAA-ATPase, p...	ACCEPT	Summary: IDA: Vcp forms the VCP-NPL4-UFD1 complex: shown in rat liver cytosol and with recombinant rat proteins, and visualised by cryo-EM. Reason: Direct rat evidence (IDA, EXP) plus PAINT placement and ortholog data. This is the principal ERAD/proteasome-targeting complex of Vcp. Supporting Evidence: PMID:10811609 Binding experiments with recombinant proteins revealed that Npl4 and Ufd1 form a binary complex on their own that can bind p97 to form a ternary complex. PMID:10811609 Cytosolic p97 therefore comprises at least two alternative complexes: p97/p47 and p97/Ufd1/Npl4. PMID:22232657 Our reconstructions show that p97-Ufd1-Npl4 is highly dynamic and that Ufd1-Npl4 assumes distinct positions relative to the p97 ring upon addition of nucleotide.
GO:0034098 VCP-NPL4-UFD1 AAA ATPase complex	IEA GO_REF:0000120	ACCEPT	Summary: IEA: Vcp forms the VCP-NPL4-UFD1 complex: shown in rat liver cytosol and with recombinant rat proteins, and visualised by cryo-EM. Reason: Direct rat evidence (IDA, EXP) plus PAINT placement and ortholog data. This is the principal ERAD/proteasome-targeting complex of Vcp. Supporting Evidence: PMID:10811609 Binding experiments with recombinant proteins revealed that Npl4 and Ufd1 form a binary complex on their own that can bind p97 to form a ternary complex. PMID:10811609 Cytosolic p97 therefore comprises at least two alternative complexes: p97/p47 and p97/Ufd1/Npl4. PMID:22232657 Our reconstructions show that p97-Ufd1-Npl4 is highly dynamic and that Ufd1-Npl4 assumes distinct positions relative to the p97 ring upon addition of nucleotide.
GO:0034098 VCP-NPL4-UFD1 AAA ATPase complex	ISO GO_REF:0000121	ACCEPT	Summary: ISO: Vcp forms the VCP-NPL4-UFD1 complex: shown in rat liver cytosol and with recombinant rat proteins, and visualised by cryo-EM. Reason: Direct rat evidence (IDA, EXP) plus PAINT placement and ortholog data. This is the principal ERAD/proteasome-targeting complex of Vcp. Supporting Evidence: PMID:10811609 Binding experiments with recombinant proteins revealed that Npl4 and Ufd1 form a binary complex on their own that can bind p97 to form a ternary complex. PMID:10811609 Cytosolic p97 therefore comprises at least two alternative complexes: p97/p47 and p97/Ufd1/Npl4. PMID:22232657 Our reconstructions show that p97-Ufd1-Npl4 is highly dynamic and that Ufd1-Npl4 assumes distinct positions relative to the p97 ring upon addition of nucleotide.
GO:0034098 VCP-NPL4-UFD1 AAA ATPase complex	ISO GO_REF:0000121	ACCEPT	Summary: ISO: Vcp forms the VCP-NPL4-UFD1 complex: shown in rat liver cytosol and with recombinant rat proteins, and visualised by cryo-EM. Reason: Direct rat evidence (IDA, EXP) plus PAINT placement and ortholog data. This is the principal ERAD/proteasome-targeting complex of Vcp. Supporting Evidence: PMID:10811609 Binding experiments with recombinant proteins revealed that Npl4 and Ufd1 form a binary complex on their own that can bind p97 to form a ternary complex. PMID:10811609 Cytosolic p97 therefore comprises at least two alternative complexes: p97/p47 and p97/Ufd1/Npl4. PMID:22232657 Our reconstructions show that p97-Ufd1-Npl4 is highly dynamic and that Ufd1-Npl4 assumes distinct positions relative to the p97 ring upon addition of nucleotide.
GO:0034605 cellular response to heat	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: IEA: Cellular response to heat (ISS/ISO/IEA from the human ZFAND1 stress-granule study). Reason: The source characterises stress granule clearance; VCP's role is the clearance step (captured by GO:0035617), not a heat-response activity. A stress-response process term over-states its role. Supporting Evidence: PMID:29804830 ZFAND1 interacts with two key factors of protein degradation, the 26S proteasome and the ubiquitin-selective segregase p97, and recruits them to arsenite-induced SGs.
GO:0034605 cellular response to heat	ISO GO_REF:0000121	MARK AS OVER ANNOTATED	Summary: ISO: Cellular response to heat (ISS/ISO/IEA from the human ZFAND1 stress-granule study). Reason: The source characterises stress granule clearance; VCP's role is the clearance step (captured by GO:0035617), not a heat-response activity. A stress-response process term over-states its role. Propagation Review Root cause: SOURCE BAD Failure modes: ROLE CONFLATION Sources checked: UniProtKB:P55072 SOURCE BAD The donor study (PMID:29804830) concerns stress granule clearance; the stress-response term conflates the experimental trigger with VCP's role. Supporting Evidence: PMID:29804830 ZFAND1 interacts with two key factors of protein degradation, the 26S proteasome and the ubiquitin-selective segregase p97, and recruits them to arsenite-induced SGs.
GO:0034605 cellular response to heat	ISS GO_REF:0000024	MARK AS OVER ANNOTATED	Summary: ISS: Cellular response to heat (ISS/ISO/IEA from the human ZFAND1 stress-granule study). Reason: The source characterises stress granule clearance; VCP's role is the clearance step (captured by GO:0035617), not a heat-response activity. A stress-response process term over-states its role. Supporting Evidence: PMID:29804830 ZFAND1 interacts with two key factors of protein degradation, the 26S proteasome and the ubiquitin-selective segregase p97, and recruits them to arsenite-induced SGs.
GO:0035331 negative regulation of hippo signaling	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA: Negative regulation of hippo signaling (ISO/IEA). Source is Drosophila Ter94; human VCP substitutes for Ter94 in wing-size assays. Reason: Ter94 binds Merlin and disrupts the Ex-Mer-Kib complex; the effect on Hippo signalling is a context-specific regulatory output. Kept as non-core. Supporting Evidence: PMID:38710747 Biochemical experiments reveal that Ter94 reciprocally binds to Mer, a critical upstream component of the Hippo pathway, and disrupts its interaction with Ex and Kib.
GO:0035331 negative regulation of hippo signaling	ISO GO_REF:0000121	KEEP AS NON CORE	Summary: ISO: Negative regulation of hippo signaling (ISO/IEA). Source is Drosophila Ter94; human VCP substitutes for Ter94 in wing-size assays. Reason: Ter94 binds Merlin and disrupts the Ex-Mer-Kib complex; the effect on Hippo signalling is a context-specific regulatory output. Kept as non-core. Supporting Evidence: PMID:38710747 Biochemical experiments reveal that Ter94 reciprocally binds to Mer, a critical upstream component of the Hippo pathway, and disrupts its interaction with Ex and Kib.
GO:0035617 cytoplasmic stress granule disassembly	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA: Stress granule disassembly (ISS/ISO/IEA from human VCP): ZFAND1 recruits p97 to arsenite-induced granules, and VCP extracts G3BP1 to clear them. Reason: VCP performs an extraction step in granule clearance; supported for the ortholog and kept as a non-core process. Supporting Evidence: PMID:29804830 ZFAND1 interacts with two key factors of protein degradation, the 26S proteasome and the ubiquitin-selective segregase p97, and recruits them to arsenite-induced SGs. file:rat/Vcp/Vcp-uniprot.txt Involved in clearance process by mediating G3BP1 extraction from stress granules
GO:0035617 cytoplasmic stress granule disassembly	ISO GO_REF:0000121	KEEP AS NON CORE	Summary: ISO: Stress granule disassembly (ISS/ISO/IEA from human VCP): ZFAND1 recruits p97 to arsenite-induced granules, and VCP extracts G3BP1 to clear them. Reason: VCP performs an extraction step in granule clearance; supported for the ortholog and kept as a non-core process. Supporting Evidence: PMID:29804830 ZFAND1 interacts with two key factors of protein degradation, the 26S proteasome and the ubiquitin-selective segregase p97, and recruits them to arsenite-induced SGs. file:rat/Vcp/Vcp-uniprot.txt Involved in clearance process by mediating G3BP1 extraction from stress granules
GO:0035617 cytoplasmic stress granule disassembly	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS: Stress granule disassembly (ISS/ISO/IEA from human VCP): ZFAND1 recruits p97 to arsenite-induced granules, and VCP extracts G3BP1 to clear them. Reason: VCP performs an extraction step in granule clearance; supported for the ortholog and kept as a non-core process. Supporting Evidence: PMID:29804830 ZFAND1 interacts with two key factors of protein degradation, the 26S proteasome and the ubiquitin-selective segregase p97, and recruits them to arsenite-induced SGs. file:rat/Vcp/Vcp-uniprot.txt Involved in clearance process by mediating G3BP1 extraction from stress granules
GO:0035800 deubiquitinase activator activity	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA: Deubiquitinase activator activity transferred from human VCP: recombinant VCP stimulates deubiquitination by wild-type ataxin-3 in vitro. Reason: In vitro activation of ATXN3 by VCP is reported; a single-substrate regulatory observation that is peripheral to the core segregase function. Supporting Evidence: PMID:22970133 VCP/p97 was shown to be an activator specifically of wild-type ataxin-3, exhibiting no effect on expanded ataxin-3
GO:0035800 deubiquitinase activator activity	ISO GO_REF:0000121	KEEP AS NON CORE	Summary: ISO: Deubiquitinase activator activity transferred from human VCP: recombinant VCP stimulates deubiquitination by wild-type ataxin-3 in vitro. Reason: In vitro activation of ATXN3 by VCP is reported; a single-substrate regulatory observation that is peripheral to the core segregase function. Supporting Evidence: PMID:22970133 VCP/p97 was shown to be an activator specifically of wild-type ataxin-3, exhibiting no effect on expanded ataxin-3
GO:0035861 site of double-strand break	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA: VCP and NPL4 are recruited to double-strand break sites in an RNF8/RNF168-dependent manner (human cells). Reason: Damage-induced recruitment is well documented in human cells; a conditional location supporting a non-core DNA damage role. Supporting Evidence: PMID:22120668 Here we show that RNF8-mediated ubiquitylation facilitates the recruitment of the AAA-ATPase valosin-containing protein (VCP, also known as p97) and its cofactor NPL4 to sites of double-strand breaks. file:rat/Vcp/Vcp-uniprot.txt Following DNA double-strand breaks, recruited to the sites of damage.
GO:0035861 site of double-strand break	ISO GO_REF:0000121	KEEP AS NON CORE	Summary: ISO: VCP and NPL4 are recruited to double-strand break sites in an RNF8/RNF168-dependent manner (human cells). Reason: Damage-induced recruitment is well documented in human cells; a conditional location supporting a non-core DNA damage role. Supporting Evidence: PMID:22120668 Here we show that RNF8-mediated ubiquitylation facilitates the recruitment of the AAA-ATPase valosin-containing protein (VCP, also known as p97) and its cofactor NPL4 to sites of double-strand breaks. file:rat/Vcp/Vcp-uniprot.txt Following DNA double-strand breaks, recruited to the sites of damage.
