VCP (valosin-containing protein, also known as p97 or CDC48 in yeast) is a highly conserved, abundant homohexameric AAA+ ATPase (EC 3.6.4.6) that functions as a cofactor-programmable protein unfoldase/segregase. It uses ATP hydrolysis to generate mechanical force that extracts or unfolds ubiquitinated client proteins from membranes, chromatin, ribosomes, and macromolecular complexes. Each protomer contains an N-terminal cofactor-binding domain and two tandem ATPase domains (D1 and D2) that form stacked hexameric rings with a central pore for substrate threading. VCP is a central hub for ubiquitin-dependent protein quality control, with core roles in ERAD (via the VCP-UFD1-NPLOC4 complex), autophagosome maturation, stress granule clearance, DNA damage response (including DPC repair and DSB repair), and mitochondrial/lysosomal quality control. Its functional versatility is determined by a large network of cofactors (UFD1-NPL4, UBX-domain proteins, PLAA, SPRTN, etc.) that specify substrates, subcellular targeting, and outcomes. Mutations cause multisystem proteinopathy (IBMPFD1/MSP1), FTDALS6, and CMT2Y.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005634 nucleus | IBA GO_REF:0000033 | ACCEPT | Summary: VCP/p97 is well documented to localize to the nucleus where it functions in DNA damage response and DNA replication. Nuclear localization is actively regulated by VCF1/VCF2 cofactors (Korner et al. 2023, eLife). IBA annotation is well supported. Reason: Nuclear localization of VCP is supported by multiple experimental studies (PMID:23042605, PMID:26842564, PMID:10855792) and the UniProt subcellular location annotation. The IBA annotation correctly captures this conserved localization. Supporting Evidence: PMID:23042605 DVC1 recruitment to sites of replication stress requires its ubiquitin-binding UBZ domain and PCNA-binding PIP box motif PMID:26842564 Chromatin-associated degradation is defined by UBXN-3/FAF1 to safeguard DNA replication fork progression |
| GO:0016887 ATP hydrolysis activity | IBA GO_REF:0000033 | ACCEPT | Summary: ATP hydrolysis is the fundamental enzymatic activity of VCP/p97 (EC 3.6.4.6). The D1 and D2 AAA+ ATPase domains hydrolyze ATP to power substrate unfolding/extraction. This is the core molecular function. Reason: ATP hydrolysis activity is the defining catalytic activity of VCP, confirmed by direct biochemical assays (PMID:26471729) and structural studies. UniProt assigns EC 3.6.4.6. The IBA annotation is at the correct level of specificity. Supporting Evidence: PMID:26471729 p97 ATPase activity |
| GO:0051228 mitotic spindle disassembly | IBA GO_REF:0000033 | ACCEPT | Summary: The NPLOC4-UFD1-VCP complex regulates spindle disassembly at the end of mitosis, as noted in UniProt. This is a conserved function of Cdc48/p97. IBA is appropriate. Reason: UniProt states the NPLOC4-UFD1-VCP complex is necessary for spindle disassembly at the end of mitosis. This is a well-established conserved function of the Cdc48/p97 family. Supporting Evidence: PMID:28819009 The AAA+ ATPase p97, a cellular multitool |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: VCP/p97 is a highly abundant cytosolic protein (up to ~1% of cytoplasmic protein). Cytosolic localization is its primary compartment. Well-supported IBA. Reason: Cytosolic localization is confirmed by UniProt subcellular location, multiple IDA/TAS annotations, and the deep research review noting VCP can comprise ~1% of cytoplasmic protein. Supporting Evidence: PMID:15215856 cytosolic p97 ATPase |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: VCP extracts ubiquitinated proteins from various contexts (ER membrane, chromatin, ribosomes) and delivers them to the proteasome for degradation. This is a core function of VCP/p97 across all eukaryotes. Reason: This is one of the most well-established functions of VCP, supported by extensive literature on ERAD, cytoplasmic QC, and chromatin-associated degradation. Supporting Evidence: PMID:20104022 VCP is essential to some aspects of ubiquitin-dependent proteasomal degradation including endoplasmic reticulum-associated degradation (ERAD) |
| GO:0031593 polyubiquitin modification-dependent protein binding | IBA GO_REF:0000033 | ACCEPT | Summary: VCP recognizes polyubiquitinated substrates, primarily through its cofactors (UFD1-NPL4) but also directly. Polyubiquitin binding is central to VCP function. IBA is well supported. Reason: Polyubiquitin-dependent protein binding is a core molecular function of VCP, demonstrated experimentally (PMID:11483959) and integral to all its proteostasis roles. Supporting Evidence: PMID:11483959 Valosin-containing protein is a multi-ubiquitin chain-targeting factor required in ubiquitin-proteasome degradation |
| GO:0030970 retrograde protein transport, ER to cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: VCP/p97 is essential for retrotranslocation of misfolded ER proteins to the cytosol for proteasomal degradation (ERAD). This is one of the best-characterized core functions. Reason: ER-to-cytosol retrotranslocation is a defining function of VCP in ERAD, demonstrated in the landmark Ye et al. 2004 study (PMID:15215856) and many subsequent studies. Supporting Evidence: PMID:15215856 Elimination of misfolded proteins from the endoplasmic reticulum (ER) by retro-translocation is an important physiological adaptation to ER stress. This process requires recognition of a substrate in the ER lumen and its subsequent movement through the membrane by the cytosolic p97 ATPase. |
| GO:0034098 VCP-NPL4-UFD1 AAA ATPase complex | IBA GO_REF:0000033 | ACCEPT | Summary: The VCP-NPL4-UFD1 complex is the primary functional unit for most VCP-dependent ubiquitin-processing pathways (ERAD, chromatin extraction, etc.). VCP is a core component of this complex. Reason: VCP-NPL4-UFD1 complex membership is extensively documented in UniProt subunit annotation and the deep research review. This is a core complex for VCP function. Supporting Evidence: PMID:16186510 Recruitment of the p97 ATPase and ubiquitin ligases to the site of retrotranslocation at the endoplasmic reticulum membrane |
| GO:0097352 autophagosome maturation | IBA GO_REF:0000033 | ACCEPT | Summary: VCP is essential for maturation of ubiquitin-containing autophagosomes. This was demonstrated by Tresse et al. 2010 (PMID:20104022) and is impaired by IBMPFD mutations. Reason: Autophagosome maturation is a well-established core function of VCP, supported by direct experimental evidence and disease relevance (IBMPFD mutations impair this function). Supporting Evidence: PMID:20104022 VCP is essential for autophagosome maturation |
| GO:0000153 cytoplasmic ubiquitin ligase complex | IEA GO_REF:0000107 | ACCEPT | Summary: VCP interacts with multiple cytoplasmic E3 ubiquitin ligases (AMFR/gp78, RNF19A, SYVN1, STUB1/CHIP, RNF125) as part of its proteostasis functions. However, VCP itself is not a ubiquitin ligase - it is the ATPase engine that works alongside these complexes. Reason: While VCP is not itself a ubiquitin ligase, it is a bona fide component of multiple ubiquitin ligase complexes (e.g., the VCP-AMFR/gp78 complex). The CC term is appropriate for VCP as a complex member. Supporting Evidence: PMID:16168377 Gp78, a membrane-anchored ubiquitin ligase, associates with Insig-1 and couples sterol-regulated ubiquitination to degradation of HMG CoA reductase |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000107 | ACCEPT | Summary: VCP is recruited to the ER membrane via interaction with membrane-anchored cofactors (AMFR/gp78, Derlin-1, SELENOS, SYVN1) during ERAD. Well supported by multiple studies. Reason: ER membrane association during ERAD is extensively documented. UniProt subcellular location confirms ER localization. VCP is recruited to the cytoplasmic face of the ER membrane. Supporting Evidence: PMID:16168377 gp78 couples regulated ubiquitination to degradation of reductase by binding to VCP, an ATPase that plays a key role in recognition and degradation of ERAD substrates |
| GO:0006888 endoplasmic reticulum to Golgi vesicle-mediated transport | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: VCP is involved in the formation of transitional ER (tER) and vesicle budding from the tER is ATP-dependent. UniProt describes this role. However, this is a secondary/indirect function compared to ERAD. Reason: UniProt documents VCP involvement in tER formation and ER-to-Golgi transport, but this is a secondary function. The primary role of VCP at the ER is ERAD, not anterograde transport. Supporting Evidence: PMID:28819009 The AAA+ ATPase p97, a cellular multitool |
| GO:0010918 positive regulation of mitochondrial membrane potential | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: VCP has a role in mitochondrial quality control by extracting ubiquitinated outer mitochondrial membrane proteins. Positive regulation of mitochondrial membrane potential is an indirect downstream consequence. Reason: VCP's role in mitochondrial QC is to extract ubiquitinated OMM proteins for degradation (PMID:21118995). The effect on membrane potential is indirect/downstream rather than a direct VCP function. Supporting Evidence: PMID:23498975 VCP deficiency causes profound mitochondrial uncoupling leading to decreased mitochondrial membrane potential |
| GO:0030970 retrograde protein transport, ER to cytosol | IEA GO_REF:0000120 | ACCEPT | Summary: Duplicate of IBA annotation for the same GO term. Both are correct - retrograde protein transport from ER to cytosol is a core function. Reason: Same term as IBA annotation above. Independent electronic evidence supports this core ERAD function. Supporting Evidence: PMID:15215856 This process requires recognition of a substrate in the ER lumen and its subsequent movement through the membrane by the cytosolic p97 ATPase. |
| GO:0031593 polyubiquitin modification-dependent protein binding | IEA GO_REF:0000107 | ACCEPT | Summary: Duplicate of IBA annotation for the same GO term. Polyubiquitin binding is a core molecular function. Reason: Same term as IBA annotation above. This core MF is independently supported by electronic evidence. Supporting Evidence: PMID:11483959 Valosin-containing protein is a multi-ubiquitin chain-targeting factor |
| GO:0032991 protein-containing complex | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: VCP is part of multiple protein complexes (VCP-UFD1-NPLOC4, Derlin-1 complex, VCP-NSFL1C complex, etc.). However, this term is too general - more specific complex terms exist and are used. Reason: The generic 'protein-containing complex' term is uninformative when VCP has more specific complex annotations (VCP-NPL4-UFD1 complex GO:0034098, Derlin-1 retrotranslocation complex GO:0036513, VCP-NSFL1C complex GO:1990730). This adds no information beyond what the specific terms provide. |
| GO:0034098 VCP-NPL4-UFD1 AAA ATPase complex | IEA GO_REF:0000120 | ACCEPT | Summary: Duplicate of IBA annotation. VCP-NPL4-UFD1 complex membership is a core annotation. Reason: Same term as IBA annotation. Independent electronic evidence for this core complex. Supporting Evidence: PMID:16186510 Recruitment of the p97 ATPase and ubiquitin ligases to the site of retrotranslocation |
| GO:0036435 K48-linked polyubiquitin modification-dependent protein binding | IEA GO_REF:0000107 | ACCEPT | Summary: VCP preferentially recognizes K48-linked polyubiquitin chains, which is the canonical degradation signal. This is a more specific child of polyubiquitin binding and is well supported. Reason: K48-linked polyubiquitin binding is experimentally validated (PMID:37816088) and consistent with VCP's role in extracting substrates for proteasomal degradation. Supporting Evidence: PMID:37816088 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:0036503 ERAD pathway | IEA GO_REF:0000107 | ACCEPT | Summary: VCP is essential for ERAD. This is one of the best-characterized core functions. Reason: ERAD is a core VCP function, supported by extensive experimental evidence from multiple studies and the IBA annotations. Supporting Evidence: PMID:15215856 Elimination of misfolded proteins from the endoplasmic reticulum (ER) by retro-translocation |
| GO:0036513 Derlin-1 retrotranslocation complex | IEA GO_REF:0000107 | ACCEPT | Summary: VCP interacts with Derlin-1 as part of the ERAD retrotranslocation machinery. VCP is a component of this complex. Reason: VCP interaction with DERL1 is well documented (PMID:15215856, PMID:16186510, PMID:27714797). VCP is a bona fide component of the Derlin-1 retrotranslocation complex. Supporting Evidence: PMID:15215856 Derlin-1 associates with different substrates as they move through the membrane, and inactivation of Derlin-1 in C. elegans causes ER stress. Derlin-1 interacts with US11 |
| GO:0042288 MHC class I protein binding | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: VCP participates in ERAD of MHC class I heavy chains via the US11/Derlin-1 pathway during CMV infection. However, VCP does not directly bind MHC class I - it is recruited via the Derlin-1/VIMP complex. Reason: VCP is involved in ERAD of MHC class I via the Derlin-1 pathway (PMID:15215856), but the direct binding annotation is misleading. VCP interacts with the ERAD machinery (Derlin-1, VIMP) rather than directly binding MHC class I proteins. Supporting Evidence: PMID:15215856 Derlin-1 interacts with US11, a virally encoded ER protein that specifically targets MHC class I heavy chains for export from the ER |
| GO:0042802 identical protein binding | IEA GO_REF:0000120 | ACCEPT | Summary: VCP forms a homohexamer. Self-association is required for its function. Identical protein binding reflects VCP homohexamerization. Reason: VCP homohexamerization is essential for function and well documented structurally (UniProt: "Homohexamer. Forms a ring-shaped particle of 12.5 nm diameter, that displays 6-fold radial symmetry"). Supporting Evidence: PMID:20512113 A novel ATP-dependent conformation in p97 N-D1 fragment revealed by crystal structures |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | IEA GO_REF:0000107 | ACCEPT | Summary: Duplicate of IBA annotation for this core function. Reason: This core function is independently supported by electronic evidence. Supporting Evidence: PMID:20104022 VCP is essential to some aspects of ubiquitin-dependent proteasomal degradation |
| GO:0043531 ADP binding | IEA GO_REF:0000120 | ACCEPT | Summary: VCP binds both ATP and ADP as part of its ATPase cycle. ADP binding is inherent to the ATP hydrolysis mechanism. Acceptable but less informative than the ATPase activity annotation. Reason: ADP binding is an intrinsic property of VCP's ATPase domains, confirmed by structural studies showing ADP-bound conformations. Supporting Evidence: PMID:20512113 A novel ATP-dependent conformation in p97 N-D1 fragment |
| GO:0044877 protein-containing complex binding | IEA GO_REF:0000120 | MARK AS OVER ANNOTATED | Summary: VCP binds multiple protein complexes (proteasome, ubiquitin ligase complexes, etc.). However, this is a very generic term. Reason: This term is too vague and uninformative for VCP. More specific binding terms (polyubiquitin binding, ubiquitin ligase binding, etc.) better capture VCP's actual binding activities. |
| GO:0045202 synapse | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: VCP is abundant and ubiquitous, so synaptic localization is plausible but this likely reflects VCP abundance rather than a specific synaptic function. Reason: VCP is a highly abundant housekeeping protein present in all cellular compartments. Synaptic localization is not a defining feature - it reflects VCP ubiquity rather than synaptic specialization. |
| GO:0046034 ATP metabolic process | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: VCP hydrolyzes ATP but does not play a role in ATP metabolism per se. This is an over-annotation - VCP consumes ATP as a substrate for mechanical work, not as part of ATP metabolic pathways. Reason: VCP uses ATP hydrolysis for mechanical work (substrate extraction/unfolding), not for ATP metabolism. The correct annotation is ATP hydrolysis activity (GO:0016887), not ATP metabolic process. VCP is not an enzyme in ATP biosynthesis or degradation pathways. |
| GO:0050807 regulation of synapse organization | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: While VCP disease mutations affect neuromuscular function, direct evidence for VCP regulating synapse organization is limited. This likely reflects pleiotropic effects of proteostasis disruption. Reason: VCP is a general proteostasis factor. Any effect on synapse organization is likely indirect and downstream of its core protein quality control functions rather than a specific synapse-organizing role. |
| GO:0098978 glutamatergic synapse | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: VCP presence at glutamatergic synapses likely reflects its ubiquitous cytosolic distribution rather than a specific glutamatergic synapse function. Reason: VCP is an abundant cytosolic protein present throughout the cell. Localization to glutamatergic synapses does not indicate a specific function there. |
| GO:1904949 ATPase complex | IEA GO_REF:0000107 | ACCEPT | Summary: VCP forms a homohexameric ATPase complex. This is correct but the more specific VCP-NPL4-UFD1 complex term is more informative. Reason: VCP is indeed an ATPase complex (homohexamer). While the term is somewhat generic, it correctly describes the VCP homohexamer as a CC term. |
| GO:1990381 ubiquitin-specific protease binding | IEA GO_REF:0000107 | ACCEPT | Summary: VCP interacts with deubiquitinating enzymes including YOD1 and ATXN3 (both are ubiquitin-specific proteases). Reason: VCP interaction with DUBs (YOD1, ATXN3, USP25) is well documented (PMID:19818707, PMID:30455355, PMID:22590560). These interactions are functionally important for VCP-mediated substrate processing. Supporting Evidence: PMID:19818707 The otubain YOD1 is a deubiquitinating enzyme that associates with p97 to facilitate protein dislocation from the ER |
| GO:1990730 VCP-NSFL1C complex | IEA GO_REF:0000120 | ACCEPT | Summary: VCP forms a complex with NSFL1C (p47) that has membrane fusion activity required for Golgi and ER biogenesis. This is a named VCP complex. Reason: UniProt documents VCP-NSFL1C interaction. NSFL1C forms a homotrimer that binds to one end of a VCP homohexamer. The complex binds to membranes enriched in phosphatidylethanolamine-containing lipids and promotes Golgi membrane fusion. |
| GO:2000060 positive regulation of ubiquitin-dependent protein catabolic process | IEA GO_REF:0000107 | ACCEPT | Summary: VCP promotes ubiquitin-dependent protein catabolism by extracting ubiquitinated substrates and delivering them to the proteasome or autophagy pathways. Reason: VCP is a positive regulator of ubiquitin-dependent catabolism, demonstrated across ERAD, cytoplasmic QC, and chromatin-associated degradation pathways. Supporting Evidence: PMID:9452483 Involvement of valosin-containing protein, an ATPase Co-purified with IkappaBalpha and 26 S proteasome, in ubiquitin-proteasome-mediated degradation of IkappaBalpha |
| GO:0005515 protein binding | IPI PMID:10364224 Identification of the cell cycle regulator VCP (p97/CDC48) a... | MARK AS OVER ANNOTATED | Summary: Documents VCP interaction with PTPH1 phosphatase. The more informative annotation is protein phosphatase binding (GO:0019903) which is also present. Reason: 'Protein binding' is uninformative per curation guidelines. A more specific term (protein phosphatase binding GO:0019903) exists for this interaction. |
| GO:0005515 protein binding | IPI PMID:15161933 Comprehensive proteomic analysis of interphase and mitotic 1... | MARK AS OVER ANNOTATED | Summary: High-throughput 14-3-3 binding protein identification. VCP protein binding is generic. Reason: 'Protein binding' is uninformative. This is from a large-scale 14-3-3 interaction study. |
| GO:0005515 protein binding | IPI PMID:16275660 Identification of VCP/p97, carboxyl terminus of Hsp70-intera... | MARK AS OVER ANNOTATED | Summary: Proteome array study identifying VCP interactions. Generic protein binding. Reason: 'Protein binding' is uninformative. From a high-throughput proteome array study. |
| GO:0005515 protein binding | IPI PMID:16306228 14-3-3 cooperates with LKB1 to regulate the activity and loc... | MARK AS OVER ANNOTATED | Summary: Documents interaction between VCP and kinase regulators. Generic protein binding. Reason: 'Protein binding' is uninformative per curation guidelines. |
| GO:0005515 protein binding | IPI PMID:16407162 The activity of a human endoplasmic reticulum-associated deg... | MARK AS OVER ANNOTATED | Summary: Documents VCP-gp78/AMFR interaction in ERAD context. More informative as ubiquitin-like protein ligase binding. Reason: 'Protein binding' is uninformative. The VCP-AMFR interaction is better captured by ubiquitin-like protein ligase binding (GO:0044389). |
| GO:0005515 protein binding | IPI PMID:16525503 An arginine/lysine-rich motif is crucial for VCP/p97-mediate... | MARK AS OVER ANNOTATED | Summary: Documents VCP-ataxin-3 interaction. Generic protein binding. Reason: 'Protein binding' is uninformative. VCP-ATXN3 interaction is better captured by ubiquitin-specific protease binding. |
| GO:0005515 protein binding | IPI PMID:17525332 ATM and ATR substrate analysis reveals extensive protein net... | MARK AS OVER ANNOTATED | Summary: Large-scale ATM/ATR substrate analysis. VCP identified as DNA damage-responsive phosphoprotein. Reason: 'Protein binding' from a high-throughput phosphoproteomics screen is uninformative. |
| GO:0005515 protein binding | IPI PMID:18654987 Identification of multi-SH3 domain-containing protein intera... | MARK AS OVER ANNOTATED | Summary: Yeast two-hybrid interaction study in pancreatic cancer. Generic protein binding. Reason: 'Protein binding' is uninformative per curation guidelines. |
| GO:0005515 protein binding | IPI PMID:18656546 Ubxd1 is a novel co-factor of the human p97 ATPase. | MARK AS OVER ANNOTATED | Summary: Documents VCP-UBXN6/UBXD1 interaction. Generic protein binding. Reason: 'Protein binding' is uninformative. The VCP-UBXN6 interaction is a cofactor interaction relevant to endolysosomal sorting. |
| GO:0005515 protein binding | IPI PMID:18711132 SEL1L nucleates a protein complex required for dislocation o... | MARK AS OVER ANNOTATED | Summary: SEL1L complex identification by mass spectrometry. Generic protein binding. Reason: 'Protein binding' is uninformative. This documents VCP as part of the SEL1L ERAD complex. |
| GO:0005515 protein binding | IPI PMID:18775313 UBXD7 binds multiple ubiquitin ligases and implicates p97 in... | MARK AS OVER ANNOTATED | Summary: Documents VCP-UBXN7 interaction. UBXN7 implicates p97 in HIF1alpha turnover. Reason: 'Protein binding' is uninformative per curation guidelines. |
| GO:0005515 protein binding | IPI PMID:19570996 The proapoptotic function of SAP provides a clue to the clin... | MARK AS OVER ANNOTATED | Summary: Generic protein binding from interaction study. Reason: 'Protein binding' is uninformative per curation guidelines. |
| GO:0005515 protein binding | IPI PMID:20414249 Imbalances in p97 co-factor interactions in human proteinopa... | MARK AS OVER ANNOTATED | Summary: Documents imbalances in p97 cofactor interactions in proteinopathy. Reason: 'Protein binding' is uninformative per curation guidelines. |
| GO:0005515 protein binding | IPI PMID:21343306 Membrane-associated ubiquitin ligase complex containing gp78... | MARK AS OVER ANNOTATED | Summary: VCP in gp78-mediated HMGCR degradation complex. Generic protein binding. Reason: 'Protein binding' is uninformative. VCP-AMFR interaction in ERAD is better captured by more specific terms. |
| GO:0005515 protein binding | IPI PMID:21645854 Hierarchical binding of cofactors to the AAA ATPase p97. | MARK AS OVER ANNOTATED | Summary: Hierarchical binding of cofactors to the AAA ATPase p97. Characterizes cofactor binding hierarchy. Reason: 'Protein binding' is uninformative per curation guidelines. |
| GO:0005515 protein binding | IPI PMID:21900206 A directed protein interaction network for investigating int... | MARK AS OVER ANNOTATED | Summary: Directed protein interaction network study. Generic interaction. Reason: 'Protein binding' from a high-throughput interactome study is uninformative. |
| GO:0005515 protein binding | IPI PMID:21988832 Toward an understanding of the protein interaction network o... | MARK AS OVER ANNOTATED | Summary: Human liver protein interaction network study. Generic protein binding. Reason: 'Protein binding' from a high-throughput interactome study is uninformative. |
| GO:0005515 protein binding | IPI PMID:22119785 Defining human ERAD networks through an integrative mapping ... | MARK AS OVER ANNOTATED | Summary: ERAD network mapping study. VCP identified as ERAD component. Reason: 'Protein binding' is uninformative. VCP's role in ERAD is better captured by ERAD pathway (GO:0036503) and related terms. |
| GO:0005515 protein binding | IPI PMID:22466964 NEDD8 links cullin-RING ubiquitin ligase function to the p97... | MARK AS OVER ANNOTATED | Summary: NEDD8-CRL-p97 pathway study. Generic protein binding. Reason: 'Protein binding' is uninformative per curation guidelines. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: Proteome-scale interactome map. High-throughput generic protein binding. Reason: 'Protein binding' from a high-throughput interactome study is uninformative. |
| GO:0005515 protein binding | IPI PMID:25593058 Alterations in the interactome of serine/threonine protein p... | MARK AS OVER ANNOTATED | Summary: Phosphatase interactome in atrial fibrillation. Generic protein binding. Reason: 'Protein binding' is uninformative per curation guidelines. |
| GO:0005515 protein binding | IPI PMID:25814554 Phospho-tyrosine dependent protein-protein interaction netwo... | MARK AS OVER ANNOTATED | Summary: Phospho-tyrosine dependent interactome study. Generic protein binding. Reason: 'Protein binding' is uninformative per curation guidelines. |