GO:0035861 site of double-strand break	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS: VCP and NPL4 are recruited to double-strand break sites in an RNF8/RNF168-dependent manner (human cells). Reason: Damage-induced recruitment is well documented in human cells; a conditional location supporting a non-core DNA damage role. Supporting Evidence: PMID:22120668 Here we show that RNF8-mediated ubiquitylation facilitates the recruitment of the AAA-ATPase valosin-containing protein (VCP, also known as p97) and its cofactor NPL4 to sites of double-strand breaks. file:rat/Vcp/Vcp-uniprot.txt Following DNA double-strand breaks, recruited to the sites of damage.
GO:0036297 interstrand cross-link repair	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS: Interstrand cross-link repair (ISS from Xenopus p97): p97 unloads the ubiquitinated CMG helicase in response to replication stress. Reason: Supported for the amphibian ortholog in egg extracts; conserved mechanism, kept as non-core. Supporting Evidence: file:rat/Vcp/Vcp-uniprot.txt Involved in interstrand cross-link repair in response to replication stress by mediating unloading of the ubiquitinated CMG helicase complex.
GO:0036435 K48-linked polyubiquitin modification-dependent protein binding	IEA GO_REF:0000120	ACCEPT	Summary: IEA: K48-linked polyubiquitin binding transferred from human/mouse VCP; VCP and its UFD1-NPL4 cofactor recognise K48-linked chains on proteasome-bound substrates. Reason: Consistent with the accepted polyubiquitin binding and with the role of VCP in delivering K48-ubiquitinated substrates to the proteasome; the rat sequence is near-identical to the human donor. Supporting Evidence: PMID:12847084 Together, these data suggest that both p97 and Ufd1 can bind polyubiquitin chains. PMID:11483959 VCP associates with ubiquitinated proteins through the direct binding of its amino-terminal domain to the multi-ubiquitin chains of substrates.
GO:0036435 K48-linked polyubiquitin modification-dependent protein binding	ISO GO_REF:0000121	ACCEPT	Summary: ISO: K48-linked polyubiquitin binding transferred from human/mouse VCP; VCP and its UFD1-NPL4 cofactor recognise K48-linked chains on proteasome-bound substrates. Reason: Consistent with the accepted polyubiquitin binding and with the role of VCP in delivering K48-ubiquitinated substrates to the proteasome; the rat sequence is near-identical to the human donor. Supporting Evidence: PMID:12847084 Together, these data suggest that both p97 and Ufd1 can bind polyubiquitin chains. PMID:11483959 VCP associates with ubiquitinated proteins through the direct binding of its amino-terminal domain to the multi-ubiquitin chains of substrates.
GO:0036435 K48-linked polyubiquitin modification-dependent protein binding	ISO GO_REF:0000121	ACCEPT	Summary: ISO: K48-linked polyubiquitin binding transferred from human/mouse VCP; VCP and its UFD1-NPL4 cofactor recognise K48-linked chains on proteasome-bound substrates. Reason: Consistent with the accepted polyubiquitin binding and with the role of VCP in delivering K48-ubiquitinated substrates to the proteasome; the rat sequence is near-identical to the human donor. Supporting Evidence: PMID:12847084 Together, these data suggest that both p97 and Ufd1 can bind polyubiquitin chains. PMID:11483959 VCP associates with ubiquitinated proteins through the direct binding of its amino-terminal domain to the multi-ubiquitin chains of substrates.
GO:0036503 ERAD quality control pathway	IDA PMID:12847084 Function of the p97-Ufd1-Npl4 complex in retrotranslocation ...	ACCEPT	Summary: IDA: ERAD: Vcp, as the p97-Ufd1-Npl4 complex, extracts ubiquitinated ER substrates for proteasomal degradation; shown for MHC class I heavy chains and for endogenous IP3 receptors in rat cells. Reason: Core process with direct evidence and rat-cell data (PMID:16103111); Vcp supplies the ATP-driven extraction step. Supporting Evidence: PMID:12847084 Thus, both ubiquitin binding and ATP hydrolysis by p97–Ufd1–Npl4 complex are required for the release of polyubiquitinated substrates into the cytosol. PMID:16103111 Our results indicate that the p97-Ufd1-Npl4 complex is required for the processing of ubiquitinated IP 3 Rs and, thus, that this complex plays a key role in ERAD in mammalian cells. file:rat/Vcp/Vcp-uniprot.txt The ternary complex containing UFD1, VCP and NPLOC4 binds ubiquitinated proteins and is necessary for the export of misfolded proteins from the ER to the cytoplasm, where they are degraded by the proteasome
GO:0036503 ERAD quality control pathway	IEA GO_REF:0000107	ACCEPT	Summary: IEA: ERAD: Vcp, as the p97-Ufd1-Npl4 complex, extracts ubiquitinated ER substrates for proteasomal degradation; shown for MHC class I heavy chains and for endogenous IP3 receptors in rat cells. Reason: Core process with direct evidence and rat-cell data (PMID:16103111); Vcp supplies the ATP-driven extraction step. Supporting Evidence: PMID:12847084 Thus, both ubiquitin binding and ATP hydrolysis by p97–Ufd1–Npl4 complex are required for the release of polyubiquitinated substrates into the cytosol. PMID:16103111 Our results indicate that the p97-Ufd1-Npl4 complex is required for the processing of ubiquitinated IP 3 Rs and, thus, that this complex plays a key role in ERAD in mammalian cells. file:rat/Vcp/Vcp-uniprot.txt The ternary complex containing UFD1, VCP and NPLOC4 binds ubiquitinated proteins and is necessary for the export of misfolded proteins from the ER to the cytoplasm, where they are degraded by the proteasome
GO:0036503 ERAD quality control pathway	ISO GO_REF:0000121	ACCEPT	Summary: ISO: ERAD: Vcp, as the p97-Ufd1-Npl4 complex, extracts ubiquitinated ER substrates for proteasomal degradation; shown for MHC class I heavy chains and for endogenous IP3 receptors in rat cells. Reason: Core process with direct evidence and rat-cell data (PMID:16103111); Vcp supplies the ATP-driven extraction step. Supporting Evidence: PMID:12847084 Thus, both ubiquitin binding and ATP hydrolysis by p97–Ufd1–Npl4 complex are required for the release of polyubiquitinated substrates into the cytosol. PMID:16103111 Our results indicate that the p97-Ufd1-Npl4 complex is required for the processing of ubiquitinated IP 3 Rs and, thus, that this complex plays a key role in ERAD in mammalian cells. file:rat/Vcp/Vcp-uniprot.txt The ternary complex containing UFD1, VCP and NPLOC4 binds ubiquitinated proteins and is necessary for the export of misfolded proteins from the ER to the cytoplasm, where they are degraded by the proteasome
GO:0036503 ERAD quality control pathway	ISO GO_REF:0000121	ACCEPT	Summary: ISO: ERAD: Vcp, as the p97-Ufd1-Npl4 complex, extracts ubiquitinated ER substrates for proteasomal degradation; shown for MHC class I heavy chains and for endogenous IP3 receptors in rat cells. Reason: Core process with direct evidence and rat-cell data (PMID:16103111); Vcp supplies the ATP-driven extraction step. Supporting Evidence: PMID:12847084 Thus, both ubiquitin binding and ATP hydrolysis by p97–Ufd1–Npl4 complex are required for the release of polyubiquitinated substrates into the cytosol. PMID:16103111 Our results indicate that the p97-Ufd1-Npl4 complex is required for the processing of ubiquitinated IP 3 Rs and, thus, that this complex plays a key role in ERAD in mammalian cells. file:rat/Vcp/Vcp-uniprot.txt The ternary complex containing UFD1, VCP and NPLOC4 binds ubiquitinated proteins and is necessary for the export of misfolded proteins from the ER to the cytoplasm, where they are degraded by the proteasome
GO:0036503 ERAD quality control pathway	ISS GO_REF:0000024	ACCEPT	Summary: ISS: ERAD: Vcp, as the p97-Ufd1-Npl4 complex, extracts ubiquitinated ER substrates for proteasomal degradation; shown for MHC class I heavy chains and for endogenous IP3 receptors in rat cells. Reason: Core process with direct evidence and rat-cell data (PMID:16103111); Vcp supplies the ATP-driven extraction step. Supporting Evidence: PMID:12847084 Thus, both ubiquitin binding and ATP hydrolysis by p97–Ufd1–Npl4 complex are required for the release of polyubiquitinated substrates into the cytosol. PMID:16103111 Our results indicate that the p97-Ufd1-Npl4 complex is required for the processing of ubiquitinated IP 3 Rs and, thus, that this complex plays a key role in ERAD in mammalian cells. file:rat/Vcp/Vcp-uniprot.txt The ternary complex containing UFD1, VCP and NPLOC4 binds ubiquitinated proteins and is necessary for the export of misfolded proteins from the ER to the cytoplasm, where they are degraded by the proteasome
GO:0036513 Derlin-1 retrotranslocation complex	IEA GO_REF:0000120	ACCEPT	Summary: IEA: Derlin-1 retrotranslocation complex transferred from human/mouse VCP: p97 is bound at the ER membrane by Derlin-1 and VIMP. Reason: Well supported for the ortholog; p97 is the ATPase of the Derlin-1 retrotranslocation machinery, central to ERAD. Supporting Evidence: PMID:16186510 In higher eukaryotes, p97 is bound to the ER membrane by a membrane protein complex containing Derlin-1 and VCP-interacting membrane protein (VIMP). PMID:15215856 VIMP, a novel membrane protein that recruits the p97 ATPase and its cofactor
GO:0036513 Derlin-1 retrotranslocation complex	ISO GO_REF:0000121	ACCEPT	Summary: ISO: Derlin-1 retrotranslocation complex transferred from human/mouse VCP: p97 is bound at the ER membrane by Derlin-1 and VIMP. Reason: Well supported for the ortholog; p97 is the ATPase of the Derlin-1 retrotranslocation machinery, central to ERAD. Supporting Evidence: PMID:16186510 In higher eukaryotes, p97 is bound to the ER membrane by a membrane protein complex containing Derlin-1 and VCP-interacting membrane protein (VIMP). PMID:15215856 VIMP, a novel membrane protein that recruits the p97 ATPase and its cofactor
GO:0036513 Derlin-1 retrotranslocation complex	ISO GO_REF:0000121	ACCEPT	Summary: ISO: Derlin-1 retrotranslocation complex transferred from human/mouse VCP: p97 is bound at the ER membrane by Derlin-1 and VIMP. Reason: Well supported for the ortholog; p97 is the ATPase of the Derlin-1 retrotranslocation machinery, central to ERAD. Supporting Evidence: PMID:16186510 In higher eukaryotes, p97 is bound to the ER membrane by a membrane protein complex containing Derlin-1 and VCP-interacting membrane protein (VIMP). PMID:15215856 VIMP, a novel membrane protein that recruits the p97 ATPase and its cofactor
GO:0042288 MHC class I protein binding	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: IEA: MHC class I protein binding transferred from human VCP. MHC class I heavy chains are model ERAD substrates (US11-dependent dislocation) that p97 engages during retrotranslocation. Reason: The binding reflects substrate engagement in an experimental ERAD system rather than a specific MHC-I binding function; it over-specifies one of many ERAD clients. Supporting Evidence: PMID:12847084 These data suggest that p97 can specifically interact with substrate that has not been modified by a polyubiquitin chain, and that binding of p97 is an early step after emergence of the polypeptide from the ER.