| GO:0005515 protein binding | IPI PMID:25959826 Quantitative interaction proteomics of neurodegenerative dis... | MARK AS OVER ANNOTATED | Summary: Neurodegenerative disease protein interaction study. Generic protein binding. Reason: 'Protein binding' from a large-scale interaction proteomics study is uninformative. |
| GO:0005515 protein binding | IPI PMID:26471729 A non-canonical role of the p97 complex in RIG-I antiviral s... | MARK AS OVER ANNOTATED | Summary: Documents VCP-RIG-I and VCP-RNF125 interactions. These are functionally significant interactions in antiviral signaling. Reason: 'Protein binding' is uninformative. The VCP-RIGI interaction has functional significance in innate immune regulation but is better captured by more specific terms. |
| GO:0005515 protein binding | IPI PMID:26496610 A human interactome in three quantitative dimensions organiz... | MARK AS OVER ANNOTATED | Summary: High-throughput interactome study. Generic protein binding. Reason: 'Protein binding' from a high-throughput stoichiometry/abundance study is uninformative. |
| GO:0005515 protein binding | IPI PMID:26712280 Characterization of an Additional Binding Surface on the p97... | MARK AS OVER ANNOTATED | Summary: Characterization of p97 N-terminal domain cofactor binding. Generic protein binding. Reason: 'Protein binding' is uninformative per curation guidelines. |
| GO:0005515 protein binding | IPI PMID:27812135 Characterization and Genetic Analyses of New Genes Coding fo... | MARK AS OVER ANNOTATED | Summary: NOD2 interacting proteins study. Generic protein binding. Reason: 'Protein binding' is uninformative per curation guidelines. |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | MARK AS OVER ANNOTATED | Summary: Human interactome architecture study. High-throughput generic interaction. Reason: 'Protein binding' from a high-throughput interactome study is uninformative. |
| GO:0005515 protein binding | IPI PMID:29892012 An interactome perturbation framework prioritizes damaging m... | MARK AS OVER ANNOTATED | Summary: Interactome perturbation framework study. Generic protein binding. Reason: 'Protein binding' from a high-throughput study is uninformative. |
| GO:0005515 protein binding | IPI PMID:29997244 LuTHy: a double-readout bioluminescence-based two-hybrid tec... | MARK AS OVER ANNOTATED | Summary: LuTHy two-hybrid technology study. Generic protein binding. Reason: 'Protein binding' from a two-hybrid methodology study is uninformative. |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | MARK AS OVER ANNOTATED | Summary: Genetic variant disruption of protein interactions. Generic protein binding. Reason: 'Protein binding' from a high-throughput interaction disruption study is uninformative. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: HuRI human binary interactome reference. Generic protein binding. Reason: 'Protein binding' from a reference interactome map is uninformative. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | MARK AS OVER ANNOTATED | Summary: Neurodegenerative disease protein interactome mapping. Generic protein binding. Reason: 'Protein binding' from a large-scale interactome study is uninformative. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: Dual proteome-scale network study. Generic protein binding. Reason: 'Protein binding' from a high-throughput interactome study is uninformative. |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | MARK AS OVER ANNOTATED | Summary: OpenCell endogenous tagging interactome. Generic protein binding. Reason: 'Protein binding' from a high-throughput interactome study is uninformative. |
| GO:0005515 protein binding | IPI PMID:35273242 Valosin-containing protein-regulated endoplasmic reticulum s... | MARK AS OVER ANNOTATED | Summary: Generic protein binding from interaction study. Reason: 'Protein binding' is uninformative per curation guidelines. |
| GO:0005515 protein binding | IPI PMID:37316325 N-terminal proteoforms may engage in different protein compl... | MARK AS OVER ANNOTATED | Summary: N-terminal proteoform complex study. Generic protein binding. Reason: 'Protein binding' is uninformative per curation guidelines. |
| GO:0005515 protein binding | IPI PMID:37776851 Analysis of proteome-wide degradation dynamics in ALS SOD1 i... | MARK AS OVER ANNOTATED | Summary: ALS SOD1 iPSC proteome degradation dynamics. Generic protein binding. Reason: 'Protein binding' is uninformative per curation guidelines. |
| GO:0005515 protein binding | IPI PMID:38884001 Mapping adipocyte interactome networks by HaloTag-enrichment... | MARK AS OVER ANNOTATED | Summary: Adipocyte interactome mapping study. Generic protein binding. Reason: 'Protein binding' from a high-throughput HaloTag-enrichment study is uninformative. |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | MARK AS OVER ANNOTATED | Summary: Multimodal cell map study. Generic protein binding. Reason: 'Protein binding' from a high-throughput cell mapping study is uninformative. |
| GO:0042802 identical protein binding | IPI PMID:20512113 A novel ATP-dependent conformation in p97 N-D1 fragment reve... | ACCEPT | Summary: Crystal structure study of p97 N-D1 fragment confirms homohexameric assembly. Reason: VCP homohexamerization is a core structural feature confirmed by X-ray crystallography (PMID:20512113) and cryo-EM studies. Supporting Evidence: PMID:20512113 A novel ATP-dependent conformation in p97 N-D1 fragment revealed by crystal structures of disease-related mutants |
| GO:0042802 identical protein binding | IPI PMID:24055316 High-speed atomic force microscopic observation of ATP-depen... | ACCEPT | Summary: High-speed AFM observation of ATP-dependent rotation of p97. Reason: Direct observation of VCP hexamer dynamics by AFM confirms self-association. |
| GO:0042802 identical protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | ACCEPT | Summary: VCP self-interaction from proteome-scale interactome map. Reason: VCP homohexamerization is well established. This is an independent confirmation. |
| GO:0042802 identical protein binding | IPI PMID:26712278 Structural Basis of ATP Hydrolysis and Intersubunit Signalin... | ACCEPT | Summary: Structural basis of ATP hydrolysis and intersubunit signaling in p97. Reason: Structural study directly examining VCP hexamer intersubunit communication. |
| GO:0042802 identical protein binding | IPI PMID:26822609 2.3 Å resolution cryo-EM structure of human p97 and mechanis... | ACCEPT | Summary: 2.3 A cryo-EM structure of human p97 hexamer. Reason: High-resolution cryo-EM structure directly demonstrates VCP homohexamer. |
| GO:0042802 identical protein binding | IPI PMID:26849035 Nucleotide-dependent conformational changes of the AAA+ ATPa... | ACCEPT | Summary: Nucleotide-dependent conformational changes of p97 hexamer. Reason: Study of VCP hexamer conformational dynamics confirms self-association. |
| GO:0005524 ATP binding | IEA GO_REF:0000120 | ACCEPT | Summary: VCP has two ATP-binding AAA+ ATPase domains (D1 and D2). ATP binding is a core molecular function. Reason: ATP binding is inherent to VCP's AAA+ ATPase domains, confirmed by extensive structural studies showing ATP and ATP analog binding. |
| GO:0005634 nucleus | IEA GO_REF:0000044 | ACCEPT | Summary: Duplicate nuclear localization annotation from UniProt mapping. Correct. Reason: Nuclear localization is confirmed by multiple experimental studies and IBA annotation. |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000044 | ACCEPT | Summary: VCP localizes to the ER for its ERAD function. Correct. Reason: ER localization is well documented (PMID:15215856). VCP is recruited to the ER during ERAD. |
| GO:0005829 cytosol | IEA GO_REF:0000120 | ACCEPT | Summary: Duplicate cytosol annotation. Correct. Reason: Cytosol is VCP's primary compartment, confirmed by multiple methods. |
| GO:0010494 cytoplasmic stress granule | IEA GO_REF:0000044 | ACCEPT | Summary: VCP localizes to stress granules where it mediates G3BP1 extraction and stress granule disassembly. Reason: VCP localization to stress granules is experimentally confirmed (PMID:29804830) and documented in UniProt subcellular location. Supporting Evidence: PMID:29804830 ZFAND1 is an evolutionarily conserved regulator of SG clearance. 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:0016787 hydrolase activity | IEA GO_REF:0000002 | ACCEPT | Summary: VCP is a hydrolase (ATPase). This is correct but the more specific term ATP hydrolysis activity (GO:0016887) is more informative. Reason: VCP is indeed a hydrolase (ATP hydrolase). While the term is general, it is not wrong and the more specific ATP hydrolysis activity term is also annotated. |
| GO:0016887 ATP hydrolysis activity | IEA GO_REF:0000120 | ACCEPT | Summary: Duplicate of IBA annotation for ATP hydrolysis activity. Core function. Reason: ATP hydrolysis activity is VCP's core enzymatic function, independently confirmed. |
| GO:0018023 peptidyl-lysine trimethylation | IDA PMID:22948820 Lysine methylation of VCP by a member of a novel human prote... | KEEP AS NON CORE | Summary: VCP is trimethylated at Lys-315 by VCPKMT. This is a PTM on VCP, not an activity of VCP. The annotation describes VCP as a substrate of methylation. Reason: Lys-315 trimethylation is a regulatory PTM on VCP that may decrease ATPase activity (PMID:22948820, PMID:23349634). This describes VCP as a substrate, not VCP catalyzing the trimethylation. It is a real annotation but not a core function. Supporting Evidence: PMID:22948820 Lysine methylation of VCP by a member of a novel human protein methyltransferase family |
| GO:0036503 ERAD pathway | NAS PMID:36656859 Structural remodeling of AAA+ ATPase p97 by adaptor protein ... | ACCEPT | Summary: ERAD pathway annotation from a study on ASPL-mediated structural remodeling facilitating METTL21D methylation. ERAD is a core function. Reason: ERAD is a core VCP function, extensively documented. NAS evidence here is redundant with stronger IDA/IMP/IBA evidence. |
| GO:0000423 mitophagy | IDA PMID:30120381 UBXD1 is a mitochondrial recruitment factor for p97/VCP and ... | ACCEPT | Summary: VCP is involved in mitophagy - the selective autophagy of damaged mitochondria. VCP extracts ubiquitinated outer mitochondrial membrane proteins. Reason: VCP's role in mitophagy/mitochondrial QC is well established. VCP extracts ubiquitinated OMM proteins for proteasomal degradation (PMID:21118995) and participates in mitophagy pathways. Supporting Evidence: PMID:21118995 The AAA-ATPase p97 is essential for outer mitochondrial membrane protein turnover |
| GO:0005737 cytoplasm | NAS PMID:16601695 Conformational changes in the AAA ATPase p97-p47 adaptor com... | ACCEPT | Summary: VCP is a cytoplasmic protein. This is correct but less specific than cytosol. Reason: Cytoplasm localization is correct. While cytosol is more specific, cytoplasm is not wrong. |
| GO:0005789 endoplasmic reticulum membrane | NAS PMID:16449189 Derlin-2 and Derlin-3 are regulated by the mammalian unfolde... | ACCEPT | Summary: ER membrane localization from Derlin-2/3 ERAD study. Correct. Reason: VCP association with the ER membrane during ERAD is well documented. |
| GO:0005789 endoplasmic reticulum membrane | NAS PMID:37831771 The cryo-EM structure of the human ERAD retrotranslocation c... | ACCEPT | Summary: ER membrane from cryo-EM structure of ERAD retrotranslocation complex. Correct. Reason: Directly demonstrates VCP at the ER membrane in the retrotranslocation complex. |
| GO:0006511 ubiquitin-dependent protein catabolic process | NAS PMID:16449189 Derlin-2 and Derlin-3 are regulated by the mammalian unfolde... | ACCEPT | Summary: VCP is central to ubiquitin-dependent protein catabolism. Core function. Reason: Ubiquitin-dependent catabolism is a core VCP function. The more specific term proteasome-mediated ubiquitin-dependent protein catabolic process is also annotated. |
| GO:0006511 ubiquitin-dependent protein catabolic process | NAS PMID:16601695 Conformational changes in the AAA ATPase p97-p47 adaptor com... | ACCEPT | Summary: Ubiquitin-dependent catabolism from p97-p47 adaptor study. Core function. Reason: Core VCP function, redundant with other annotations. |
| GO:0006511 ubiquitin-dependent protein catabolic process | NAS PMID:28819009 The AAA+ ATPase p97, a cellular multitool. | ACCEPT | Summary: From the comprehensive p97 review "The AAA+ ATPase p97, a cellular multitool." Reason: Core function confirmed in authoritative review. |
| GO:0006511 ubiquitin-dependent protein catabolic process | NAS PMID:33712450 The p97-UBXN1 complex regulates aggresome formation. | ACCEPT | Summary: Ubiquitin-dependent catabolism. Core function. Reason: Core VCP function, redundant with stronger evidence. |
| GO:0036503 ERAD pathway | NAS PMID:21645854 Hierarchical binding of cofactors to the AAA ATPase p97. | ACCEPT | Summary: ERAD from hierarchical cofactor binding study. Core function. Reason: ERAD is a core VCP function, extensively documented. |
| GO:0036503 ERAD pathway | NAS PMID:28819009 The AAA+ ATPase p97, a cellular multitool. | ACCEPT | Summary: ERAD from comprehensive p97 review. Core function. Reason: Core VCP function confirmed in authoritative review. |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | NAS PMID:24424410 USP13 antagonizes gp78 to maintain functionality of a chaper... | ACCEPT | Summary: From USP13-gp78 ERAD study. Core function. Reason: Core VCP function, redundant with IBA/IEA annotations. |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | NAS PMID:39329031 Study of Clinical Characteristics of Intellectual Disability... | ACCEPT | Summary: Proteasome-mediated ubiquitin-dependent catabolism. Core function. Reason: Core VCP function, redundant with stronger evidence. |
| GO:0043335 protein unfolding | NAS PMID:16275660 Identification of VCP/p97, carboxyl terminus of Hsp70-intera... | ACCEPT | Summary: VCP is a protein unfoldase. It uses ATP hydrolysis to unfold/extract substrates through the central pore. This is a core molecular function. Reason: Protein unfolding is the core mechanistic output of VCP's ATPase activity. VCP threads substrates through its central pore for unfolding. Supporting Evidence: PMID:33058883 Protein Phosphatase-1 Complex Disassembly by p97 is Initiated through Multivalent Recognition |
| GO:0043335 protein unfolding | IMP PMID:19818707 The otubain YOD1 is a deubiquitinating enzyme that associate... | ACCEPT | Summary: Demonstrated by YOD1 study showing p97 facilitates protein dislocation from ER. Reason: Direct functional evidence for VCP-mediated protein unfolding during ERAD. Supporting Evidence: PMID:19818707 The otubain YOD1 is a deubiquitinating enzyme that associates with p97 to facilitate protein dislocation from the ER |
| GO:0043335 protein unfolding | NAS PMID:19887378 Structure and function of the PLAA/Ufd3-p97/Cdc48 complex. | ACCEPT | Summary: From PLAA/Ufd3-p97 complex structure study. Protein unfolding confirmed. Reason: Structural basis for VCP unfoldase function. |
| GO:0043335 protein unfolding | NAS PMID:24163436 Phosphorylation regulates VCIP135 function in Golgi membrane... | ACCEPT | Summary: From VCIP135 phosphorylation/Golgi membrane fusion study. Protein unfolding is a core VCP function. Reason: Core VCP function, redundant with other evidence. |
| GO:0043335 protein unfolding | IDA PMID:33058883 Protein Phosphatase-1 Complex Disassembly by p97 is Initiate... | ACCEPT | Summary: Direct demonstration of VCP-mediated PP1 complex disassembly through unfolding. Reason: Direct experimental evidence for VCP unfoldase activity on PP1 complexes. Supporting Evidence: PMID:33058883 Protein Phosphatase-1 Complex Disassembly by p97 is Initiated through Multivalent Recognition of Catalytic and Regulatory Subunits by the p97 SEP-domain Adapters |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | ACCEPT | Summary: Nucleoplasm localization from immunofluorescence curation. VCP is found in the nucleoplasm where it functions in DNA damage response. Reason: Nucleoplasm localization is consistent with VCP's known nuclear functions in DNA repair and chromatin-associated degradation. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Cytosol localization from immunofluorescence curation. Primary VCP compartment. Reason: Cytosol is VCP's primary compartment, confirmed by immunofluorescence. |
| GO:0005634 nucleus | EXP PMID:23042605 DVC1 (C1orf124) is a DNA damage-targeting p97 adaptor that p... | ACCEPT | Summary: Nuclear localization demonstrated in the SPRTN/DVC1 DNA damage study. Reason: Experimental evidence for VCP nuclear recruitment via SPRTN to stalled replication forks. Supporting Evidence: PMID:23042605 DVC1 (C1orf124) is a DNA damage-targeting p97 adaptor that promotes ubiquitin-dependent responses to replication blocks |
| GO:0016887 ATP hydrolysis activity | EXP PMID:26471729 A non-canonical role of the p97 complex in RIG-I antiviral s... | ACCEPT | Summary: Direct experimental demonstration of VCP ATPase activity in the RIG-I study. Reason: Direct biochemical measurement of VCP ATPase activity. This study confirmed EC 3.6.4.6 enzymatic activity. Supporting Evidence: PMID:26471729 p97 ATPase activity |
| GO:0072344 rescue of stalled cytosolic ribosome | NAS PMID:35452614 Ribosome-associated quality-control mechanisms from bacteria... | ACCEPT | Summary: VCP/p97 participates in ribosome-associated quality control (RQC) by extracting ubiquitinated nascent chains from stalled ribosomes. This is an emerging VCP function. Reason: VCP's role in RQC/ribosome rescue is supported by the ANKZF1 interaction (PMID:28302725) and the Reactome pathway for ribosome stalling (Reactome:R-HSA-9948427). Supporting Evidence: PMID:28302725 Ankyrin repeat and zinc-finger domain-containing 1 mutations are associated with infantile-onset inflammatory bowel disease |
| GO:1990116 ribosome-associated ubiquitin-dependent protein catabolic process | NAS PMID:35452614 Ribosome-associated quality-control mechanisms from bacteria... | ACCEPT | Summary: VCP participates in ribosome-associated protein quality control. Consistent with the rescue of stalled ribosome annotation. Reason: VCP's role in RQC/ribosome-associated degradation is consistent with its ANKZF1 interaction and role in extracting ubiquitinated substrates from stalled ribosomes. |
| GO:0005515 protein binding | IPI PMID:31847414 Structure of the PUB Domain from Ubiquitin Regulatory X Doma... | MARK AS OVER ANNOTATED | Summary: Generic protein binding. Reason: 'Protein binding' is uninformative per curation guidelines. |
| GO:0005829 cytosol | IMP PMID:38710747 The AAA-ATPase Ter94 regulates wing size in Drosophila by su... | ACCEPT | Summary: Cytosol localization from Drosophila Ter94 Hippo signaling study. Reason: Cytosol is VCP's primary compartment. Consistent with all other evidence. |
| GO:0035331 negative regulation of hippo signaling | IGI PMID:38710747 The AAA-ATPase Ter94 regulates wing size in Drosophila by su... | KEEP AS NON CORE | Summary: Based on Drosophila Ter94 study showing regulation of wing size via Hippo pathway suppression. Evidence is from fly and may not directly translate to human VCP. Reason: Evidence is from Drosophila Ter94 (VCP ortholog). While VCP may have indirect effects on Hippo signaling through general proteostasis, this is likely a pleiotropic/indirect effect rather than a specific VCP function. The IGI evidence from fly studies requires caution for human annotation. |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | IDA PMID:31387940 BIK ubiquitination by the E3 ligase Cul5-ASB11 determines ce... | ACCEPT | Summary: From BIK ubiquitination study. VCP role in proteasomal degradation. Reason: Core VCP function with direct experimental evidence. |
| GO:0140036 ubiquitin-modified protein reader activity | IDA PMID:31387940 BIK ubiquitination by the E3 ligase Cul5-ASB11 determines ce... | ACCEPT | Summary: VCP reads ubiquitin modifications on substrates to initiate extraction. This is a core molecular function. Reason: Ubiquitin-modified protein reader activity accurately describes VCP's ability to recognize and bind ubiquitinated substrates for processing. |
| GO:0140036 ubiquitin-modified protein reader activity | IDA PMID:29033132 Assembly and Function of Heterotypic Ubiquitin Chains in Cel... | ACCEPT | Summary: VCP reads heterotypic ubiquitin chains in cell-cycle and protein QC contexts. Reason: Core molecular function. VCP recognizes various ubiquitin chain types. |
| GO:0140455 cytoplasm protein quality control | IDA PMID:29033132 Assembly and Function of Heterotypic Ubiquitin Chains in Cel... | ACCEPT | Summary: VCP is essential for cytoplasmic protein quality control, extracting ubiquitinated substrates for proteasomal degradation. Reason: Cytoplasmic protein QC is a core VCP function, demonstrated across multiple substrate types and pathways. |
| GO:0036503 ERAD pathway | IMP PMID:24089527 Caveolin-1 interacts with Derlin-1 and promotes ubiquitinati... | ACCEPT | Summary: ERAD from caveolin-1/Derlin-1/COX-2 degradation study. Core function. Reason: Direct experimental evidence for VCP in ERAD. |
| GO:0071218 cellular response to misfolded protein | IMP PMID:24089527 Caveolin-1 interacts with Derlin-1 and promotes ubiquitinati... | ACCEPT | Summary: VCP responds to misfolded proteins by extracting them for degradation. This is inherent to its ERAD and cytoplasmic QC functions. Reason: Response to misfolded proteins is central to VCP function in ERAD and cytoplasmic QC. |
| GO:0036435 K48-linked polyubiquitin modification-dependent protein binding | IDA PMID:37816088 TRIM55 promotes noncanonical NF-kappaB signaling and B cell-... | ACCEPT | Summary: Direct demonstration of VCP binding K48-linked polyubiquitin chains. Reason: K48-linked polyubiquitin binding is experimentally validated and consistent with VCP's role in proteasomal targeting. |
| GO:1901224 positive regulation of non-canonical NF-kappaB signal transduction | IDA PMID:37816088 TRIM55 promotes noncanonical NF-kappaB signaling and B cell-... | KEEP AS NON CORE | Summary: VCP promotes non-canonical NF-kB signaling through p100 processing. This is a relatively specific signaling outcome. Reason: While experimentally supported, NF-kB regulation is not a core VCP function. It represents one of many downstream effects of VCP's ubiquitin-dependent substrate processing activity. |
| GO:0005515 protein binding | IPI PMID:26265139 UBXN2A regulates nicotinic receptor degradation by modulatin... | MARK AS OVER ANNOTATED | Summary: VCP-UBXN2A interaction in CHRNA3 ERAD context. Reason: 'Protein binding' is uninformative per curation guidelines. |
| GO:0036503 ERAD pathway | IMP PMID:26265139 UBXN2A regulates nicotinic receptor degradation by modulatin... | ACCEPT | Summary: VCP mediates ERAD of CHRNA3 via STUB1-VCP-UBXN2A complex. Reason: Direct experimental evidence for VCP in ERAD of a specific substrate (CHRNA3). Supporting Evidence: PMID:26265139 UBXN2A regulates nicotinic receptor degradation by modulating the E3 ligase activity of CHIP |
| GO:0035617 stress granule disassembly | IDA PMID:36692217 Stress granule homeostasis is modulated by TRIM21-mediated u... | ACCEPT | Summary: VCP mediates stress granule disassembly via G3BP1 extraction. This is a core VCP function in stress response. Reason: Stress granule clearance is a well-established VCP function (PMID:29804830, PMID:34739333). VCP extracts ubiquitinated G3BP1 from stress granules. Supporting Evidence: PMID:29804830 ZFAND1 Recruits p97 and the 26S Proteasome to Promote the Clearance of Arsenite-Induced Stress Granules |
| GO:0120186 negative regulation of protein localization to chromatin | IDA PMID:35013556 The ubiquitin-dependent ATPase p97 removes cytotoxic trapped... | ACCEPT | Summary: VCP removes trapped PARP1 from chromatin. It negatively regulates chromatin localization of ubiquitinated substrates by extracting them. Reason: Direct experimental evidence: VCP recognizes ubiquitinated PARP1 and promotes its removal from chromatin (PMID:35013556). Supporting Evidence: PMID:35013556 The ubiquitin-dependent ATPase p97 removes cytotoxic trapped PARP1 from chromatin |
| GO:0140036 ubiquitin-modified protein reader activity | IDA PMID:35013556 The ubiquitin-dependent ATPase p97 removes cytotoxic trapped... | ACCEPT | Summary: VCP reads ubiquitin modifications on PARP1 to initiate extraction from chromatin. Reason: Core molecular function demonstrated in the context of PARP1 removal. |
| GO:0005789 endoplasmic reticulum membrane | IDA PMID:24129571 Interaction between salt-inducible kinase 2 (SIK2) and p97/v... | ACCEPT | Summary: ER membrane localization from SIK2-VCP interaction study. Reason: ER membrane association confirmed by direct experimental evidence in ERAD context. |
| GO:0016887 ATP hydrolysis activity | IDA PMID:24129571 Interaction between salt-inducible kinase 2 (SIK2) and p97/v... | ACCEPT | Summary: ATP hydrolysis activity demonstrated in SIK2-VCP interaction study. Reason: Direct experimental evidence for VCP ATPase activity. |
| GO:0036503 ERAD pathway | IDA PMID:24129571 Interaction between salt-inducible kinase 2 (SIK2) and p97/v... | ACCEPT | Summary: ERAD function from SIK2-VCP study. Core function. Reason: Direct experimental evidence for VCP in ERAD, regulated by SIK2 interaction. |
| GO:0005515 protein binding | IPI PMID:27714797 Structural insights into the interaction of human p97 N-term... | MARK AS OVER ANNOTATED | Summary: VCP-Derlin-1 structural interaction study. More informative terms available. Reason: 'Protein binding' is uninformative. The VCP-DERL1 interaction is better captured by Derlin-1 retrotranslocation complex (GO:0036513). |
| GO:0016887 ATP hydrolysis activity | TAS PMID:15215856 A membrane protein complex mediates retro-translocation from... | ACCEPT | Summary: ATP hydrolysis from landmark ERAD retrotranslocation study. Core function. Reason: Core enzymatic function, TAS evidence from an authoritative study. |