GO:0042288 MHC class I protein binding	ISO GO_REF:0000121	MARK AS OVER ANNOTATED	Summary: ISO: MHC class I protein binding transferred from human VCP. MHC class I heavy chains are model ERAD substrates (US11-dependent dislocation) that p97 engages during retrotranslocation. Reason: The binding reflects substrate engagement in an experimental ERAD system rather than a specific MHC-I binding function; it over-specifies one of many ERAD clients. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: MGI:MGI:99919 SOURCE WEAK OR INFERRED MHC class I heavy chains are model ERAD substrates; substrate engagement is recorded as a specific binding function. Supporting Evidence: PMID:12847084 These data suggest that p97 can specifically interact with substrate that has not been modified by a polyubiquitin chain, and that binding of p97 is an early step after emergence of the polypeptide from the ER.
GO:0042802 identical protein binding	IDA PMID:7806566 Isolation and characterization of the principal ATPase assoc...	KEEP AS NON CORE	Summary: IDA: Vcp self-associates into a stable homohexamer (two stacked AAA rings), shown for the native rat TER ATPase and for recombinant rat p97. Reason: Homo-oligomerisation is well supported but is a structural prerequisite of the ATPase rather than its function, so this binding term is kept as non-core. Supporting Evidence: PMID:7806566 The native TER ATPase has been characterized as a hexamer of six 100-kD subunits by gel filtration. The protein catalyzes the hydrolysis of [gamma 32-P]ATP PMID:18332143 p97 has a stable homohexameric structure with the D1 and the D2 domains forming two stacked rings around a central pore file:rat/Vcp/Vcp-uniprot.txt Homohexamer. Forms a ring-shaped particle of 12.5 nm diameter, that displays 6-fold radial symmetry
GO:0042802 identical protein binding	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: IEA: Vcp self-associates into a stable homohexamer (two stacked AAA rings), shown for the native rat TER ATPase and for recombinant rat p97. Reason: Homo-oligomerisation is well supported but is a structural prerequisite of the ATPase rather than its function, so this binding term is kept as non-core. Supporting Evidence: PMID:7806566 The native TER ATPase has been characterized as a hexamer of six 100-kD subunits by gel filtration. The protein catalyzes the hydrolysis of [gamma 32-P]ATP PMID:18332143 p97 has a stable homohexameric structure with the D1 and the D2 domains forming two stacked rings around a central pore file:rat/Vcp/Vcp-uniprot.txt Homohexamer. Forms a ring-shaped particle of 12.5 nm diameter, that displays 6-fold radial symmetry
GO:0042802 identical protein binding	IPI PMID:18332143 Analysis of nucleotide binding to P97 reveals the properties...	KEEP AS NON CORE	Summary: IPI: Vcp self-associates into a stable homohexamer (two stacked AAA rings), shown for the native rat TER ATPase and for recombinant rat p97. Reason: Homo-oligomerisation is well supported but is a structural prerequisite of the ATPase rather than its function, so this binding term is kept as non-core. Supporting Evidence: PMID:7806566 The native TER ATPase has been characterized as a hexamer of six 100-kD subunits by gel filtration. The protein catalyzes the hydrolysis of [gamma 32-P]ATP PMID:18332143 p97 has a stable homohexameric structure with the D1 and the D2 domains forming two stacked rings around a central pore file:rat/Vcp/Vcp-uniprot.txt Homohexamer. Forms a ring-shaped particle of 12.5 nm diameter, that displays 6-fold radial symmetry
GO:0042802 identical protein binding	IPI PMID:7806566 Isolation and characterization of the principal ATPase assoc...	KEEP AS NON CORE	Summary: IPI: Vcp self-associates into a stable homohexamer (two stacked AAA rings), shown for the native rat TER ATPase and for recombinant rat p97. Reason: Homo-oligomerisation is well supported but is a structural prerequisite of the ATPase rather than its function, so this binding term is kept as non-core. Supporting Evidence: PMID:7806566 The native TER ATPase has been characterized as a hexamer of six 100-kD subunits by gel filtration. The protein catalyzes the hydrolysis of [gamma 32-P]ATP PMID:18332143 p97 has a stable homohexameric structure with the D1 and the D2 domains forming two stacked rings around a central pore file:rat/Vcp/Vcp-uniprot.txt Homohexamer. Forms a ring-shaped particle of 12.5 nm diameter, that displays 6-fold radial symmetry
GO:0042802 identical protein binding	ISO GO_REF:0000121	KEEP AS NON CORE	Summary: ISO: Vcp self-associates into a stable homohexamer (two stacked AAA rings), shown for the native rat TER ATPase and for recombinant rat p97. Reason: Homo-oligomerisation is well supported but is a structural prerequisite of the ATPase rather than its function, so this binding term is kept as non-core. Supporting Evidence: PMID:7806566 The native TER ATPase has been characterized as a hexamer of six 100-kD subunits by gel filtration. The protein catalyzes the hydrolysis of [gamma 32-P]ATP PMID:18332143 p97 has a stable homohexameric structure with the D1 and the D2 domains forming two stacked rings around a central pore file:rat/Vcp/Vcp-uniprot.txt Homohexamer. Forms a ring-shaped particle of 12.5 nm diameter, that displays 6-fold radial symmetry
GO:0042802 identical protein binding	ISO GO_REF:0000121	KEEP AS NON CORE	Summary: ISO: Vcp self-associates into a stable homohexamer (two stacked AAA rings), shown for the native rat TER ATPase and for recombinant rat p97. Reason: Homo-oligomerisation is well supported but is a structural prerequisite of the ATPase rather than its function, so this binding term is kept as non-core. Supporting Evidence: PMID:7806566 The native TER ATPase has been characterized as a hexamer of six 100-kD subunits by gel filtration. The protein catalyzes the hydrolysis of [gamma 32-P]ATP PMID:18332143 p97 has a stable homohexameric structure with the D1 and the D2 domains forming two stacked rings around a central pore file:rat/Vcp/Vcp-uniprot.txt Homohexamer. Forms a ring-shaped particle of 12.5 nm diameter, that displays 6-fold radial symmetry
GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process	IBA GO_REF:0000033	ACCEPT	Summary: IBA: Vcp targets ubiquitinated substrates for proteasomal degradation (ERAD substrates, IkappaBalpha, HIF1alpha and others). Reason: Core process supported by PAINT placement, ortholog experimental data and the rat ERAD work; Vcp extracts and delivers ubiquitinated substrates to the proteasome. Supporting Evidence: PMID:11483959 VCP associates with ubiquitinated proteins through the direct binding of its amino-terminal domain to the multi-ubiquitin chains of substrates. file:rat/Vcp/Vcp-uniprot.txt The ternary complex containing UFD1, VCP and NPLOC4 binds ubiquitinated proteins and is necessary for the export of misfolded proteins from the ER to the cytoplasm, where they are degraded by the proteasome PMID:16103111 Our results indicate that the p97-Ufd1-Npl4 complex is required for the processing of ubiquitinated IP 3 Rs and, thus, that this complex plays a key role in ERAD in mammalian cells.
GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process	IEA GO_REF:0000120	ACCEPT	Summary: IEA: Vcp targets ubiquitinated substrates for proteasomal degradation (ERAD substrates, IkappaBalpha, HIF1alpha and others). Reason: Core process supported by PAINT placement, ortholog experimental data and the rat ERAD work; Vcp extracts and delivers ubiquitinated substrates to the proteasome. Supporting Evidence: PMID:11483959 VCP associates with ubiquitinated proteins through the direct binding of its amino-terminal domain to the multi-ubiquitin chains of substrates. file:rat/Vcp/Vcp-uniprot.txt The ternary complex containing UFD1, VCP and NPLOC4 binds ubiquitinated proteins and is necessary for the export of misfolded proteins from the ER to the cytoplasm, where they are degraded by the proteasome PMID:16103111 Our results indicate that the p97-Ufd1-Npl4 complex is required for the processing of ubiquitinated IP 3 Rs and, thus, that this complex plays a key role in ERAD in mammalian cells.
GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process	ISO GO_REF:0000121	ACCEPT	Summary: ISO: Vcp targets ubiquitinated substrates for proteasomal degradation (ERAD substrates, IkappaBalpha, HIF1alpha and others). Reason: Core process supported by PAINT placement, ortholog experimental data and the rat ERAD work; Vcp extracts and delivers ubiquitinated substrates to the proteasome. Supporting Evidence: PMID:11483959 VCP associates with ubiquitinated proteins through the direct binding of its amino-terminal domain to the multi-ubiquitin chains of substrates. file:rat/Vcp/Vcp-uniprot.txt The ternary complex containing UFD1, VCP and NPLOC4 binds ubiquitinated proteins and is necessary for the export of misfolded proteins from the ER to the cytoplasm, where they are degraded by the proteasome PMID:16103111 Our results indicate that the p97-Ufd1-Npl4 complex is required for the processing of ubiquitinated IP 3 Rs and, thus, that this complex plays a key role in ERAD in mammalian cells.
GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process	ISO GO_REF:0000121	ACCEPT	Summary: ISO: Vcp targets ubiquitinated substrates for proteasomal degradation (ERAD substrates, IkappaBalpha, HIF1alpha and others). Reason: Core process supported by PAINT placement, ortholog experimental data and the rat ERAD work; Vcp extracts and delivers ubiquitinated substrates to the proteasome. Supporting Evidence: PMID:11483959 VCP associates with ubiquitinated proteins through the direct binding of its amino-terminal domain to the multi-ubiquitin chains of substrates. file:rat/Vcp/Vcp-uniprot.txt The ternary complex containing UFD1, VCP and NPLOC4 binds ubiquitinated proteins and is necessary for the export of misfolded proteins from the ER to the cytoplasm, where they are degraded by the proteasome PMID:16103111 Our results indicate that the p97-Ufd1-Npl4 complex is required for the processing of ubiquitinated IP 3 Rs and, thus, that this complex plays a key role in ERAD in mammalian cells.
GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process	ISS GO_REF:0000024	ACCEPT	Summary: ISS: Vcp targets ubiquitinated substrates for proteasomal degradation (ERAD substrates, IkappaBalpha, HIF1alpha and others). Reason: Core process supported by PAINT placement, ortholog experimental data and the rat ERAD work; Vcp extracts and delivers ubiquitinated substrates to the proteasome. Supporting Evidence: PMID:11483959 VCP associates with ubiquitinated proteins through the direct binding of its amino-terminal domain to the multi-ubiquitin chains of substrates. file:rat/Vcp/Vcp-uniprot.txt The ternary complex containing UFD1, VCP and NPLOC4 binds ubiquitinated proteins and is necessary for the export of misfolded proteins from the ER to the cytoplasm, where they are degraded by the proteasome PMID:16103111 Our results indicate that the p97-Ufd1-Npl4 complex is required for the processing of ubiquitinated IP 3 Rs and, thus, that this complex plays a key role in ERAD in mammalian cells.
GO:0043335 protein unfolding	IEA GO_REF:0000107	ACCEPT	Summary: IEA: Protein unfolding (ISO/IEA from human VCP): the ATPase threads and unfolds ubiquitinated substrates to extract them from membranes and complexes. Reason: Mechanistically this is what the Vcp ATPase does with its substrates; the ATP-dependent movement of the polypeptide chain into the cytosol in ERAD reflects the same activity. Supporting Evidence: PMID:12847084 ATP hydrolysis by the D2 domain, and probably also the D1 domain, are needed to move the polypeptide chain into the cytosol. PMID:12847084 Thus, both ubiquitin binding and ATP hydrolysis by p97–Ufd1–Npl4 complex are required for the release of polyubiquitinated substrates into the cytosol.