| GO:0016887 ATP hydrolysis activity | IMP PMID:23349634 A newly uncovered group of distantly related lysine methyltr... | ACCEPT | Summary: ATP hydrolysis activity affected by Lys-315 methylation. Core function. Reason: Demonstrates that VCP ATPase activity is regulated by post-translational modification (methylation at K315). |
| GO:0106300 protein-DNA covalent cross-linking repair | IDA PMID:32152270 TEX264 coordinates p97- and SPRTN-mediated resolution of top... | ACCEPT | Summary: VCP together with SPRTN metalloprotease repairs covalent DNA-protein crosslinks (DPCs) during DNA synthesis. This is a specific DNA repair function. Reason: Direct experimental evidence from Fielden et al. 2020 demonstrating VCP-SPRTN cooperation in DPC repair. UniProt confirms this function. Supporting Evidence: PMID:32152270 TEX264 coordinates p97- and SPRTN-mediated resolution of topoisomerase 1-DNA adducts |
| GO:0005515 protein binding | IPI PMID:32152270 TEX264 coordinates p97- and SPRTN-mediated resolution of top... | MARK AS OVER ANNOTATED | Summary: VCP-TEX264 interaction in DPC repair context. Generic protein binding. Reason: 'Protein binding' is uninformative per curation guidelines. |
| GO:0036297 interstrand cross-link repair | ISS GO_REF:0000024 | ACCEPT | Summary: VCP is involved in ICL repair by mediating unloading of the ubiquitinated CMG helicase complex. Evidence is by sequence similarity from yeast Cdc48. Reason: UniProt documents this function (by similarity). VCP-mediated CMG helicase unloading during ICL repair is consistent with its general role in extracting ubiquitinated proteins from complexes. |
| GO:1905634 regulation of protein localization to chromatin | IDA PMID:32152270 TEX264 coordinates p97- and SPRTN-mediated resolution of top... | ACCEPT | Summary: VCP regulates protein localization to chromatin by extracting ubiquitinated substrates (DPCs, trapped PARP1, L3MBTL1). Reason: Direct experimental evidence for VCP regulating chromatin protein localization in the context of DPC repair. |
| GO:0045879 negative regulation of smoothened signaling pathway | IMP PMID:23747190 Ter94 ATPase complex targets k11-linked ubiquitinated ci to ... | KEEP AS NON CORE | Summary: Based on Drosophila Ter94 study showing regulation of Ci/Gli processing. VCP mediates K11-linked ubiquitin-dependent partial degradation of Ci. Reason: Evidence is primarily from Drosophila. VCP processes Hedgehog pathway components through ERAD (also captured in Reactome annotations for Hh-C processing). This is a pathway-specific outcome of VCP's general ERAD function. |
| GO:0005515 protein binding | IPI PMID:30455355 Physiological and pathophysiological characteristics of atax... | MARK AS OVER ANNOTATED | Summary: VCP-ataxin-3 interaction study. Generic protein binding. Reason: 'Protein binding' is uninformative. The VCP-ATXN3 interaction is better captured by ubiquitin-specific protease binding. |
| GO:0005515 protein binding | IPI PMID:31073040 LMBR1L regulates lymphopoiesis through Wnt/beta-catenin sign... | MARK AS OVER ANNOTATED | Summary: VCP-LMBR1L interaction in Wnt/beta-catenin signaling study. Reason: 'Protein binding' is uninformative per curation guidelines. |
| GO:0005515 protein binding | IPI PMID:29804830 ZFAND1 Recruits p97 and the 26S Proteasome to Promote the Cl... | MARK AS OVER ANNOTATED | Summary: VCP-ZFAND1 interaction in stress granule clearance. Functionally relevant. Reason: 'Protein binding' is uninformative. The functional relevance is captured by stress granule disassembly (GO:0035617). |
| GO:0010494 cytoplasmic stress granule | IDA PMID:29804830 ZFAND1 Recruits p97 and the 26S Proteasome to Promote the Cl... | ACCEPT | Summary: VCP localizes to stress granules during arsenite stress. Directly demonstrated. Reason: VCP stress granule localization is directly shown by ZFAND1 study. Supporting Evidence: PMID:29804830 ZFAND1 is an evolutionarily conserved regulator of SG clearance. 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 | IMP PMID:29804830 ZFAND1 Recruits p97 and the 26S Proteasome to Promote the Cl... | KEEP AS NON CORE | Summary: VCP is involved in cellular response to heat stress, mediating stress granule clearance after heat shock. Reason: Heat stress response is a context in which VCP's stress granule clearance function operates. It is a non-core phenotypic annotation. |
| GO:0035617 stress granule disassembly | IMP PMID:29804830 ZFAND1 Recruits p97 and the 26S Proteasome to Promote the Cl... | ACCEPT | Summary: VCP promotes stress granule disassembly. Direct functional evidence from the ZFAND1 recruitment study. Reason: Core VCP function in stress granule clearance, directly demonstrated. Supporting Evidence: PMID:29804830 ZFAND1 Recruits p97 and the 26S Proteasome to Promote the Clearance of Arsenite-Induced Stress Granules |
| GO:1903843 cellular response to arsenite ion | IMP PMID:29804830 ZFAND1 Recruits p97 and the 26S Proteasome to Promote the Cl... | KEEP AS NON CORE | Summary: VCP is involved in the response to arsenite-induced stress, mediating stress granule clearance. Reason: Arsenite response is a specific stress context in which VCP operates. It is not a core function but a phenotypic context. |
| GO:0005515 protein binding | IPI PMID:26842564 Chromatin-associated degradation is defined by UBXN-3/FAF1 t... | MARK AS OVER ANNOTATED | Summary: VCP-FAF1 interaction in chromatin-associated degradation context. Reason: 'Protein binding' is uninformative per curation guidelines. |
| GO:0005634 nucleus | IDA PMID:26842564 Chromatin-associated degradation is defined by UBXN-3/FAF1 t... | ACCEPT | Summary: Nuclear localization directly demonstrated in chromatin degradation study. Reason: Direct experimental evidence for VCP nuclear localization in the context of chromatin-associated degradation via FAF1. |
| GO:0090263 positive regulation of canonical Wnt signaling pathway | IDA PMID:28689657 Wnt-Dependent Inactivation of the Groucho/TLE Co-repressor b... | KEEP AS NON CORE | Summary: VCP positively regulates Wnt signaling. This may relate to VCP-LMBR1L interaction (PMID:31073040). Reason: Wnt signaling regulation is likely an indirect downstream effect of VCP's proteostasis functions rather than a direct VCP function. |
| GO:0005737 cytoplasm | IDA PMID:27753622 VCP/p97 cooperates with YOD1, UBXD1 and PLAA to drive cleara... | ACCEPT | Summary: Cytoplasm localization from lysophagy study. Correct but less specific than cytosol. Reason: Cytoplasm localization is correct. Consistent with VCP's primary compartment. |
| GO:0005515 protein binding | IPI PMID:27753622 VCP/p97 cooperates with YOD1, UBXD1 and PLAA to drive cleara... | MARK AS OVER ANNOTATED | Summary: VCP interactions with YOD1, UBXD1, PLAA in lysophagy context. Reason: 'Protein binding' is uninformative. These functionally important interactions are better captured by specific complex/process terms. |
| GO:0016236 macroautophagy | IMP PMID:27753622 VCP/p97 cooperates with YOD1, UBXD1 and PLAA to drive cleara... | ACCEPT | Summary: VCP cooperates with YOD1, UBXD1 and PLAA to drive clearance of ruptured lysosomes by autophagy (lysophagy). Reason: Direct experimental evidence for VCP in macroautophagy/lysophagy. Supporting Evidence: PMID:27753622 VCP/p97 cooperates with YOD1, UBXD1 and PLAA to drive clearance of ruptured lysosomes by autophagy |
| GO:0005515 protein binding | IPI PMID:19275885 UBXD1 is a VCP-interacting protein that is involved in ER-as... | MARK AS OVER ANNOTATED | Summary: VCP-UBXN6/UBXD1 interaction. Generic protein binding. Reason: 'Protein binding' is uninformative per curation guidelines. |
| GO:0032510 endosome to lysosome transport via multivesicular body sorting pathway | IMP PMID:21822278 Endolysosomal sorting of ubiquitylated caveolin-1 is regulat... | KEEP AS NON CORE | Summary: VCP mediates endolysosomal sorting of ubiquitylated caveolin-1 via the MVB pathway. This is a specific cargo-routing function. Reason: While experimentally demonstrated for caveolin-1, MVB sorting is a specific context of VCP's general ubiquitin-dependent membrane protein processing rather than a core function. Supporting Evidence: PMID:21822278 Endolysosomal sorting of ubiquitylated caveolin-1 is regulated by VCP and UBXD1 |
| GO:0005515 protein binding | IPI PMID:21822278 Endolysosomal sorting of ubiquitylated caveolin-1 is regulat... | MARK AS OVER ANNOTATED | Summary: VCP-CAV1-UBXN6 ternary complex. Generic protein binding. Reason: 'Protein binding' is uninformative per curation guidelines. |
| GO:0032991 protein-containing complex | IDA PMID:21822278 Endolysosomal sorting of ubiquitylated caveolin-1 is regulat... | MARK AS OVER ANNOTATED | Summary: VCP-CAV1-UBXN6 complex demonstrated. The term is generic. Reason: Generic 'protein-containing complex' is uninformative when VCP has specific complex annotations. |
| GO:0005515 protein binding | IPI PMID:23349634 A newly uncovered group of distantly related lysine methyltr... | MARK AS OVER ANNOTATED | Summary: VCP-VCPKMT interaction for K315 methylation. Reason: 'Protein binding' is uninformative per curation guidelines. |
| GO:0032991 protein-containing complex | IDA PMID:23349634 A newly uncovered group of distantly related lysine methyltr... | MARK AS OVER ANNOTATED | Summary: VCP in complex with methyltransferases. Generic term. Reason: Generic 'protein-containing complex' is uninformative. |
| GO:0005515 protein binding | IPI PMID:26389662 Systematic proteomics of the VCP-UBXD adaptor network identi... | MARK AS OVER ANNOTATED | Summary: VCP-UBXN10 interaction identified in VCP-UBXD adaptor proteomics. Reason: 'Protein binding' is uninformative per curation guidelines. |
| GO:0061857 endoplasmic reticulum stress-induced pre-emptive quality control | IMP PMID:26565908 Pre-emptive Quality Control Protects the ER from Protein Ove... | ACCEPT | Summary: VCP is involved in ER stress-induced pre-emptive QC, which selectively attenuates translocation of newly synthesized proteins into the ER and reroutes them to the cytosol for proteasomal degradation. Reason: Direct experimental evidence from Kadowaki et al. 2015. UniProt confirms this function. This is a specific mechanism by which VCP contributes to ER proteostasis. Supporting Evidence: PMID:26565908 Pre-emptive Quality Control Protects the ER from Protein Overload via the Proximity of ERAD Components and SRP |
| GO:0010498 proteasomal protein catabolic process | IMP PMID:26565908 Pre-emptive Quality Control Protects the ER from Protein Ove... | ACCEPT | Summary: VCP directs rerouted pre-emptive QC substrates to proteasomal degradation. Reason: Proteasomal catabolism is a core outcome of VCP-mediated substrate processing. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-8943080 | ACCEPT | Summary: VCP at ER membrane in CMV US11-mediated MHC class I degradation pathway. Reason: Reactome pathway annotation consistent with VCP's ER membrane ERAD function. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-8943083 | ACCEPT | Summary: VCP in DERL1:TMEM129 ERAD complex at ER membrane. Reason: Consistent with VCP's ER membrane localization during ERAD. |
| GO:0005515 protein binding | IPI PMID:24726327 Binding of OTULIN to the PUB domain of HOIP controls NF-kapp... | MARK AS OVER ANNOTATED | Summary: VCP-RNF31/HOIP interaction via PUB-PIM motif. Reason: 'Protein binding' is uninformative per curation guidelines. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8932276 | ACCEPT | Summary: VCP in cytosol for VCPKMT methylation. Reason: Cytosol localization from Reactome. Consistent with other evidence. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-6798748 | KEEP AS NON CORE | Summary: VCP found in secretory granule lumen contents released extracellularly. This is from neutrophil degranulation pathway. Reason: VCP is found in neutrophil granules and released extracellularly during degranulation. This is not a core VCP function but reflects its presence in secretory granule contents. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-6798751 | KEEP AS NON CORE | Summary: VCP in azurophil granule contents released extracellularly. Reason: Non-core localization from neutrophil degranulation. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-6800434 | KEEP AS NON CORE | Summary: VCP in ficolin-1-rich granule contents released extracellularly. Reason: Non-core localization from neutrophil degranulation. |
| GO:0034774 secretory granule lumen | TAS Reactome:R-HSA-6798748 | KEEP AS NON CORE | Summary: VCP found in secretory granule lumen. Neutrophil granule content. Reason: Non-core localization from neutrophil degranulation pathway. |
| GO:0035578 azurophil granule lumen | TAS Reactome:R-HSA-6798751 | KEEP AS NON CORE | Summary: VCP in azurophil granule lumen. Neutrophil granule content. Reason: Non-core localization from neutrophil degranulation pathway. |