GO:0043335 protein unfolding	ISO GO_REF:0000121	ACCEPT	Summary: ISO: Protein unfolding (ISO/IEA from human VCP): the ATPase threads and unfolds ubiquitinated substrates to extract them from membranes and complexes. Reason: Mechanistically this is what the Vcp ATPase does with its substrates; the ATP-dependent movement of the polypeptide chain into the cytosol in ERAD reflects the same activity. Supporting Evidence: PMID:12847084 ATP hydrolysis by the D2 domain, and probably also the D1 domain, are needed to move the polypeptide chain into the cytosol. PMID:12847084 Thus, both ubiquitin binding and ATP hydrolysis by p97–Ufd1–Npl4 complex are required for the release of polyubiquitinated substrates into the cytosol.
GO:0043531 ADP binding	IEA GO_REF:0000120	ACCEPT	Summary: IEA: ADP binding by rat p97 was quantified; ADP binds D1 with higher affinity than D2 and is prebound to D1 in purified protein. Reason: Direct measurement on recombinant rat p97 with Walker A mutants (IMP row). ADP occupancy of D1 is a defining mechanistic feature of the p97 ATPase cycle. Supporting Evidence: PMID:18332143 We report that adenosine 5'-O-(thiotriphosphate) (ATPgammaS) binds with similar affinity to D1 and D2, but ADP binds with higher affinity to D1 than D2 PMID:18332143 heat denaturation measurements of the amount of ADP prebound to wild type and Walker A mutants show that ADP is prebound to D1.
GO:0043531 ADP binding	IMP PMID:18332143 Analysis of nucleotide binding to P97 reveals the properties...	ACCEPT	Summary: IMP: ADP binding by rat p97 was quantified; ADP binds D1 with higher affinity than D2 and is prebound to D1 in purified protein. Reason: Direct measurement on recombinant rat p97 with Walker A mutants (IMP row). ADP occupancy of D1 is a defining mechanistic feature of the p97 ATPase cycle. Supporting Evidence: PMID:18332143 We report that adenosine 5'-O-(thiotriphosphate) (ATPgammaS) binds with similar affinity to D1 and D2, but ADP binds with higher affinity to D1 than D2 PMID:18332143 heat denaturation measurements of the amount of ADP prebound to wild type and Walker A mutants show that ADP is prebound to D1.
GO:0043531 ADP binding	ISO GO_REF:0000121	ACCEPT	Summary: ISO: ADP binding by rat p97 was quantified; ADP binds D1 with higher affinity than D2 and is prebound to D1 in purified protein. Reason: Direct measurement on recombinant rat p97 with Walker A mutants (IMP row). ADP occupancy of D1 is a defining mechanistic feature of the p97 ATPase cycle. Supporting Evidence: PMID:18332143 We report that adenosine 5'-O-(thiotriphosphate) (ATPgammaS) binds with similar affinity to D1 and D2, but ADP binds with higher affinity to D1 than D2 PMID:18332143 heat denaturation measurements of the amount of ADP prebound to wild type and Walker A mutants show that ADP is prebound to D1.
GO:0044389 ubiquitin-like protein ligase binding	IEA GO_REF:0000107	TOO GENERAL	Summary: IEA: Ubiquitin-like protein ligase binding transferred from human VCP. Reason: The more specific child term GO:0031625 ubiquitin protein ligase binding is kept in this review and entails this parent. Supporting Evidence: PMID:16186510 Here, we report that p97 interacts directly with several ubiquitin ligases and facilitates their recruitment to Derlin-1.
GO:0044389 ubiquitin-like protein ligase binding	ISO GO_REF:0000121	TOO GENERAL	Summary: ISO: Ubiquitin-like protein ligase binding transferred from human VCP. Reason: The more specific child term GO:0031625 ubiquitin protein ligase binding is kept in this review and entails this parent. Supporting Evidence: PMID:16186510 Here, we report that p97 interacts directly with several ubiquitin ligases and facilitates their recruitment to Derlin-1.
GO:0044877 protein-containing complex binding	IPI PMID:10811609 A complex of mammalian ufd1 and npl4 links the AAA-ATPase, p...	KEEP AS NON CORE	Summary: IPI: IPI with Ufd1 and Npl4: in rat liver cytosol and with recombinant proteins, the Ufd1-Npl4 heterodimer binds p97 as a unit to form the ternary complex. Reason: The evidence supports binding of a preformed protein complex (Ufd1-Npl4) by p97. True, but the more informative statement is membership of GO:0034098 VCP-NPL4-UFD1 AAA ATPase complex (accepted), so this is kept as non-core. Supporting Evidence: PMID:10811609 Binding experiments with recombinant proteins revealed that Npl4 and Ufd1 form a binary complex on their own that can bind p97 to form a ternary complex.
GO:0045202 synapse	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA: Synapse (ISO/IEA from mouse SynGO data). Reason: Consistent with the rat glutamatergic synapse annotation (PMID:22105171). VCP is ubiquitous; synaptic presence is non-core. Supporting Evidence: PMID:22105171 Here, we show that neurofibromin and VCP interact and work together to control the density of dendritic spines.
GO:0045202 synapse	ISO GO_REF:0000121	KEEP AS NON CORE	Summary: ISO: Synapse (ISO/IEA from mouse SynGO data). Reason: Consistent with the rat glutamatergic synapse annotation (PMID:22105171). VCP is ubiquitous; synaptic presence is non-core. Supporting Evidence: PMID:22105171 Here, we show that neurofibromin and VCP interact and work together to control the density of dendritic spines.
GO:0045732 positive regulation of protein catabolic process	IEA GO_REF:0000107	MODIFY	Summary: IEA: Positive regulation of protein catabolic process (ISO/IEA from human VCP; HIF1alpha and multi-ubiquitin chain-targeting studies). Reason: The sources show VCP acting as a ubiquitin-chain targeting factor required for degradation of substrates, which is participation in proteasomal catabolism rather than its regulation; replace with GO:0043161 (already accepted). Proposed replacements: proteasome-mediated ubiquitin-dependent protein catabolic process Supporting Evidence: PMID:11483959 VCP associates with ubiquitinated proteins through the direct binding of its amino-terminal domain to the multi-ubiquitin chains of substrates. PMID:18775313 Depletion of p97 leads to accumulation of endogenous HIF1alpha and increased expression of a HIF1alpha target gene.
GO:0045732 positive regulation of protein catabolic process	ISO GO_REF:0000121	MODIFY	Summary: ISO: Positive regulation of protein catabolic process (ISO/IEA from human VCP; HIF1alpha and multi-ubiquitin chain-targeting studies). Reason: The sources show VCP acting as a ubiquitin-chain targeting factor required for degradation of substrates, which is participation in proteasomal catabolism rather than its regulation; replace with GO:0043161 (already accepted). Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: UniProtKB:P55072 SUPPORTS TRANSFER The donor evidence (PMID:11483959, PMID:18775313) is sound and transfers to rat, but shows participation in proteasomal degradation rather than its regulation. Proposed replacements: proteasome-mediated ubiquitin-dependent protein catabolic process Supporting Evidence: PMID:11483959 VCP associates with ubiquitinated proteins through the direct binding of its amino-terminal domain to the multi-ubiquitin chains of substrates. PMID:18775313 Depletion of p97 leads to accumulation of endogenous HIF1alpha and increased expression of a HIF1alpha target gene.
GO:0045879 negative regulation of smoothened signaling pathway	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA: Negative regulation of smoothened signaling (ISO/IEA). Source: Ter94/p97 processes Ci/Gli3 into repressor forms. Reason: p97 participates in partial proteasomal processing of Gli3 into its repressor; the signalling effect is a downstream consequence of that processing. Kept as non-core. Supporting Evidence: PMID:23747190 Here, we show that Ter94 ATPase and its mammalian counterpart, p97, are involved in processing Ci and Gli3 into Ci75 and Gli3(R), respectively.
GO:0045879 negative regulation of smoothened signaling pathway	ISO GO_REF:0000121	KEEP AS NON CORE	Summary: ISO: Negative regulation of smoothened signaling (ISO/IEA). Source: Ter94/p97 processes Ci/Gli3 into repressor forms. Reason: p97 participates in partial proteasomal processing of Gli3 into its repressor; the signalling effect is a downstream consequence of that processing. Kept as non-core. Supporting Evidence: PMID:23747190 Here, we show that Ter94 ATPase and its mammalian counterpart, p97, are involved in processing Ci and Gli3 into Ci75 and Gli3(R), respectively.
GO:0046034 ATP metabolic process	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: IEA: ATP metabolic process (ISO/IEA from human VCP). Reason: VCP hydrolyses ATP as an energy source for mechanical work; that is captured by ATP hydrolysis activity. Placing it in ATP metabolism, from fibroblast ATP-level phenotypes, over-annotates. Supporting Evidence: PMID:23498975 we show that VCP deficiency causes profound mitochondrial uncoupling leading to decreased mitochondrial membrane potential and increased mitochondrial oxygen consumption.
GO:0046034 ATP metabolic process	ISO GO_REF:0000121	MARK AS OVER ANNOTATED	Summary: ISO: ATP metabolic process (ISO/IEA from human VCP). Reason: VCP hydrolyses ATP as an energy source for mechanical work; that is captured by ATP hydrolysis activity. Placing it in ATP metabolism, from fibroblast ATP-level phenotypes, over-annotates. Propagation Review Root cause: SOURCE BAD Failure modes: ROLE CONFLATION SOURCE EVIDENCE WEAK Sources checked: MGI:MGI:99919 SOURCE BAD The donor annotation rests on a phenotype of VCP-deficient human fibroblasts (mitochondrial uncoupling, PMID:23498975), not on an activity of VCP; the transfer is faithful but the source over-reaches. Supporting Evidence: PMID:23498975 we show that VCP deficiency causes profound mitochondrial uncoupling leading to decreased mitochondrial membrane potential and increased mitochondrial oxygen consumption.
GO:0048471 perinuclear region of cytoplasm	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA: Perinuclear region of cytoplasm transferred from human VCP. Reason: VCP is diffusely cytosolic with perinuclear/ER enrichment; the term is not wrong but is a descriptive sub-location of cytoplasm, non-core. Supporting Evidence: file:rat/Vcp/Vcp-uniprot.txt Recruited to the cytoplasmic surface of the endoplasmic reticulum via interaction with AMFR/gp78.
GO:0048471 perinuclear region of cytoplasm	ISO GO_REF:0000121	KEEP AS NON CORE	Summary: ISO: Perinuclear region of cytoplasm transferred from human VCP. Reason: VCP is diffusely cytosolic with perinuclear/ER enrichment; the term is not wrong but is a descriptive sub-location of cytoplasm, non-core. Supporting Evidence: file:rat/Vcp/Vcp-uniprot.txt Recruited to the cytoplasmic surface of the endoplasmic reticulum via interaction with AMFR/gp78.
GO:0050807 regulation of synapse organization	IDA PMID:22105171 Valosin-containing protein and neurofibromin interact to reg...	KEEP AS NON CORE	Summary: IDA: Rat hippocampal neurons: VCP and neurofibromin interact and together regulate dendritic spine density; VCP knockdown impairs spinogenesis (IDA/IMP, SynGO). Reason: Experimental rat evidence (abstract only for us; the curator read the full text). The spine phenotype may be downstream of VCP's general proteostasis role, so it is kept as non-core rather than accepted as core. Supporting Evidence: PMID:22105171 Here, we show that neurofibromin and VCP interact and work together to control the density of dendritic spines. PMID:22105171 The data presented here demonstrate that there is a link between IBMPFD and NF1 and indicate a role for VCP in synapse formation.