| GO:1904813 ficolin-1-rich granule lumen | TAS Reactome:R-HSA-6800434 | KEEP AS NON CORE | Summary: VCP in ficolin-1-rich granule lumen. Neutrophil granule content. Reason: Non-core localization from neutrophil degranulation pathway. |
| GO:0006914 autophagy | IMP PMID:20104022 VCP/p97 is essential for maturation of ubiquitin-containing ... | ACCEPT | Summary: VCP is essential for autophagy, specifically maturation of ubiquitin-containing autophagosomes. Landmark study by Tresse et al. Reason: Core VCP function. IBMPFD mutations impair this autophagy function. Supporting Evidence: PMID:20104022 VCP is essential for autophagosome maturation |
| GO:0006914 autophagy | IMP PMID:25125609 A novel mutation in VCP causes Charcot-Marie-Tooth Type 2 di... | ACCEPT | Summary: Autophagy defects in VCP disease mutant (CMT2Y) context. Reason: Consistent with VCP's core role in autophagy, confirmed in disease context. |
| GO:0036503 ERAD pathway | IMP PMID:20104022 VCP/p97 is essential for maturation of ubiquitin-containing ... | ACCEPT | Summary: ERAD function from autophagy study. IBMPFD mutants show ERAD defects. Reason: Core VCP function confirmed in disease mutant context. |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | IMP PMID:20104022 VCP/p97 is essential for maturation of ubiquitin-containing ... | ACCEPT | Summary: Proteasome-mediated catabolism from autophagy study. Core function. Reason: Core VCP function. IBMPFD mutations do not detectably impair proteasomal degradation but do impair autophagy (per PMID:20104022). |
| GO:0097352 autophagosome maturation | IMP PMID:20104022 VCP/p97 is essential for maturation of ubiquitin-containing ... | ACCEPT | Summary: VCP is essential for autophagosome maturation. Core function. Reason: Directly demonstrated by Tresse et al. 2010. IBMPFD mutations impair this. Supporting Evidence: PMID:20104022 VCP deficiency by RNAi-mediated knockdown or overexpression of dominant-negative VCP results in significant accumulation of immature autophagic vesicles |
| GO:0036503 ERAD pathway | IDA PMID:25088257 Ubiquitin-specific protease 19 regulates the stability of th... | ACCEPT | Summary: ERAD from USP19-MARCH6 stability study. Core function. Reason: Core ERAD function with direct experimental evidence. |
| GO:0036513 Derlin-1 retrotranslocation complex | IDA PMID:15215856 A membrane protein complex mediates retro-translocation from... | ACCEPT | Summary: VCP is a component of the Derlin-1 retrotranslocation complex, demonstrated in the landmark Ye et al. 2004 Nature study. Reason: Directly demonstrated in an authoritative study. VCP associates with Derlin-1 via VIMP for ERAD retrotranslocation. Supporting Evidence: PMID:15215856 Here we identify a p97-interacting membrane protein complex in the mammalian ER that links these two events. The central component of the complex, Derlin-1 |
| GO:0036513 Derlin-1 retrotranslocation complex | IDA PMID:17872946 Identification of SVIP as an endogenous inhibitor of endopla... | ACCEPT | Summary: VCP in Derlin-1 complex with SVIP as an endogenous ERAD inhibitor. Reason: VCP-DERL1-SVIP complex directly demonstrated. |
| GO:1904288 BAT3 complex binding | IPI PMID:21636303 A ubiquitin ligase-associated chaperone holdase maintains po... | ACCEPT | Summary: VCP interacts with BAG6 (BAT3), a chaperone holdase that maintains polypeptides in soluble states for proteasome degradation. Reason: VCP-BAG6 interaction is documented in UniProt and experimentally validated. BAT3 complex binding is a specific and informative MF term. Supporting Evidence: PMID:21636303 A ubiquitin ligase-associated chaperone holdase maintains polypeptides in soluble states for proteasome degradation |
| GO:0010918 positive regulation of mitochondrial membrane potential | IMP PMID:23498975 Pathogenic VCP mutations induce mitochondrial uncoupling and... | KEEP AS NON CORE | Summary: VCP positively regulates mitochondrial membrane potential, likely through its role in mitochondrial quality control. Reason: Mitochondrial membrane potential regulation is an indirect downstream effect of VCP's OMM protein QC function rather than a direct activity. |
| GO:0019674 NAD+ metabolic process | IMP PMID:23498975 Pathogenic VCP mutations induce mitochondrial uncoupling and... | MARK AS OVER ANNOTATED | Summary: VCP involvement in NAD+ metabolism, likely indirect through mitochondrial QC effects. Reason: NAD+ metabolism is likely an indirect downstream effect of VCP's mitochondrial QC function rather than a direct VCP role in NAD+ metabolism. |
| GO:0072389 flavin adenine dinucleotide catabolic process | IMP PMID:23498975 Pathogenic VCP mutations induce mitochondrial uncoupling and... | MARK AS OVER ANNOTATED | Summary: FAD catabolism is an indirect downstream effect of VCP mitochondrial QC. Reason: FAD catabolism is not a direct VCP function. This is a downstream metabolic consequence of VCP's mitochondrial quality control activity. |
| GO:1903715 regulation of aerobic respiration | IMP PMID:23498975 Pathogenic VCP mutations induce mitochondrial uncoupling and... | MARK AS OVER ANNOTATED | Summary: Regulation of aerobic respiration is an indirect downstream effect of VCP mitochondrial QC. Reason: Not a direct VCP function. Downstream metabolic consequence of mitochondrial protein quality control. |
| GO:1903862 positive regulation of oxidative phosphorylation | IMP PMID:23498975 Pathogenic VCP mutations induce mitochondrial uncoupling and... | MARK AS OVER ANNOTATED | Summary: Positive regulation of oxidative phosphorylation is an indirect downstream effect of VCP mitochondrial QC. Reason: Not a direct VCP function. Downstream metabolic consequence of mitochondrial protein quality control. |
| GO:2001171 positive regulation of ATP biosynthetic process | IMP PMID:23498975 Pathogenic VCP mutations induce mitochondrial uncoupling and... | MARK AS OVER ANNOTATED | Summary: Positive regulation of ATP biosynthesis is an indirect downstream effect of VCP mitochondrial QC. Reason: Not a direct VCP function. Downstream metabolic consequence of mitochondrial protein quality control. |
| GO:0005515 protein binding | IPI PMID:21135095 The UBX protein SAKS1 negatively regulates endoplasmic retic... | MARK AS OVER ANNOTATED | Summary: Generic protein binding from interaction study. Reason: 'Protein binding' is uninformative per curation guidelines. |
| GO:0031625 ubiquitin protein ligase binding | IPI PMID:22590560 Ubiquitin-specific protease 25 functions in Endoplasmic Reti... | ACCEPT | Summary: VCP binds ubiquitin protein ligases. This is a more informative MF term that captures VCP's interaction with E3 ligases. Reason: VCP interacts with multiple E3 ubiquitin ligases (AMFR/gp78, SYVN1, RNF19A, STUB1, RNF125, RNF8). This binding is functionally important for substrate ubiquitination and delivery to VCP. Supporting Evidence: PMID:22590560 Ubiquitin-specific protease 25 functions in Endoplasmic Reticulum-associated degradation |
| GO:1990381 ubiquitin-specific protease binding | IPI PMID:22590560 Ubiquitin-specific protease 25 functions in Endoplasmic Reti... | ACCEPT | Summary: VCP binds ubiquitin-specific proteases (USP25, YOD1, ATXN3). Reason: VCP-DUB interactions are functionally important for substrate processing. Experimentally validated. |
| GO:0005515 protein binding | IPI PMID:17872946 Identification of SVIP as an endogenous inhibitor of endopla... | MARK AS OVER ANNOTATED | Summary: VCP-SVIP interaction in ERAD inhibition context. Reason: 'Protein binding' is uninformative per curation guidelines. |
| GO:0030970 retrograde protein transport, ER to cytosol | IMP PMID:25660456 Identification of ERAD components essential for dislocation ... | ACCEPT | Summary: VCP required for dislocation of NHK (alpha-1-antitrypsin variant). Reason: Core ERAD/retrotranslocation function with direct experimental evidence on a specific ERAD substrate (NHK). Supporting Evidence: PMID:25660456 Identification of ERAD components essential for dislocation of the null Hong Kong variant of alpha-1-antitrypsin (NHK) |
| GO:0034098 VCP-NPL4-UFD1 AAA ATPase complex | ISS GO_REF:0000024 | ACCEPT | Summary: VCP-NPL4-UFD1 complex membership inferred from yeast Cdc48 ortholog. Reason: This conserved complex is well established and directly demonstrated in human. |
| GO:1990730 VCP-NSFL1C complex | ISS GO_REF:0000024 | ACCEPT | Summary: VCP-NSFL1C (p47) complex inferred from ortholog. Reason: VCP-NSFL1C complex is directly demonstrated in human (UniProt subunit annotation). |
| GO:0005515 protein binding | IPI PMID:24089527 Caveolin-1 interacts with Derlin-1 and promotes ubiquitinati... | MARK AS OVER ANNOTATED | Summary: VCP-caveolin-1/Derlin-1 interaction in COX-2 degradation. Reason: 'Protein binding' is uninformative per curation guidelines. |
| GO:0005783 endoplasmic reticulum | IDA PMID:24089527 Caveolin-1 interacts with Derlin-1 and promotes ubiquitinati... | ACCEPT | Summary: ER localization directly demonstrated. Reason: ER localization consistent with VCP's ERAD function. |
| GO:0005515 protein binding | IPI PMID:16186510 Recruitment of the p97 ATPase and ubiquitin ligases to the s... | MARK AS OVER ANNOTATED | Summary: VCP interactions with AMFR, DERL1, SYVN1, SELENOS from landmark ERAD study. Reason: 'Protein binding' is uninformative. These interactions are better captured by Derlin-1 retrotranslocation complex and ubiquitin-like protein ligase binding. |
| GO:0005829 cytosol | TAS PMID:16186510 Recruitment of the p97 ATPase and ubiquitin ligases to the s... | ACCEPT | Summary: Cytosol localization from ERAD study. Correct. Reason: Cytosol is VCP's primary compartment. |
| GO:0034098 VCP-NPL4-UFD1 AAA ATPase complex | TAS PMID:16186510 Recruitment of the p97 ATPase and ubiquitin ligases to the s... | ACCEPT | Summary: VCP-NPL4-UFD1 complex from landmark ERAD study. Core complex. Reason: Core VCP complex confirmed by authoritative study. |
| GO:0044389 ubiquitin-like protein ligase binding | IPI PMID:16186510 Recruitment of the p97 ATPase and ubiquitin ligases to the s... | ACCEPT | Summary: VCP binds ubiquitin ligases (AMFR, SYVN1) at the ER membrane. This is a more informative term than generic protein binding. Reason: VCP interaction with E3 ubiquitin ligases is central to ERAD. This captures VCP's functional interaction with ligases. |
| GO:0005515 protein binding | IPI PMID:19822669 Ubiquilin and p97/VCP bind erasin, forming a complex involve... | MARK AS OVER ANNOTATED | Summary: VCP-UBXN4-UBQLN1 complex in ERAD. Generic protein binding. Reason: 'Protein binding' is uninformative per curation guidelines. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5654985 | ACCEPT | Summary: VCP in nucleoplasm for SPRTN-mediated POLH release from PCNA. Reason: Nucleoplasm localization consistent with VCP's DNA damage response function. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5654989 | ACCEPT | Summary: VCP in nucleoplasm for SPRTN-VCP-mediated POLH release. Reason: Consistent with VCP nuclear DNA damage response function. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5688834 | ACCEPT | Summary: VCP in nucleoplasm for ATXN3 binding. Reason: VCP-ATXN3 interaction occurs in the nucleus as well as cytoplasm. |
| GO:0070062 extracellular exosome | HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres... | KEEP AS NON CORE | Summary: VCP identified in extracellular exosomes by proteomics. VCP is an abundant cytosolic protein often found in exosome preparations. Reason: VCP presence in exosomes likely reflects its cytoplasmic abundance rather than a specific exosomal function. High-throughput data. |
| GO:0005789 endoplasmic reticulum membrane | IDA PMID:17872946 Identification of SVIP as an endogenous inhibitor of endopla... | ACCEPT | Summary: ER membrane localization from SVIP ERAD study. Reason: ER membrane association directly demonstrated in ERAD context. |
| GO:0036503 ERAD pathway | IDA PMID:17872946 Identification of SVIP as an endogenous inhibitor of endopla... | ACCEPT | Summary: ERAD function from SVIP endogenous inhibitor study. Core function. Reason: Core ERAD function with direct experimental evidence. |
| GO:1990381 ubiquitin-specific protease binding | IPI PMID:22970133 Valosin-containing protein (VCP/p97) is an activator of wild... | ACCEPT | Summary: VCP activates wild-type ataxin-3 DUB activity. Reason: VCP-ATXN3 interaction is a functionally significant DUB interaction. Supporting Evidence: PMID:22970133 Valosin-containing protein (VCP/p97) is an activator of wild-type ataxin-3 |
| GO:0035800 deubiquitinase activator activity | IDA PMID:22970133 Valosin-containing protein (VCP/p97) is an activator of wild... | ACCEPT | Summary: VCP activates ATXN3 deubiquitinase activity. This is a specific molecular function of VCP in regulating ubiquitin chain processing. Reason: Direct demonstration that VCP activates ATXN3 DUB activity. This is a specific molecular function relevant to VCP's ubiquitin biology. Supporting Evidence: PMID:22970133 Valosin-containing protein (VCP/p97) is an activator of wild-type ataxin-3 |
| GO:1903006 positive regulation of protein K63-linked deubiquitination | IDA PMID:22970133 Valosin-containing protein (VCP/p97) is an activator of wild... | ACCEPT | Summary: VCP promotes K63-linked deubiquitination via ATXN3 activation. Reason: Directly demonstrated that VCP promotes ATXN3-mediated K63-linked deubiquitination. |
| GO:0005634 nucleus | HDA PMID:21630459 Proteomic characterization of the human sperm nucleus. | ACCEPT | Summary: VCP identified in sperm nucleus proteomics. Reason: Nuclear localization consistent with other evidence. High-throughput proteomics data. |
| GO:0003723 RNA binding | HDA PMID:22681889 The mRNA-bound proteome and its global occupancy profile on ... | KEEP AS NON CORE | Summary: VCP identified in mRNA-bound proteome. Given VCP's role in stress granules (which contain mRNPs) and ribosome QC, RNA association is plausible. Reason: RNA binding is likely indirect, reflecting VCP's association with ribonucleoprotein complexes (stress granules, stalled ribosomes) rather than direct RNA binding. High-throughput data. |
| GO:0048471 perinuclear region of cytoplasm | IDA PMID:16275660 Identification of VCP/p97, carboxyl terminus of Hsp70-intera... | ACCEPT | Summary: VCP localization to perinuclear region, consistent with ER association. Reason: Perinuclear localization is consistent with VCP's ER membrane association and nuclear functions. |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | KEEP AS NON CORE | Summary: VCP in urinary exosome proteomics. Non-core localization. Reason: VCP in exosomes reflects its cytoplasmic abundance. High-throughput data. |
| GO:0005811 lipid droplet | IDA PMID:23297223 Spatial regulation of UBXD8 and p97/VCP controls ATGL-mediat... | ACCEPT | Summary: VCP localizes to lipid droplets where it regulates ATGL-mediated lipid droplet turnover via UBXD8 interaction. Reason: VCP lipid droplet localization is experimentally demonstrated and functionally relevant to ATGL regulation. Supporting Evidence: PMID:23297223 Spatial regulation of UBXD8 and p97/VCP controls ATGL-mediated lipid droplet turnover |
| GO:0005515 protein binding | IPI PMID:21949850 The tissue-specific Rep8/UBXD6 tethers p97 to the endoplasmi... | MARK AS OVER ANNOTATED | Summary: VCP-UBXN8/Rep8 interaction for ER-tethered ERAD. Reason: 'Protein binding' is uninformative per curation guidelines. |
| GO:0070062 extracellular exosome | HDA PMID:20458337 MHC class II-associated proteins in B-cell exosomes and pote... | KEEP AS NON CORE | Summary: VCP in B-cell exosome proteomics. Non-core localization. Reason: VCP in exosomes reflects its cytoplasmic abundance. High-throughput data. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5324632 | ACCEPT | Summary: VCP in cytosol from HSF1/HSP90 dissociation pathway. Reason: Cytosol localization from Reactome. Consistent with other evidence. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5362412 | ACCEPT | Summary: VCP in cytosol for Hh C-terminal fragment ubiquitination. Reason: Cytosol localization from Reactome Hedgehog pathway. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5362441 | ACCEPT | Summary: VCP in cytosol for Hh fragment recruitment to ERAD machinery. Reason: Cytosol localization from Reactome. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5362459 | ACCEPT | Summary: VCP-catalyzed ATP hydrolysis promotes Hh-C translocation to cytosol. Reason: Cytosol localization from Reactome. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5387386 | ACCEPT | Summary: VCP in cytosol for Hh variant processing. Reason: Cytosol localization from Reactome. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5387389 | ACCEPT | Summary: VCP in cytosol for Hh variant translocation. Reason: Cytosol localization from Reactome. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5483238 | ACCEPT | Summary: VCP in cytosol for Hh variant ubiquitination. Reason: Cytosol localization from Reactome. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-6781953 | ACCEPT | Summary: VCP in cytosol for YOD1 binding. Reason: Cytosol localization from Reactome. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8850594 | ACCEPT | Summary: VCP in cytosol for deglycosylation complex. Reason: Cytosol localization from Reactome. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8866542 | ACCEPT | Summary: VCP in cytosol for CFTR ERAD. Reason: Cytosol localization from Reactome. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8866546 | ACCEPT | Summary: VCP in cytosol for CFTR ubiquitination. Reason: Cytosol localization from Reactome. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8866551 | ACCEPT | Summary: VCP in cytosol for CFTR ERAD complex binding. Reason: Cytosol localization from Reactome. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8866854 | ACCEPT | Summary: VCP in cytosol for CFTR F508del ERAD. Reason: Cytosol localization from Reactome. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8866856 | ACCEPT | Summary: VCP in cytosol for CFTR F508del ubiquitination. Reason: Cytosol localization from Reactome. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-8866857 | ACCEPT | Summary: VCP in cytosol for CFTR F508del ERAD complex. Reason: Cytosol localization from Reactome. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9755507 | ACCEPT | Summary: VCP in cytosol for UBXN7-NFE2L2/NRF2 CRL3 complex interaction. Reason: Cytosol localization from Reactome. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9758088 | ACCEPT | Summary: VCP in cytosol for UBXN7 binding. Reason: Cytosol localization from Reactome. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9758090 | ACCEPT | Summary: VCP in cytosol for ubiquitinated NFE2L2 extraction. Reason: Cytosol localization from Reactome. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9931264 | ACCEPT | Summary: VCP in cytosol for CD274/PD-L1 ERAD. Reason: Cytosol localization from Reactome. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9931298 | ACCEPT | Summary: VCP in cytosol for CD274 ubiquitination by ERAD complex. Reason: Cytosol localization from Reactome. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9931313 | ACCEPT | Summary: VCP in cytosol for CD274 ERAD complex binding. Reason: Cytosol localization from Reactome. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9948427 | ACCEPT | Summary: VCP in cytosol for ANKZF1-mediated ribosome QC. Reason: Cytosol localization from Reactome ribosome QC pathway. |
| GO:0019079 viral genome replication | IMP PMID:22379090 Valosin-containing protein (VCP/p97) is required for poliovi... | KEEP AS NON CORE | Summary: VCP/p97 is required for poliovirus replication and cellular protein secretion during infection. Reason: Viral genome replication dependency on VCP reflects co-option of host proteostasis machinery by the virus, not a core VCP function. This is a host-pathogen interaction context. Supporting Evidence: PMID:22379090 Valosin-containing protein (VCP/p97) is required for poliovirus replication and is involved in cellular protein secretion pathway in poliovirus infection |
| GO:0005515 protein binding | IPI PMID:22902628 Proliferating cell nuclear antigen (PCNA)-binding protein C1... | MARK AS OVER ANNOTATED | Summary: VCP-SPRTN/C1orf124 interaction for DNA damage response. Reason: 'Protein binding' is uninformative per curation guidelines. |
| GO:0005515 protein binding | IPI PMID:22948820 Lysine methylation of VCP by a member of a novel human prote... | MARK AS OVER ANNOTATED | Summary: VCP-VCPKMT methyltransferase interaction. Reason: 'Protein binding' is uninformative per curation guidelines. |
| GO:0005515 protein binding | IPI PMID:23042605 DVC1 (C1orf124) is a DNA damage-targeting p97 adaptor that p... | MARK AS OVER ANNOTATED | Summary: VCP-SPRTN/DVC1 interaction in DNA damage context. Reason: 'Protein binding' is uninformative per curation guidelines. |
| GO:0005515 protein binding | IPI PMID:23042607 DVC1 (C1orf124) recruits the p97 protein segregase to sites ... | MARK AS OVER ANNOTATED | Summary: VCP-SPRTN/DVC1 interaction for DNA damage recruitment. Reason: 'Protein binding' is uninformative per curation guidelines. |
| GO:0006974 DNA damage response | IDA PMID:23042605 DVC1 (C1orf124) is a DNA damage-targeting p97 adaptor that p... | ACCEPT | Summary: VCP is recruited to stalled replication forks via SPRTN, mediating DNA damage response. Core nuclear function. Reason: Direct experimental evidence. VCP's DNA damage response function is well established and disease-relevant. Supporting Evidence: PMID:23042605 DVC1 (C1orf124) is a DNA damage-targeting p97 adaptor that promotes ubiquitin-dependent responses to replication blocks |
| GO:0019985 translesion synthesis | IMP PMID:23042605 DVC1 (C1orf124) is a DNA damage-targeting p97 adaptor that p... | ACCEPT | Summary: VCP limits excessive translesion synthesis by extracting POLH from stalled replication forks. This is a regulatory role. Reason: VCP regulates translesion synthesis by mediating POLH extraction from PCNA. UniProt confirms this function. |
| GO:0036503 ERAD pathway | IMP PMID:22607976 STT3B-dependent posttranslational N-glycosylation as a surve... | ACCEPT | Summary: ERAD from STT3B post-translational N-glycosylation surveillance study. Reason: Core ERAD function with experimental evidence. |
| GO:0005515 protein binding | IPI PMID:22120668 The AAA-ATPase VCP/p97 promotes 53BP1 recruitment by removin... | MARK AS OVER ANNOTATED | Summary: VCP-L3MBTL1 interaction at DNA damage sites. Reason: 'Protein binding' is uninformative per curation guidelines. |
| GO:0006302 double-strand break repair | IDA PMID:22120668 The AAA-ATPase VCP/p97 promotes 53BP1 recruitment by removin... | ACCEPT | Summary: VCP promotes 53BP1 recruitment by removing L3MBTL1 from DNA DSBs. Core nuclear function. Reason: Direct experimental evidence for VCP in DSB repair (PMID:22120668). VCP extracts L3MBTL1 from DSB sites to allow 53BP1 recruitment. Supporting Evidence: PMID:22120668 The AAA-ATPase VCP/p97 promotes 53BP1 recruitment by removing L3MBTL1 from DNA double-strand breaks |
| GO:0006974 DNA damage response | IDA PMID:22120668 The AAA-ATPase VCP/p97 promotes 53BP1 recruitment by removin... | ACCEPT | Summary: DNA damage response from L3MBTL1/53BP1 study. Core nuclear function. Reason: Direct experimental evidence for VCP in DNA damage response. |
| GO:0016567 protein ubiquitination | IDA PMID:22120668 The AAA-ATPase VCP/p97 promotes 53BP1 recruitment by removin... | ACCEPT | Summary: VCP promotes ubiquitination and removal of L3MBTL1 from DSB sites. Reason: VCP promotes L3MBTL1 ubiquitination at DSB sites. This is a specific context of VCP-mediated ubiquitin-dependent processing. |
| GO:0035861 site of double-strand break | IDA PMID:22120668 The AAA-ATPase VCP/p97 promotes 53BP1 recruitment by removin... | ACCEPT | Summary: VCP is recruited to DSB sites. Directly demonstrated. Reason: VCP recruitment to DSB sites is directly demonstrated and is a core feature of its DNA damage response function. Supporting Evidence: PMID:22120668 VCP/p97 promotes 53BP1 recruitment by removing L3MBTL1 from DNA double-strand breaks |
| GO:0005515 protein binding | IPI PMID:22795130 Ubiquitin-dependent intramembrane rhomboid protease promotes... | MARK AS OVER ANNOTATED | Summary: VCP-RHBDD1 interaction in ERAD of membrane proteins. Reason: 'Protein binding' is uninformative per curation guidelines. |
| GO:0031334 positive regulation of protein-containing complex assembly | IDA PMID:18775313 UBXD7 binds multiple ubiquitin ligases and implicates p97 in... | KEEP AS NON CORE | Summary: VCP promotes complex assembly via UBXN7 interactions. Reason: This is a generic regulatory outcome. VCP's role is to extract/unfold ubiquitinated proteins, which can secondarily affect complex assembly. |
| GO:0045732 positive regulation of protein catabolic process | IDA PMID:18775313 UBXD7 binds multiple ubiquitin ligases and implicates p97 in... | ACCEPT | Summary: VCP promotes protein catabolism via UBXN7/HIF1alpha turnover. Reason: Positive regulation of protein catabolism is a core VCP function. |
| GO:0005515 protein binding | IPI PMID:17314412 The RBCC gene RFP2 (Leu5) encodes a novel transmembrane E3 u... | MARK AS OVER ANNOTATED | Summary: VCP-TRIM13/RFP2 interaction in ERAD. Reason: 'Protein binding' is uninformative per curation guidelines. |
| GO:0031593 polyubiquitin modification-dependent protein binding | IDA PMID:11483959 Valosin-containing protein is a multi-ubiquitin chain-target... | ACCEPT | Summary: Direct demonstration of VCP multi-ubiquitin chain targeting. Core MF. Reason: Landmark study directly demonstrating VCP as a multi-ubiquitin chain targeting factor. Core molecular function. Supporting Evidence: PMID:11483959 Valosin-containing protein is a multi-ubiquitin chain-targeting factor required in ubiquitin-proteasome degradation |