GO:0050807 regulation of synapse organization	IMP PMID:22105171 Valosin-containing protein and neurofibromin interact to reg...	KEEP AS NON CORE	Summary: IMP: Rat hippocampal neurons: VCP and neurofibromin interact and together regulate dendritic spine density; VCP knockdown impairs spinogenesis (IDA/IMP, SynGO). Reason: Experimental rat evidence (abstract only for us; the curator read the full text). The spine phenotype may be downstream of VCP's general proteostasis role, so it is kept as non-core rather than accepted as core. Supporting Evidence: PMID:22105171 Here, we show that neurofibromin and VCP interact and work together to control the density of dendritic spines. PMID:22105171 The data presented here demonstrate that there is a link between IBMPFD and NF1 and indicate a role for VCP in synapse formation.
GO:0051228 mitotic spindle disassembly	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: IBA: Mitotic spindle disassembly (IBA; PAINT node seeded by yeast Cdc48 and placed at the ancestral node). Reason: The NPLOC4-UFD1-VCP complex regulates spindle disassembly at the end of mitosis (Xenopus/ortholog data cited by UniProt); rat Vcp sits inside the inheriting clade with no evidence of divergence. Kept as non-core. Supporting Evidence: file:rat/Vcp/Vcp-uniprot.txt The NPLOC4-UFD1-VCP complex regulates spindle disassembly at the end of mitosis and is necessary for the formation of a closed nuclear envelope.
GO:0061857 endoplasmic reticulum stress-induced pre-emptive quality control	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA: ER stress-induced pre-emptive quality control (ISS/ISO/IEA from human/mouse VCP): p97 with BAG6 degrades proteins rerouted from the translocon. Reason: Supported in hepatocytes for the ortholog; a specialised ER-stress branch of VCP-dependent degradation, kept as non-core. Supporting Evidence: PMID:26565908 Moreover, the cytosolic chaperone Bag6 and the AAA-ATPase p97 contribute to the degradation of ER pQC substrates. file:rat/Vcp/Vcp-uniprot.txt Involved in endoplasmic reticulum stress-induced pre-emptive quality control, a mechanism that selectively attenuates the translocation of newly synthesized proteins into the endoplasmic reticulum and reroutes them to the cytosol for proteasomal degradation.
GO:0061857 endoplasmic reticulum stress-induced pre-emptive quality control	ISO GO_REF:0000121	KEEP AS NON CORE	Summary: ISO: ER stress-induced pre-emptive quality control (ISS/ISO/IEA from human/mouse VCP): p97 with BAG6 degrades proteins rerouted from the translocon. Reason: Supported in hepatocytes for the ortholog; a specialised ER-stress branch of VCP-dependent degradation, kept as non-core. Supporting Evidence: PMID:26565908 Moreover, the cytosolic chaperone Bag6 and the AAA-ATPase p97 contribute to the degradation of ER pQC substrates. file:rat/Vcp/Vcp-uniprot.txt Involved in endoplasmic reticulum stress-induced pre-emptive quality control, a mechanism that selectively attenuates the translocation of newly synthesized proteins into the endoplasmic reticulum and reroutes them to the cytosol for proteasomal degradation.
GO:0061857 endoplasmic reticulum stress-induced pre-emptive quality control	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS: ER stress-induced pre-emptive quality control (ISS/ISO/IEA from human/mouse VCP): p97 with BAG6 degrades proteins rerouted from the translocon. Reason: Supported in hepatocytes for the ortholog; a specialised ER-stress branch of VCP-dependent degradation, kept as non-core. Supporting Evidence: PMID:26565908 Moreover, the cytosolic chaperone Bag6 and the AAA-ATPase p97 contribute to the degradation of ER pQC substrates. file:rat/Vcp/Vcp-uniprot.txt Involved in endoplasmic reticulum stress-induced pre-emptive quality control, a mechanism that selectively attenuates the translocation of newly synthesized proteins into the endoplasmic reticulum and reroutes them to the cytosol for proteasomal degradation.
GO:0070842 aggresome assembly	ISO GO_REF:0000121	KEEP AS NON CORE	Summary: ISO: Aggresome assembly (ISO, acts upstream of or within, from human VCP): p97-UBXN1 mediates aggresome formation. Reason: Supported in human cells; a peripheral aspect of VCP's handling of ubiquitylated aggregates. Supporting Evidence: PMID:33712450 We demonstrate that p97 mediates aggresome formation and clearance, and identify a novel role for the adaptor UBXN1 in the process of aggresome formation.
GO:0071218 cellular response to misfolded protein	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA: Cellular response to misfolded protein (ISO/IEA from human VCP; COX-2 degradation via Derlin-1/Cav-1). Reason: VCP degrades misfolded proteins as part of ERAD; this response-level term is consistent but less informative than the accepted ERAD and quality-control terms, so kept as non-core. Supporting Evidence: PMID:24089527 Moreover, suppression of p97 increased the ubiquitination of COX-2 and up-regulated COX-2 but not COX-1.
GO:0071218 cellular response to misfolded protein	ISO GO_REF:0000121	KEEP AS NON CORE	Summary: ISO: Cellular response to misfolded protein (ISO/IEA from human VCP; COX-2 degradation via Derlin-1/Cav-1). Reason: VCP degrades misfolded proteins as part of ERAD; this response-level term is consistent but less informative than the accepted ERAD and quality-control terms, so kept as non-core. Supporting Evidence: PMID:24089527 Moreover, suppression of p97 increased the ubiquitination of COX-2 and up-regulated COX-2 but not COX-1.
GO:0072389 flavin adenine dinucleotide catabolic process	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: IEA: Flavin adenine dinucleotide catabolic process (ISO/IEA from the human fibroblast study PMID:23498975). Reason: VCP has no FAD-catabolising activity; the annotation reflects a metabolic phenotype of VCP-deficient cells. Supporting Evidence: PMID:23498975 we show that VCP deficiency causes profound mitochondrial uncoupling leading to decreased mitochondrial membrane potential and increased mitochondrial oxygen consumption.
GO:0072389 flavin adenine dinucleotide catabolic process	ISO GO_REF:0000121	MARK AS OVER ANNOTATED	Summary: ISO: Flavin adenine dinucleotide catabolic process (ISO/IEA from the human fibroblast study PMID:23498975). Reason: VCP has no FAD-catabolising activity; the annotation reflects a metabolic phenotype of VCP-deficient cells. Propagation Review Root cause: SOURCE BAD Failure modes: ROLE CONFLATION SOURCE EVIDENCE WEAK Sources checked: UniProtKB:P55072 SOURCE BAD The donor annotation rests on a phenotype of VCP-deficient human fibroblasts (mitochondrial uncoupling, PMID:23498975), not on an activity of VCP; the transfer is faithful but the source over-reaches. Supporting Evidence: PMID:23498975 we show that VCP deficiency causes profound mitochondrial uncoupling leading to decreased mitochondrial membrane potential and increased mitochondrial oxygen consumption.
GO:0090263 positive regulation of canonical Wnt signaling pathway	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA: Positive regulation of canonical Wnt signaling (ISO/IEA): VCP is involved in UBR5-dependent inactivation of the Groucho/TLE co-repressor. Reason: Supported in Drosophila and human cell lines; a downstream regulatory consequence of VCP's ubiquitin-dependent extraction function. Kept as non-core. Supporting Evidence: PMID:28689657 Inactivation of TLE by UBR5-dependent ubiquitylation also involves VCP/p97, an AAA ATPase regulating the folding of various cellular substrates including ubiquitylated chromatin proteins.
GO:0090263 positive regulation of canonical Wnt signaling pathway	ISO GO_REF:0000121	KEEP AS NON CORE	Summary: ISO: Positive regulation of canonical Wnt signaling (ISO/IEA): VCP is involved in UBR5-dependent inactivation of the Groucho/TLE co-repressor. Reason: Supported in Drosophila and human cell lines; a downstream regulatory consequence of VCP's ubiquitin-dependent extraction function. Kept as non-core. Supporting Evidence: PMID:28689657 Inactivation of TLE by UBR5-dependent ubiquitylation also involves VCP/p97, an AAA ATPase regulating the folding of various cellular substrates including ubiquitylated chromatin proteins.
GO:0097352 autophagosome maturation	IBA GO_REF:0000033	ACCEPT	Summary: IBA: Autophagosome maturation: VCP is required for maturation of ubiquitin-containing autophagosomes (human cells; ISS/ISO/IEA and PAINT IBA). Reason: Supported by ortholog experimental data and PAINT placement; the rat protein is near-identical. VCP acts on ubiquitinated cargo during autophagosome maturation. Supporting Evidence: PMID:20104022 We conclude that VCP is essential for maturation of ubiquitin-containing autophagosomes file:rat/Vcp/Vcp-uniprot.txt Essential for the maturation of ubiquitin-containing autophagosomes and the clearance of ubiquitinated protein by autophagy.
GO:0097352 autophagosome maturation	IEA GO_REF:0000107	ACCEPT	Summary: IEA: Autophagosome maturation: VCP is required for maturation of ubiquitin-containing autophagosomes (human cells; ISS/ISO/IEA and PAINT IBA). Reason: Supported by ortholog experimental data and PAINT placement; the rat protein is near-identical. VCP acts on ubiquitinated cargo during autophagosome maturation. Supporting Evidence: PMID:20104022 We conclude that VCP is essential for maturation of ubiquitin-containing autophagosomes file:rat/Vcp/Vcp-uniprot.txt Essential for the maturation of ubiquitin-containing autophagosomes and the clearance of ubiquitinated protein by autophagy.
GO:0097352 autophagosome maturation	ISO GO_REF:0000121	ACCEPT	Summary: ISO: Autophagosome maturation: VCP is required for maturation of ubiquitin-containing autophagosomes (human cells; ISS/ISO/IEA and PAINT IBA). Reason: Supported by ortholog experimental data and PAINT placement; the rat protein is near-identical. VCP acts on ubiquitinated cargo during autophagosome maturation. Supporting Evidence: PMID:20104022 We conclude that VCP is essential for maturation of ubiquitin-containing autophagosomes file:rat/Vcp/Vcp-uniprot.txt Essential for the maturation of ubiquitin-containing autophagosomes and the clearance of ubiquitinated protein by autophagy.
GO:0097352 autophagosome maturation	ISS GO_REF:0000024	ACCEPT	Summary: ISS: Autophagosome maturation: VCP is required for maturation of ubiquitin-containing autophagosomes (human cells; ISS/ISO/IEA and PAINT IBA). Reason: Supported by ortholog experimental data and PAINT placement; the rat protein is near-identical. VCP acts on ubiquitinated cargo during autophagosome maturation. Supporting Evidence: PMID:20104022 We conclude that VCP is essential for maturation of ubiquitin-containing autophagosomes file:rat/Vcp/Vcp-uniprot.txt Essential for the maturation of ubiquitin-containing autophagosomes and the clearance of ubiquitinated protein by autophagy.
GO:0098978 glutamatergic synapse	IDA PMID:22105171 Valosin-containing protein and neurofibromin interact to reg...	KEEP AS NON CORE	Summary: IDA: SynGO annotation from Wang et al. 2011: VCP acts with neurofibromin in rat hippocampal neurons to control dendritic spine density. Reason: Abstract-only access; the curator saw the full text. The synaptic role is real but specialised and peripheral to the general ubiquitin-dependent segregase function, so kept as non-core rather than removed. Supporting Evidence: PMID:22105171 Here, we show that neurofibromin and VCP interact and work together to control the density of dendritic spines. PMID:22105171 The data presented here demonstrate that there is a link between IBMPFD and NF1 and indicate a role for VCP in synapse formation.
GO:0098978 glutamatergic synapse	IMP PMID:22105171 Valosin-containing protein and neurofibromin interact to reg...	KEEP AS NON CORE	Summary: IMP: SynGO annotation from Wang et al. 2011: VCP acts with neurofibromin in rat hippocampal neurons to control dendritic spine density. Reason: Abstract-only access; the curator saw the full text. The synaptic role is real but specialised and peripheral to the general ubiquitin-dependent segregase function, so kept as non-core rather than removed. Supporting Evidence: PMID:22105171 Here, we show that neurofibromin and VCP interact and work together to control the density of dendritic spines. PMID:22105171 The data presented here demonstrate that there is a link between IBMPFD and NF1 and indicate a role for VCP in synapse formation.
GO:0106300 protein-DNA covalent cross-linking repair	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA: Protein-DNA covalent cross-linking repair (ISS/ISO/IEA from human VCP): with SPRTN, VCP acts in repair of DPCs during DNA synthesis. Reason: Supported for the ortholog; VCP unfolds/extracts cross-linked proteins for SPRTN. Non-core relative to ERAD. Supporting Evidence: file:rat/Vcp/Vcp-uniprot.txt Together with SPRTN metalloprotease, involved in the repair of covalent DNA-protein cross-links (DPCs) during DNA synthesis.
GO:0106300 protein-DNA covalent cross-linking repair	ISO GO_REF:0000121	KEEP AS NON CORE	Summary: ISO: Protein-DNA covalent cross-linking repair (ISS/ISO/IEA from human VCP): with SPRTN, VCP acts in repair of DPCs during DNA synthesis. Reason: Supported for the ortholog; VCP unfolds/extracts cross-linked proteins for SPRTN. Non-core relative to ERAD. Supporting Evidence: file:rat/Vcp/Vcp-uniprot.txt Together with SPRTN metalloprotease, involved in the repair of covalent DNA-protein cross-links (DPCs) during DNA synthesis.
GO:0106300 protein-DNA covalent cross-linking repair	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS: Protein-DNA covalent cross-linking repair (ISS/ISO/IEA from human VCP): with SPRTN, VCP acts in repair of DPCs during DNA synthesis. Reason: Supported for the ortholog; VCP unfolds/extracts cross-linked proteins for SPRTN. Non-core relative to ERAD. Supporting Evidence: file:rat/Vcp/Vcp-uniprot.txt Together with SPRTN metalloprotease, involved in the repair of covalent DNA-protein cross-links (DPCs) during DNA synthesis.
GO:0120186 negative regulation of protein localization to chromatin	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA: Negative regulation of protein localization to chromatin (ISO/IEA from human VCP): p97 removes trapped PARP1 from chromatin. Reason: This term captures VCP's chromatin-extraction (segregase) activity; supported in human cells. Non-core relative to ERAD. Supporting Evidence: PMID:35013556 events that promote recruitment of p97 and removal of trapped PARP1 from chromatin file:rat/Vcp/Vcp-uniprot.txt Mediates extraction of PARP1 trapped to chromatin: recognizes and binds ubiquitinated PARP1 and promotes its removal
GO:0120186 negative regulation of protein localization to chromatin	ISO GO_REF:0000121	KEEP AS NON CORE	Summary: ISO: Negative regulation of protein localization to chromatin (ISO/IEA from human VCP): p97 removes trapped PARP1 from chromatin. Reason: This term captures VCP's chromatin-extraction (segregase) activity; supported in human cells. Non-core relative to ERAD. Supporting Evidence: PMID:35013556 events that promote recruitment of p97 and removal of trapped PARP1 from chromatin file:rat/Vcp/Vcp-uniprot.txt Mediates extraction of PARP1 trapped to chromatin: recognizes and binds ubiquitinated PARP1 and promotes its removal
GO:0140036 ubiquitin-modified protein reader activity	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA: Ubiquitin-modified protein reader activity transferred from human VCP (papers on K11/K48 chains, BIK, PARP1). Reason: VCP recognises ubiquitinated clients, mostly through cofactors, and this term overlaps with the accepted polyubiquitin binding terms. Kept as non-core: the reader role is secondary to the ATP-driven extraction activity. Supporting Evidence: file:rat/Vcp/Vcp-uniprot.txt Mediates extraction of PARP1 trapped to chromatin: recognizes and binds ubiquitinated PARP1 and promotes its removal PMID:12847084 Together, these data suggest that both p97 and Ufd1 can bind polyubiquitin chains.
GO:0140036 ubiquitin-modified protein reader activity	ISO GO_REF:0000121	KEEP AS NON CORE	Summary: ISO: Ubiquitin-modified protein reader activity transferred from human VCP (papers on K11/K48 chains, BIK, PARP1). Reason: VCP recognises ubiquitinated clients, mostly through cofactors, and this term overlaps with the accepted polyubiquitin binding terms. Kept as non-core: the reader role is secondary to the ATP-driven extraction activity. Supporting Evidence: file:rat/Vcp/Vcp-uniprot.txt Mediates extraction of PARP1 trapped to chromatin: recognizes and binds ubiquitinated PARP1 and promotes its removal PMID:12847084 Together, these data suggest that both p97 and Ufd1 can bind polyubiquitin chains.
GO:0140455 cytoplasm protein quality control	IEA GO_REF:0000107	ACCEPT	Summary: IEA: Cytoplasm protein quality control (ISO/IEA from human VCP; K11/K48 branched chain study). Reason: VCP is a central effector of cytosolic protein quality control, processing ubiquitinated misfolded and aggregation-prone proteins for proteasomal degradation. Supporting Evidence: PMID:11483959 VCP associates with ubiquitinated proteins through the direct binding of its amino-terminal domain to the multi-ubiquitin chains of substrates. PMID:33712450 We demonstrate that p97 mediates aggresome formation and clearance, and identify a novel role for the adaptor UBXN1 in the process of aggresome formation.
GO:0140455 cytoplasm protein quality control	ISO GO_REF:0000121	ACCEPT	Summary: ISO: Cytoplasm protein quality control (ISO/IEA from human VCP; K11/K48 branched chain study). Reason: VCP is a central effector of cytosolic protein quality control, processing ubiquitinated misfolded and aggregation-prone proteins for proteasomal degradation. Supporting Evidence: PMID:11483959 VCP associates with ubiquitinated proteins through the direct binding of its amino-terminal domain to the multi-ubiquitin chains of substrates. PMID:33712450 We demonstrate that p97 mediates aggresome formation and clearance, and identify a novel role for the adaptor UBXN1 in the process of aggresome formation.
GO:0140535 intracellular protein-containing complex	IEA GO_REF:0000107	MODIFY	Summary: IEA: Intracellular protein-containing complex (ISO/IEA). Correct but uninformative; the specific Vcp complexes are known. Reason: Replace with the supported specific complexes already carried by Vcp (VCP-NPL4-UFD1 and VCP-NSFL1C). Proposed replacements: VCP-NPL4-UFD1 AAA ATPase complex VCP-NSFL1C complex Supporting Evidence: PMID:10811609 Cytosolic p97 therefore comprises at least two alternative complexes: p97/p47 and p97/Ufd1/Npl4.
GO:0140535 intracellular protein-containing complex	ISO GO_REF:0000121	MODIFY	Summary: ISO: Intracellular protein-containing complex (ISO/IEA). Correct but uninformative; the specific Vcp complexes are known. Reason: Replace with the supported specific complexes already carried by Vcp (VCP-NPL4-UFD1 and VCP-NSFL1C). Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P55072 SUPPORTS TRANSFER The donor complex membership transfers to rat; the term is less specific than the known VCP complexes. Proposed replacements: VCP-NPL4-UFD1 AAA ATPase complex VCP-NSFL1C complex Supporting Evidence: PMID:10811609 Cytosolic p97 therefore comprises at least two alternative complexes: p97/p47 and p97/Ufd1/Npl4.
GO:1901224 positive regulation of non-canonical NF-kappaB signal transduction	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA: Positive regulation of non-canonical NF-kappaB signaling (ISO/IEA): VCP processes TRIM55-ubiquitinated p100 to p52. Reason: VCP performs p100 processing, which promotes non-canonical NF-kappaB signalling; supported in mouse B cells. Kept as non-core. Supporting Evidence: PMID:37816088 Mechanistically, the ubiquitination of p100 mediated by TRIM55 was crucial for p100 processing by VCP, an ATPase that mediates ubiquitin-dependent protein degradation by the proteasome.
GO:1901224 positive regulation of non-canonical NF-kappaB signal transduction	ISO GO_REF:0000121	KEEP AS NON CORE	Summary: ISO: Positive regulation of non-canonical NF-kappaB signaling (ISO/IEA): VCP processes TRIM55-ubiquitinated p100 to p52. Reason: VCP performs p100 processing, which promotes non-canonical NF-kappaB signalling; supported in mouse B cells. Kept as non-core. Supporting Evidence: PMID:37816088 Mechanistically, the ubiquitination of p100 mediated by TRIM55 was crucial for p100 processing by VCP, an ATPase that mediates ubiquitin-dependent protein degradation by the proteasome.
GO:1903006 positive regulation of protein K63-linked deubiquitination	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA: Positive regulation of protein K63-linked deubiquitination (ISO/IEA): VCP activates wild-type ataxin-3 in vitro. Reason: Single in vitro study; consistent with the kept deubiquitinase activator activity, non-core. Supporting Evidence: PMID:22970133 VCP/p97 was shown to be an activator specifically of wild-type ataxin-3, exhibiting no effect on expanded ataxin-3
GO:1903006 positive regulation of protein K63-linked deubiquitination	ISO GO_REF:0000121	KEEP AS NON CORE	Summary: ISO: Positive regulation of protein K63-linked deubiquitination (ISO/IEA): VCP activates wild-type ataxin-3 in vitro. Reason: Single in vitro study; consistent with the kept deubiquitinase activator activity, non-core. Supporting Evidence: PMID:22970133 VCP/p97 was shown to be an activator specifically of wild-type ataxin-3, exhibiting no effect on expanded ataxin-3
GO:1903715 regulation of aerobic respiration	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: IEA: Regulation of aerobic respiration (ISO/IEA from the same human fibroblast study). Reason: Increased oxygen consumption in VCP-deficient cells is an indirect phenotype (uncoupling), not a regulatory function of VCP. Supporting Evidence: PMID:23498975 we show that VCP deficiency causes profound mitochondrial uncoupling leading to decreased mitochondrial membrane potential and increased mitochondrial oxygen consumption.