| GO:0045732 positive regulation of protein catabolic process | IDA PMID:11483959 Valosin-containing protein is a multi-ubiquitin chain-target... | ACCEPT | Summary: VCP promotes ubiquitin-proteasome degradation. Core function. Reason: Core VCP function directly demonstrated. |
| GO:0000502 proteasome complex | IDA PMID:9452483 Involvement of valosin-containing protein, an ATPase Co-puri... | MARK AS OVER ANNOTATED | Summary: VCP co-purified with 26S proteasome and IkappaBalpha. However, VCP is not a bona fide proteasome subunit - it delivers substrates to the proteasome. Reason: VCP co-purifies with the proteasome but is not a proteasome subunit. It is a proteasome-associated factor that delivers ubiquitinated substrates. The CC term 'proteasome complex' implies subunit membership. Supporting Evidence: PMID:9452483 Involvement of valosin-containing protein, an ATPase Co-purified with IkappaBalpha and 26 S proteasome |
| GO:0005515 protein binding | IPI PMID:9452483 Involvement of valosin-containing protein, an ATPase Co-puri... | MARK AS OVER ANNOTATED | Summary: VCP-proteasome interaction. Reason: 'Protein binding' is uninformative per curation guidelines. |
| GO:0032436 positive regulation of proteasomal ubiquitin-dependent protein catabolic process | IDA PMID:9452483 Involvement of valosin-containing protein, an ATPase Co-puri... | ACCEPT | Summary: VCP promotes proteasomal ubiquitin-dependent catabolism of IkappaBalpha. Reason: Core VCP function. VCP promotes delivery of ubiquitinated substrates to the proteasome. |
| GO:0019903 protein phosphatase binding | IPI PMID:10364224 Identification of the cell cycle regulator VCP (p97/CDC48) a... | ACCEPT | Summary: VCP interacts with PTPH1 protein-tyrosine phosphatase. This is a more informative term than generic protein binding. Reason: VCP-PTPH1 interaction is directly demonstrated and the term is specific and informative. |
| GO:0005515 protein binding | IPI PMID:19818707 The otubain YOD1 is a deubiquitinating enzyme that associate... | MARK AS OVER ANNOTATED | Summary: VCP-YOD1 interaction in ERAD context. Reason: 'Protein binding' is uninformative. VCP-YOD1 interaction is better captured by ubiquitin-specific protease binding. |
| GO:0019904 protein domain specific binding | IPI PMID:15362974 A novel UBA and UBX domain protein that binds polyubiquitin ... | ACCEPT | Summary: VCP interacts with UBA and UBX domains of NGLY1 cofactor SAKS1. Reason: VCP binds multiple cofactors via specific domain interactions (UBX, VIM, SHP, PUB motifs). Protein domain specific binding is informative. |
| GO:0005515 protein binding | IPI PMID:17681147 Ufd1 is a cofactor of gp78 and plays a key role in cholester... | MARK AS OVER ANNOTATED | Summary: VCP-UFD1 interaction in cholesterol metabolism/HMGCR stability. Reason: 'Protein binding' is uninformative per curation guidelines. |
| GO:0005515 protein binding | IPI PMID:16449189 Derlin-2 and Derlin-3 are regulated by the mammalian unfolde... | MARK AS OVER ANNOTATED | Summary: VCP-Derlin-2/3 interactions in ERAD. Reason: 'Protein binding' is uninformative per curation guidelines. |
| GO:0005515 protein binding | IPI PMID:10855792 VCP, a weak ATPase involved in multiple cellular events, int... | MARK AS OVER ANNOTATED | Summary: VCP-BRCA1 interaction in the nucleus. Reason: 'Protein binding' is uninformative per curation guidelines. |
| GO:0005634 nucleus | IDA PMID:10855792 VCP, a weak ATPase involved in multiple cellular events, int... | ACCEPT | Summary: Nuclear localization from VCP-BRCA1 interaction study. Reason: Nuclear localization directly demonstrated. |
| GO:0005829 cytosol | IDA PMID:10855792 VCP, a weak ATPase involved in multiple cellular events, int... | ACCEPT | Summary: Cytosol localization from VCP-BRCA1 study. Reason: Cytosol is VCP's primary compartment. |
| GO:0006281 DNA repair | NAS PMID:16140914 Valosin-containing protein phosphorylation at Ser784 in resp... | ACCEPT | Summary: VCP is involved in DNA repair. This is a broad term; more specific DNA repair annotations (DSB repair, DPC repair, ICL repair) are also present. Reason: DNA repair is a well-established VCP function (DSB repair, DPC repair, replication fork processing). The broad term is acceptable alongside the more specific annotations. |
| GO:0006302 double-strand break repair | IDA PMID:10855792 VCP, a weak ATPase involved in multiple cellular events, int... | ACCEPT | Summary: DSB repair from VCP-BRCA1 interaction study. Reason: DSB repair is a core VCP nuclear function. |
| GO:0006974 DNA damage response | IDA PMID:16140914 Valosin-containing protein phosphorylation at Ser784 in resp... | ACCEPT | Summary: DNA damage response from VCP Ser784 phosphorylation study. Reason: VCP is phosphorylated in response to DNA damage and participates in DDR. Supporting Evidence: PMID:16140914 Valosin-containing protein phosphorylation at Ser784 in response to DNA damage |
| GO:0043231 intracellular membrane-bounded organelle | ISS GO_REF:0000024 | ACCEPT | Summary: VCP localizes to multiple intracellular membrane-bounded organelles (ER, Golgi, mitochondria, lysosomes). Very generic term. Reason: While generic, VCP does localize to multiple membrane-bounded organelles. Not wrong, but less informative than specific organelle terms. |
| GO:0005634 nucleus | TAS PMID:16130169 Proteomics of human umbilical vein endothelial cells applied... | ACCEPT | Summary: Nuclear localization from etoposide-induced apoptosis proteomics study. Reason: Nuclear localization confirmed. |
| GO:0042981 regulation of apoptotic process | TAS PMID:16130169 Proteomics of human umbilical vein endothelial cells applied... | KEEP AS NON CORE | Summary: VCP may regulate apoptosis, identified in etoposide-induced apoptosis study. Reason: Apoptosis regulation is likely an indirect downstream effect of VCP's proteostasis functions rather than a direct regulatory role. Pleiotropic. |
| GO:0005515 protein binding | IPI PMID:15743842 Human Fas-associated factor 1, interacting with ubiquitinate... | MARK AS OVER ANNOTATED | Summary: VCP-FAF1 interaction in ubiquitin-proteasome pathway. Reason: 'Protein binding' is uninformative per curation guidelines. |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | NAS PMID:15743842 Human Fas-associated factor 1, interacting with ubiquitinate... | ACCEPT | Summary: Proteasome-mediated catabolism from FAF1 study. Core function. Reason: Core VCP function, redundant with stronger evidence. |
| GO:0005515 protein binding | IPI PMID:15215856 A membrane protein complex mediates retro-translocation from... | MARK AS OVER ANNOTATED | Summary: VCP-SELENOS/VIMP interaction in ERAD retrotranslocation. Reason: 'Protein binding' is uninformative per curation guidelines. |
| GO:0005783 endoplasmic reticulum | IDA PMID:15215856 A membrane protein complex mediates retro-translocation from... | ACCEPT | Summary: ER localization from landmark retrotranslocation study. Reason: ER localization directly demonstrated in authoritative study. |
| GO:0005829 cytosol | IDA PMID:15215856 A membrane protein complex mediates retro-translocation from... | ACCEPT | Summary: Cytosol localization from ERAD study. Reason: Cytosol is VCP's primary compartment. |
| GO:0016567 protein ubiquitination | NAS PMID:15215856 A membrane protein complex mediates retro-translocation from... | ACCEPT | Summary: VCP involved in ubiquitination during ERAD retrotranslocation. VCP does not itself have E3 ligase activity but promotes ubiquitination by recruiting substrates and E3 ligases. Reason: VCP facilitates protein ubiquitination in the ERAD pathway by working with E3 ligases. While not a direct ubiquitinating enzyme, it promotes ubiquitination of ERAD substrates. |
| GO:0030968 endoplasmic reticulum unfolded protein response | TAS PMID:15215856 A membrane protein complex mediates retro-translocation from... | ACCEPT | Summary: VCP participates in the ER UPR by mediating ERAD, which is a key UPR effector mechanism. Reason: ERAD (mediated by VCP) is a core effector mechanism of the ER UPR. |
| GO:0030970 retrograde protein transport, ER to cytosol | IDA PMID:15215856 A membrane protein complex mediates retro-translocation from... | ACCEPT | Summary: Retrograde ER-to-cytosol transport from landmark retrotranslocation study. Reason: Core ERAD/retrotranslocation function directly demonstrated in authoritative study. Supporting Evidence: PMID:15215856 This process requires recognition of a substrate in the ER lumen and its subsequent movement through the membrane by the cytosolic p97 ATPase |
| GO:0036503 ERAD pathway | TAS PMID:15215856 A membrane protein complex mediates retro-translocation from... | ACCEPT | Summary: ERAD from landmark retrotranslocation study. Core function. Reason: Core ERAD function from authoritative study. |
| GO:0045184 establishment of protein localization | TAS PMID:15215856 A membrane protein complex mediates retro-translocation from... | ACCEPT | Summary: VCP establishes protein localization by extracting misfolded proteins from the ER to the cytosol. This is a general term. Reason: VCP mediates protein relocation (ER to cytosol retrotranslocation, chromatin extraction, etc.). The term is broad but correct. |
| GO:0062093 lysophagy | NAS PMID:29804830 ZFAND1 Recruits p97 and the 26S Proteasome to Promote the Cl... | NEW | Summary: VCP is recruited to damaged lysosomes via UBXD1/PLAA cofactors to promote lysophagy. VCP ATPase activity is required for clearance of damaged lysosomes. Reason: Well-supported role in lysophagy via UBXD1/PLAA-mediated recruitment to damaged lysosomes. Not previously annotated in GOA. |
| GO:0072671 mitochondria-associated ubiquitin-dependent protein catabolic process | IDA PMID:21118995 The AAA-ATPase p97 is essential for outer mitochondrial memb... | NEW | Summary: VCP/p97 is essential for extraction and proteasomal degradation of ubiquitinated outer mitochondrial membrane proteins. Demonstrated by Xu et al. 2011. Reason: Core mitochondrial quality control function. VCP extracts ubiquitinated OMM proteins for proteasomal degradation. Supported by direct experimental evidence. |
| GO:0007084 mitotic nuclear membrane reassembly | IMP PMID:18097415 Cdc48/p97 promotes reformation of the nucleus by extracting ... | NEW | Summary: VCP/p97, with its UFD1-NPL4 adaptors, drives annular fusion of the post-mitotic nuclear envelope by extracting ubiquitinated chromatin substrates (notably Aurora-B) and recruiting ESCRT-III (CHMP2A) to nucleo-cytoplasmic channels in the forming NE; the p47 adaptor separately controls membrane delivery and NE expansion. Direct p97 manipulation in vitro and in cells (Hetzer 2001, Ramadan 2007) establishes the requirement; UFD1-adaptor depletion (Olmos 2015) delays NE-rim formation, impairs CHMP2A recruitment to the telophase NE, and reduces post-mitotic nucleo-cytoplasmic compartmentalization, defining the downstream ESCRT-III recruitment step. Reason: Mechanistically distinct from the ERAD, autophagy, DDR, mitochondrial-QC and RQC core functions already captured. Flagged as a gap in the prior scanner pass on issue #268. Evidence code IMP is supported by direct p97 manipulation in PMID:18097415 (Ramadan et al. 2007, Nature) — "p97 stimulates nucleus reformation by inactivating the chromatin-associated kinase Aurora B" via ubiquitin-dependent extraction — and PMID:11781570 (Hetzer et al. 2001, Nat Cell Biol) which dissected two discrete p97 functions in NE assembly using in vitro reconstitution (p97-Ufd1-Npl4 for closed NE formation, p97-p47 for NE growth). PMID:26040713 (Olmos et al. 2015) is retained as supporting evidence for the downstream UFD1-dependent CHMP2A recruitment step. References 11781570 and 18097415 were identified via the structured bibliography of PMID:26040713 (PMC4471131 XML, refs 6 and 20) — verified primary sources, not guessed PMIDs. Supporting Evidence: PMID:18097415 Here we show that p97 stimulates nucleus reformation by inactivating the chromatin-associated kinase Aurora B. PMID:18097415 During exit from mitosis, p97 binds to Aurora B after its ubiquitylation and extracts it from chromatin. This leads to inactivation of Aurora B on chromatin, thus allowing chromatin decondensation and nuclear envelope formation. PMID:11781570 Here we show that p97, an AAA-ATPase previously implicated in fusion of Golgi and transitional endoplasmic reticulum (ER) membranes together with the adaptor p47, has two discrete functions in NE assembly. Formation of a closed NE requires the p97-Ufd1-Npl4 complex, not previously implicated in membrane fusion. Subsequent NE growth involves a p97-p47 complex. PMID:26040713 The p97 AAA-ATPase controls both phases of NE reformation; in concert with its adaptor protein p47, it regulates membrane delivery and NE expansion whilst through its adaptors Nuclear Protein Like 4 (NPL4) and UFD1 it regulates annular fusion. PMID:26040713 whilst cells depleted for UFD1 recruited CHMP2A to the midbody (Figure 3D), recruitment of CHMP2A to the forming NE was impaired (Figure 3C and 3D). |
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