GO:1903715 regulation of aerobic respiration	ISO GO_REF:0000121	MARK AS OVER ANNOTATED	Summary: ISO: Regulation of aerobic respiration (ISO/IEA from the same human fibroblast study). Reason: Increased oxygen consumption in VCP-deficient cells is an indirect phenotype (uncoupling), not a regulatory function of VCP. Propagation Review Root cause: SOURCE BAD Failure modes: ROLE CONFLATION SOURCE EVIDENCE WEAK Sources checked: UniProtKB:P55072 SOURCE BAD The donor annotation rests on a phenotype of VCP-deficient human fibroblasts (mitochondrial uncoupling, PMID:23498975), not on an activity of VCP; the transfer is faithful but the source over-reaches. Supporting Evidence: PMID:23498975 we show that VCP deficiency causes profound mitochondrial uncoupling leading to decreased mitochondrial membrane potential and increased mitochondrial oxygen consumption.
GO:1903843 cellular response to arsenite ion	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: IEA: Cellular response to arsenite ion (ISS/ISO/IEA from the human ZFAND1 study). Reason: Arsenite is the experimental trigger for stress granules; VCP's contribution is granule clearance (GO:0035617), not a specific response to arsenite. Supporting Evidence: PMID:29804830 ZFAND1 interacts with two key factors of protein degradation, the 26S proteasome and the ubiquitin-selective segregase p97, and recruits them to arsenite-induced SGs.
GO:1903843 cellular response to arsenite ion	ISO GO_REF:0000121	MARK AS OVER ANNOTATED	Summary: ISO: Cellular response to arsenite ion (ISS/ISO/IEA from the human ZFAND1 study). Reason: Arsenite is the experimental trigger for stress granules; VCP's contribution is granule clearance (GO:0035617), not a specific response to arsenite. Propagation Review Root cause: SOURCE BAD Failure modes: ROLE CONFLATION Sources checked: UniProtKB:P55072 SOURCE BAD The donor study (PMID:29804830) uses arsenite to induce stress granules; VCP's role is clearance, not an arsenite response. Supporting Evidence: PMID:29804830 ZFAND1 interacts with two key factors of protein degradation, the 26S proteasome and the ubiquitin-selective segregase p97, and recruits them to arsenite-induced SGs.
GO:1903843 cellular response to arsenite ion	ISS GO_REF:0000024	MARK AS OVER ANNOTATED	Summary: ISS: Cellular response to arsenite ion (ISS/ISO/IEA from the human ZFAND1 study). Reason: Arsenite is the experimental trigger for stress granules; VCP's contribution is granule clearance (GO:0035617), not a specific response to arsenite. Supporting Evidence: PMID:29804830 ZFAND1 interacts with two key factors of protein degradation, the 26S proteasome and the ubiquitin-selective segregase p97, and recruits them to arsenite-induced SGs.
GO:1903862 positive regulation of oxidative phosphorylation	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: IEA: Positive regulation of oxidative phosphorylation (ISO/IEA from the same human fibroblast study). Reason: Indirect phenotype of VCP deficiency; VCP has no shown role in regulating OXPHOS. Supporting Evidence: PMID:23498975 we show that VCP deficiency causes profound mitochondrial uncoupling leading to decreased mitochondrial membrane potential and increased mitochondrial oxygen consumption.
GO:1903862 positive regulation of oxidative phosphorylation	ISO GO_REF:0000121	MARK AS OVER ANNOTATED	Summary: ISO: Positive regulation of oxidative phosphorylation (ISO/IEA from the same human fibroblast study). Reason: Indirect phenotype of VCP deficiency; VCP has no shown role in regulating OXPHOS. Propagation Review Root cause: SOURCE BAD Failure modes: ROLE CONFLATION SOURCE EVIDENCE WEAK Sources checked: UniProtKB:P55072 SOURCE BAD The donor annotation rests on a phenotype of VCP-deficient human fibroblasts (mitochondrial uncoupling, PMID:23498975), not on an activity of VCP; the transfer is faithful but the source over-reaches. Supporting Evidence: PMID:23498975 we show that VCP deficiency causes profound mitochondrial uncoupling leading to decreased mitochondrial membrane potential and increased mitochondrial oxygen consumption.
GO:1904288 BAT3 complex binding	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA: BAT3 complex binding transferred from human/mouse VCP: the BAG6-UBL4A-TRC35 holdase acts with p97 in ERAD. Reason: Interaction with the BAG6 holdase complex downstream of p97-mediated retrotranslocation is documented; auxiliary to the core function. Supporting Evidence: PMID:21636303 Endoplasmic reticulum-associated degradation (ERAD) employs membrane-bound ubiquitin ligases and the translocation-driving ATPase p97 to retrotranslocate misfolded proteins for proteasomal degradation. file:rat/Vcp/Vcp-uniprot.txt Interacts with BAG6 (By similarity).
GO:1904288 BAT3 complex binding	ISO GO_REF:0000121	KEEP AS NON CORE	Summary: ISO: BAT3 complex binding transferred from human/mouse VCP: the BAG6-UBL4A-TRC35 holdase acts with p97 in ERAD. Reason: Interaction with the BAG6 holdase complex downstream of p97-mediated retrotranslocation is documented; auxiliary to the core function. Supporting Evidence: PMID:21636303 Endoplasmic reticulum-associated degradation (ERAD) employs membrane-bound ubiquitin ligases and the translocation-driving ATPase p97 to retrotranslocate misfolded proteins for proteasomal degradation. file:rat/Vcp/Vcp-uniprot.txt Interacts with BAG6 (By similarity).
GO:1904949 ATPase complex	IEA GO_REF:0000120	MODIFY	Summary: IEA: ATPase complex (ISO/IEA). Correct in essence - Vcp complexes are ATPase complexes - but the specific complexes are known. Reason: The supported specific complexes are GO:0034098 VCP-NPL4-UFD1 AAA ATPase complex and GO:1990730 VCP-NSFL1C complex, both already carried by Vcp; they are not classified under GO:1904949 in the ontology, so the replacement is by MODIFY rather than TOO_GENERAL. Proposed replacements: VCP-NPL4-UFD1 AAA ATPase complex VCP-NSFL1C complex Supporting Evidence: PMID:10811609 Cytosolic p97 therefore comprises at least two alternative complexes: p97/p47 and p97/Ufd1/Npl4.
GO:1904949 ATPase complex	ISO GO_REF:0000121	MODIFY	Summary: ISO: ATPase complex (ISO/IEA). Correct in essence - Vcp complexes are ATPase complexes - but the specific complexes are known. Reason: The supported specific complexes are GO:0034098 VCP-NPL4-UFD1 AAA ATPase complex and GO:1990730 VCP-NSFL1C complex, both already carried by Vcp; they are not classified under GO:1904949 in the ontology, so the replacement is by MODIFY rather than TOO_GENERAL. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: MGI:MGI:99919 SUPPORTS TRANSFER The donor complex membership transfers to rat; the term is less specific than the known VCP complexes. Proposed replacements: VCP-NPL4-UFD1 AAA ATPase complex VCP-NSFL1C complex Supporting Evidence: PMID:10811609 Cytosolic p97 therefore comprises at least two alternative complexes: p97/p47 and p97/Ufd1/Npl4.
GO:1904949 ATPase complex	ISO GO_REF:0000121	MODIFY	Summary: ISO: ATPase complex (ISO/IEA). Correct in essence - Vcp complexes are ATPase complexes - but the specific complexes are known. Reason: The supported specific complexes are GO:0034098 VCP-NPL4-UFD1 AAA ATPase complex and GO:1990730 VCP-NSFL1C complex, both already carried by Vcp; they are not classified under GO:1904949 in the ontology, so the replacement is by MODIFY rather than TOO_GENERAL. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:P55072 SUPPORTS TRANSFER The donor complex membership transfers to rat; the term is less specific than the known VCP complexes. Proposed replacements: VCP-NPL4-UFD1 AAA ATPase complex VCP-NSFL1C complex Supporting Evidence: PMID:10811609 Cytosolic p97 therefore comprises at least two alternative complexes: p97/p47 and p97/Ufd1/Npl4.
GO:1905634 regulation of protein localization to chromatin	IEA GO_REF:0000107	TOO GENERAL	Summary: IEA: Regulation of protein localization to chromatin (ISS from human and Xenopus p97). True, but entailed by the kept negative-regulation child term. Reason: GO:0120186 negative regulation of protein localization to chromatin is kept and is a descendant of this term; VCP removes, rather than loads, proteins on chromatin. Supporting Evidence: PMID:22120668 The ATPase activity of VCP promotes the release of the Polycomb protein L3MBTL1 from chromatin file:rat/Vcp/Vcp-uniprot.txt Mediates extraction of PARP1 trapped to chromatin: recognizes and binds ubiquitinated PARP1 and promotes its removal
GO:1905634 regulation of protein localization to chromatin	ISO GO_REF:0000121	TOO GENERAL	Summary: ISO: Regulation of protein localization to chromatin (ISS from human and Xenopus p97). True, but entailed by the kept negative-regulation child term. Reason: GO:0120186 negative regulation of protein localization to chromatin is kept and is a descendant of this term; VCP removes, rather than loads, proteins on chromatin. Supporting Evidence: PMID:22120668 The ATPase activity of VCP promotes the release of the Polycomb protein L3MBTL1 from chromatin file:rat/Vcp/Vcp-uniprot.txt Mediates extraction of PARP1 trapped to chromatin: recognizes and binds ubiquitinated PARP1 and promotes its removal
GO:1905634 regulation of protein localization to chromatin	ISS GO_REF:0000024	TOO GENERAL	Summary: ISS: Regulation of protein localization to chromatin (ISS from human and Xenopus p97). True, but entailed by the kept negative-regulation child term. Reason: GO:0120186 negative regulation of protein localization to chromatin is kept and is a descendant of this term; VCP removes, rather than loads, proteins on chromatin. Supporting Evidence: PMID:22120668 The ATPase activity of VCP promotes the release of the Polycomb protein L3MBTL1 from chromatin file:rat/Vcp/Vcp-uniprot.txt Mediates extraction of PARP1 trapped to chromatin: recognizes and binds ubiquitinated PARP1 and promotes its removal
GO:1905634 regulation of protein localization to chromatin	ISS GO_REF:0000024	TOO GENERAL	Summary: ISS: Regulation of protein localization to chromatin (ISS from human and Xenopus p97). True, but entailed by the kept negative-regulation child term. Reason: GO:0120186 negative regulation of protein localization to chromatin is kept and is a descendant of this term; VCP removes, rather than loads, proteins on chromatin. Supporting Evidence: PMID:22120668 The ATPase activity of VCP promotes the release of the Polycomb protein L3MBTL1 from chromatin file:rat/Vcp/Vcp-uniprot.txt Mediates extraction of PARP1 trapped to chromatin: recognizes and binds ubiquitinated PARP1 and promotes its removal
GO:1990381 ubiquitin-specific protease binding	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: IEA: Ubiquitin-specific protease binding transferred from human VCP (YOD1, ATXN3, USP25). Reason: VCP binds several deubiquitinases that trim chains on its substrates; real but auxiliary to the ATPase function. Supporting Evidence: file:rat/Vcp/Vcp-uniprot.txt Interacts with UBE4B and YOD1. PMID:22970133 VCP/p97 was shown to be an activator specifically of wild-type ataxin-3, exhibiting no effect on expanded ataxin-3
GO:1990381 ubiquitin-specific protease binding	ISO GO_REF:0000121	KEEP AS NON CORE	Summary: ISO: Ubiquitin-specific protease binding transferred from human VCP (YOD1, ATXN3, USP25). Reason: VCP binds several deubiquitinases that trim chains on its substrates; real but auxiliary to the ATPase function. Supporting Evidence: file:rat/Vcp/Vcp-uniprot.txt Interacts with UBE4B and YOD1. PMID:22970133 VCP/p97 was shown to be an activator specifically of wild-type ataxin-3, exhibiting no effect on expanded ataxin-3
GO:1990381 ubiquitin-specific protease binding	ISO GO_REF:0000121	KEEP AS NON CORE	Summary: ISO: Ubiquitin-specific protease binding transferred from human VCP (YOD1, ATXN3, USP25). Reason: VCP binds several deubiquitinases that trim chains on its substrates; real but auxiliary to the ATPase function. Supporting Evidence: file:rat/Vcp/Vcp-uniprot.txt Interacts with UBE4B and YOD1. PMID:22970133 VCP/p97 was shown to be an activator specifically of wild-type ataxin-3, exhibiting no effect on expanded ataxin-3
GO:1990730 VCP-NSFL1C complex	IEA GO_REF:0000120	ACCEPT	Summary: IEA: Vcp forms a stoichiometric complex with p47 (Nsfl1c), one p47 trimer per p97 hexamer; this complex drives Golgi membrane reassembly. Reason: Direct rat evidence (IPI with p47; cryo-EM of the endogenous p97 hexamer with p47). Core complex for the membrane-fusion role. Supporting Evidence: PMID:9214505 which forms a tight, stoichiometric complex with cytosolic p97 (one trimer of p47 per hexamer of p97) PMID:10811609 Cytosolic p97 therefore comprises at least two alternative complexes: p97/p47 and p97/Ufd1/Npl4. PMID:16601695 we report the three-dimensional cryo-electron microscopy structures at approximately 20 Angstroms resolution in two nucleotide states of the endogenous hexameric p97 in complex with a recombinant p47 trimer file:rat/Vcp/Vcp-uniprot.txt NSFL1C forms a homotrimer that binds to one end of a VCP homohexamer.
GO:1990730 VCP-NSFL1C complex	IPI PMID:10811609 A complex of mammalian ufd1 and npl4 links the AAA-ATPase, p...	ACCEPT	Summary: IPI: Vcp forms a stoichiometric complex with p47 (Nsfl1c), one p47 trimer per p97 hexamer; this complex drives Golgi membrane reassembly. Reason: Direct rat evidence (IPI with p47; cryo-EM of the endogenous p97 hexamer with p47). Core complex for the membrane-fusion role. Supporting Evidence: PMID:9214505 which forms a tight, stoichiometric complex with cytosolic p97 (one trimer of p47 per hexamer of p97) PMID:10811609 Cytosolic p97 therefore comprises at least two alternative complexes: p97/p47 and p97/Ufd1/Npl4. PMID:16601695 we report the three-dimensional cryo-electron microscopy structures at approximately 20 Angstroms resolution in two nucleotide states of the endogenous hexameric p97 in complex with a recombinant p47 trimer file:rat/Vcp/Vcp-uniprot.txt NSFL1C forms a homotrimer that binds to one end of a VCP homohexamer.
GO:1990730 VCP-NSFL1C complex	IPI PMID:16601695 Conformational changes in the AAA ATPase p97-p47 adaptor com...	ACCEPT	Summary: IPI: Vcp forms a stoichiometric complex with p47 (Nsfl1c), one p47 trimer per p97 hexamer; this complex drives Golgi membrane reassembly. Reason: Direct rat evidence (IPI with p47; cryo-EM of the endogenous p97 hexamer with p47). Core complex for the membrane-fusion role. Supporting Evidence: PMID:9214505 which forms a tight, stoichiometric complex with cytosolic p97 (one trimer of p47 per hexamer of p97) PMID:10811609 Cytosolic p97 therefore comprises at least two alternative complexes: p97/p47 and p97/Ufd1/Npl4. PMID:16601695 we report the three-dimensional cryo-electron microscopy structures at approximately 20 Angstroms resolution in two nucleotide states of the endogenous hexameric p97 in complex with a recombinant p47 trimer file:rat/Vcp/Vcp-uniprot.txt NSFL1C forms a homotrimer that binds to one end of a VCP homohexamer.
GO:1990730 VCP-NSFL1C complex	IPI PMID:9214505 p47 is a cofactor for p97-mediated membrane fusion.	ACCEPT	Summary: IPI: Vcp forms a stoichiometric complex with p47 (Nsfl1c), one p47 trimer per p97 hexamer; this complex drives Golgi membrane reassembly. Reason: Direct rat evidence (IPI with p47; cryo-EM of the endogenous p97 hexamer with p47). Core complex for the membrane-fusion role. Supporting Evidence: PMID:9214505 which forms a tight, stoichiometric complex with cytosolic p97 (one trimer of p47 per hexamer of p97) PMID:10811609 Cytosolic p97 therefore comprises at least two alternative complexes: p97/p47 and p97/Ufd1/Npl4. PMID:16601695 we report the three-dimensional cryo-electron microscopy structures at approximately 20 Angstroms resolution in two nucleotide states of the endogenous hexameric p97 in complex with a recombinant p47 trimer file:rat/Vcp/Vcp-uniprot.txt NSFL1C forms a homotrimer that binds to one end of a VCP homohexamer.
GO:1990730 VCP-NSFL1C complex	ISO GO_REF:0000121	ACCEPT	Summary: ISO: Vcp forms a stoichiometric complex with p47 (Nsfl1c), one p47 trimer per p97 hexamer; this complex drives Golgi membrane reassembly. Reason: Direct rat evidence (IPI with p47; cryo-EM of the endogenous p97 hexamer with p47). Core complex for the membrane-fusion role. Supporting Evidence: PMID:9214505 which forms a tight, stoichiometric complex with cytosolic p97 (one trimer of p47 per hexamer of p97) PMID:10811609 Cytosolic p97 therefore comprises at least two alternative complexes: p97/p47 and p97/Ufd1/Npl4. PMID:16601695 we report the three-dimensional cryo-electron microscopy structures at approximately 20 Angstroms resolution in two nucleotide states of the endogenous hexameric p97 in complex with a recombinant p47 trimer file:rat/Vcp/Vcp-uniprot.txt NSFL1C forms a homotrimer that binds to one end of a VCP homohexamer.
GO:1990730 VCP-NSFL1C complex	ISO GO_REF:0000121	ACCEPT	Summary: ISO: Vcp forms a stoichiometric complex with p47 (Nsfl1c), one p47 trimer per p97 hexamer; this complex drives Golgi membrane reassembly. Reason: Direct rat evidence (IPI with p47; cryo-EM of the endogenous p97 hexamer with p47). Core complex for the membrane-fusion role. Supporting Evidence: PMID:9214505 which forms a tight, stoichiometric complex with cytosolic p97 (one trimer of p47 per hexamer of p97) PMID:10811609 Cytosolic p97 therefore comprises at least two alternative complexes: p97/p47 and p97/Ufd1/Npl4. PMID:16601695 we report the three-dimensional cryo-electron microscopy structures at approximately 20 Angstroms resolution in two nucleotide states of the endogenous hexameric p97 in complex with a recombinant p47 trimer file:rat/Vcp/Vcp-uniprot.txt NSFL1C forms a homotrimer that binds to one end of a VCP homohexamer.
GO:2000060 positive regulation of ubiquitin-dependent protein catabolic process	IMP PMID:16103111 Involvement of the p97-Ufd1-Npl4 complex in the regulated en...	MODIFY	Summary: IMP: IMP in rat cells: p97 knockdown impaired the ERAD of endogenous IP3 receptors, and re-expression restored it; bulk UPP degradation was unaffected. Reason: The evidence shows Vcp performing a step (processing/extraction of ubiquitinated IP3Rs) of their ER-associated degradation, not regulating the rate of a process carried out by others. The direct-participation term GO:0036503 ERAD pathway describes this better than positive regulation of ubiquitin-dependent catabolism. Proposed replacements: ERAD pathway Supporting Evidence: PMID:16103111 Our results indicate that the p97-Ufd1-Npl4 complex is required for the processing of ubiquitinated IP 3 Rs and, thus, that this complex plays a key role in ERAD in mammalian cells. PMID:16103111 Moreover, suppression of p97 expression by RNA interference (RNAi) impaired the regulated ERAD of IP 3 Rs.
GO:2001171 positive regulation of ATP biosynthetic process	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: IEA: Positive regulation of ATP biosynthetic process (ISO/IEA from the same human fibroblast study). Reason: Reduced ATP in VCP-mutant fibroblasts is a downstream consequence of uncoupling; VCP consumes ATP and does not regulate its synthesis. Supporting Evidence: PMID:23498975 we show that VCP deficiency causes profound mitochondrial uncoupling leading to decreased mitochondrial membrane potential and increased mitochondrial oxygen consumption.
GO:2001171 positive regulation of ATP biosynthetic process	ISO GO_REF:0000121	MARK AS OVER ANNOTATED	Summary: ISO: Positive regulation of ATP biosynthetic process (ISO/IEA from the same human fibroblast study). Reason: Reduced ATP in VCP-mutant fibroblasts is a downstream consequence of uncoupling; VCP consumes ATP and does not regulate its synthesis. Propagation Review Root cause: SOURCE BAD Failure modes: ROLE CONFLATION SOURCE EVIDENCE WEAK Sources checked: UniProtKB:P55072 SOURCE BAD The donor annotation rests on a phenotype of VCP-deficient human fibroblasts (mitochondrial uncoupling, PMID:23498975), not on an activity of VCP; the transfer is faithful but the source over-reaches. Supporting Evidence: PMID:23498975 we show that VCP deficiency causes profound mitochondrial uncoupling leading to decreased mitochondrial membrane potential and increased mitochondrial oxygen consumption.
GO:0090168 Golgi reassembly	IDA PMID:10811609 A complex of mammalian ufd1 and npl4 links the AAA-ATPase, p...	NEW	Summary: Recombinant rat p97 together with p47 drives regrowth of Golgi cisternae from mitotic Golgi fragments (rat liver Golgi) in vitro; p97/Ufd1/Npl4 does not. Reason: Participation test: p97 is the ATPase that performs the p47-dependent membrane fusion reaction that rebuilds the cisternae; p47 is its cofactor and a p47 point mutant unable to bind p97 abolishes regrowth. Comparator check: rat Vcpip1 (VCIP135), a partner in the same reaction, carries GO:0090168 by IDA (PMID:15037600), and rat Nsfl1c carries Golgi organization and membrane fusion by IDA. No VCP/Vcp in rat, mouse or human currently carries GO:0090168, so an expert should confirm this is an omission rather than a convention. Supporting Evidence: PMID:10811609 Only a combination of p97 and p47 could promote reassembly. PMID:9214505 It is essential for the p97-mediated regrowth of Golgi cisternae from mitotic Golgi fragments, a process restricted to animal cells. PMID:20691684 p47(F253S) could not form a complex with p97 and did not caused any cisternal regrowth in an in vitro Golgi reassembly assay.

Gene Description

Existing Annotations Review

Core Functions

ATP-driven extraction of polyubiquitinated misfolded proteins from the ER membrane into the cytosol for proteasomal degradation (ERAD), acting as the VCP-NPL4-UFD1 complex docked on the cytosolic face of the ER membrane.

p47 (NSFL1C)-dependent membrane fusion that regrows Golgi cisternae from mitotic Golgi fragments, acting as the VCP-NSFL1C complex.

Ubiquitin-dependent maturation of autophagosomes containing ubiquitinated cargo (ortholog evidence).

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