id: Q8TAT6 gene_symbol: NPLOC4 product_type: PROTEIN status: COMPLETE taxon: id: NCBITaxon:9606 label: Homo sapiens description: >- NPLOC4 (Nuclear protein localization protein 4 homolog, NPL4) is an essential ubiquitin-binding cofactor of the AAA+ ATPase VCP/p97. With UFD1 it forms the obligate UFD1-NPL4 heterodimer, the principal substrate-recruiting adaptor of p97, generating the VCP-NPL4-UFD1 segregase complex. NPL4 binds polyubiquitin chains through its C-terminal RanBP2-type zinc finger and, together with UFD1, engages and unfolds the initiating ubiquitin to thread substrates into the p97 central pore. The complex extracts ubiquitinated proteins from membranes, chromatin, and macromolecular assemblies and delivers them for proteasomal degradation. It is central to endoplasmic-reticulum-associated degradation (ERAD), where it drives retrotranslocation of misfolded proteins from the ER to the cytosol, and it participates in many other p97-dependent processes including ribosome-associated quality control, spindle disassembly and nuclear-envelope reformation at the end of mitosis, and Golgi membrane reassembly. NPL4 also contributes to a non-canonical role of the p97 complex in innate immunity, acting as a negative regulator of type I interferon production by helping bind RIG-I (RIGI/DDX58) and recruit RNF125 for its ubiquitination and degradation. NPL4 contains an MPN(-like) domain (a catalytically inactive pseudo-DUB: it lacks the JAMM/MPN+ metalloprotease catalytic motif, so NPL4 itself has no deubiquitinase activity), a ubiquitin-like region, and the RanBP2-type zinc finger, and localizes to the cytosol, the ER membrane and the nucleus. existing_annotations: - term: id: GO:0005634 label: nucleus evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: is_active_in review: summary: Phylogenetically inferred nuclear localization. NPL4/VCP acts on nuclear substrates (e.g. chromatin-associated degradation, spindle disassembly, nuclear-envelope reformation), so nuclear localization is plausible. action: KEEP_AS_NON_CORE reason: Nuclear localization is documented (HDA) and consistent with nuclear p97 functions, but the core adaptor activity is exerted broadly (cytosol, ER, nucleus); retained as a valid non-core localization. supported_by: - reference_id: file:human/NPLOC4/NPLOC4-uniprot.txt supporting_text: Nucleus {ECO:0000250|UniProtKB:Q9ES54} - term: id: GO:0031625 label: ubiquitin protein ligase binding evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables review: summary: NPL4 (within UFD1-NPL4) associates with ubiquitin ligases/ligase-bearing machineries (e.g. recruits RNF125 in the RIG-I pathway), consistent with ubiquitin protein ligase binding. action: KEEP_AS_NON_CORE reason: Plausible and supported by the RNF125 recruitment in the RIG-I pathway, but the informative core molecular function is polyubiquitin binding as a p97 substrate-recruiting cofactor rather than ligase binding per se. supported_by: - reference_id: file:human/NPLOC4/NPLOC4-uniprot.txt supporting_text: recruits RNF125 to promote ubiquitination and degradation of RIGI - term: id: GO:0043130 label: ubiquitin binding evidence_type: IBA original_reference_id: GO_REF:0000033 qualifier: enables review: summary: NPL4 binds ubiquitin/polyubiquitin via its RanBP2-type zinc finger, the core molecular function that lets the UFD1-NPL4 heterodimer recognize ubiquitinated substrates for p97. action: ACCEPT reason: Directly supported; the RanBP2-type zinc finger binds ubiquitinated proteins, a defining function of NPL4. supported_by: - reference_id: file:human/NPLOC4/NPLOC4-uniprot.txt supporting_text: Binds ubiquitinated proteins via its RanBP2-type zinc finger - term: id: GO:0005634 label: nucleus evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Electronic annotation of nuclear localization, redundant with the IBA/HDA nuclear annotations. action: KEEP_AS_NON_CORE reason: Consistent with documented nuclear localization; non-core as the adaptor acts in multiple compartments. supported_by: - reference_id: file:human/NPLOC4/NPLOC4-uniprot.txt supporting_text: Nucleus {ECO:0000250|UniProtKB:Q9ES54} - term: id: GO:0005783 label: endoplasmic reticulum evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: ER localization, where the VCP-NPL4-UFD1 complex drives retrotranslocation of misfolded proteins during ERAD. action: ACCEPT reason: ER association is documented and corresponds to a major site of NPL4 function (ERAD retrotranslocation). supported_by: - reference_id: file:human/NPLOC4/NPLOC4-uniprot.txt supporting_text: Endoplasmic reticulum {ECO:0000250|UniProtKB:Q9ES54} - term: id: GO:0005829 label: cytosol evidence_type: IEA original_reference_id: GO_REF:0000044 qualifier: located_in review: summary: Cytosolic localization, the principal compartment where the p97-UFD1-NPL4 segregase operates and delivers extracted substrates to the proteasome. action: ACCEPT reason: Cytosolic localization is well supported and is the major site of the adaptor function. supported_by: - reference_id: file:human/NPLOC4/NPLOC4-uniprot.txt supporting_text: Cytoplasm, cytosol - term: id: GO:0006511 label: ubiquitin-dependent protein catabolic process evidence_type: IEA original_reference_id: GO_REF:0000002 qualifier: involved_in review: summary: NPL4, as the p97 substrate-recruiting cofactor, is integral to ubiquitin-dependent proteasomal degradation. action: ACCEPT reason: Core biological-process role; the UFD1-NPL4-VCP complex delivers ubiquitinated substrates for degradation by the proteasome. supported_by: - reference_id: file:human/NPLOC4/NPLOC4-uniprot.txt supporting_text: where they are degraded by the proteasome - term: id: GO:0030970 label: retrograde protein transport, ER to cytosol evidence_type: IEA original_reference_id: GO_REF:0000117 qualifier: involved_in review: summary: NPL4 (with UFD1/VCP) mediates the export (retrotranslocation) of misfolded proteins from the ER to the cytosol during ERAD. action: ACCEPT reason: Directly supported by the UniProt function and by IMP evidence; this is a core process for the complex. supported_by: - reference_id: file:human/NPLOC4/NPLOC4-uniprot.txt supporting_text: necessary for the export of misfolded proteins from the ER to the cytoplasm - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:17070805 qualifier: enables review: summary: High-throughput interaction with ubiquitin (UBC, P0CG48). Bare protein binding; reflects the ubiquitin-binding activity. action: KEEP_AS_NON_CORE reason: Records a ubiquitin interaction but bare protein binding is uninformative; the specific ubiquitin-binding function is captured elsewhere. supported_by: - reference_id: file:human/NPLOC4/NPLOC4-goa.tsv supporting_text: UniProtKB:P0CG48 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:18775313 qualifier: enables review: summary: Interaction with VCP (P55072) and UFD1 (Q92890), the core partners of the segregase complex. Bare protein binding term. action: KEEP_AS_NON_CORE reason: The interactions (VCP, UFD1) are biologically central, but bare protein binding is uninformative; the meaningful relationships are captured by the complex and ATPase-binding annotations. supported_by: - reference_id: file:human/NPLOC4/NPLOC4-goa.tsv supporting_text: UniProtKB:P55072 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:20414249 qualifier: enables review: summary: Interaction with VCP and UFD1 captured as bare protein binding. action: KEEP_AS_NON_CORE reason: Central interactions but bare protein binding is uninformative; captured by complex/ATPase-binding annotations. supported_by: - reference_id: file:human/NPLOC4/NPLOC4-goa.tsv supporting_text: UniProtKB:P55072 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:21645854 qualifier: enables review: summary: Interaction with VCP and UFD1 captured as bare protein binding. action: KEEP_AS_NON_CORE reason: Central interactions but bare protein binding is uninformative. supported_by: - reference_id: file:human/NPLOC4/NPLOC4-goa.tsv supporting_text: UniProtKB:P55072 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:26471729 qualifier: enables review: summary: Interactions with VCP (P55072) and RIG-I/RIGI (O95786), the latter underlying the antiviral-signaling role. action: KEEP_AS_NON_CORE reason: Biologically meaningful (RIG-I, VCP) but bare protein binding is uninformative; the RIG-I role is captured by the negative regulation of RIG-I signaling annotation. supported_by: - reference_id: file:human/NPLOC4/NPLOC4-goa.tsv supporting_text: UniProtKB:O95786 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32296183 qualifier: enables review: summary: HuRI interactome interactions (e.g. VPS26B Q4G0F5, UFD1). Bare protein binding. action: KEEP_AS_NON_CORE reason: High-throughput interactions; bare protein binding is uninformative. supported_by: - reference_id: file:human/NPLOC4/NPLOC4-goa.tsv supporting_text: UniProtKB:Q4G0F5 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:32814053 qualifier: enables review: summary: Neurodegeneration interactome interactions (e.g. VCP, TGFBR2 P37173). Bare protein binding. action: KEEP_AS_NON_CORE reason: High-throughput interactions; bare protein binding is uninformative. supported_by: - reference_id: file:human/NPLOC4/NPLOC4-goa.tsv supporting_text: UniProtKB:P55072 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:33961781 qualifier: enables review: summary: BioPlex interactome interactions (VCP, UFD1, TMEM62). Bare protein binding. action: KEEP_AS_NON_CORE reason: High-throughput interactions; bare protein binding is uninformative; the central partners are captured by complex annotations. supported_by: - reference_id: file:human/NPLOC4/NPLOC4-goa.tsv supporting_text: UniProtKB:P55072 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:35271311 qualifier: enables review: summary: Interactome interactions including VCP (P55072) and ubiquitin (P0CG48). Bare protein binding. action: KEEP_AS_NON_CORE reason: High-throughput interactions; bare protein binding is uninformative. supported_by: - reference_id: file:human/NPLOC4/NPLOC4-goa.tsv supporting_text: UniProtKB:P55072 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:37776851 qualifier: enables review: summary: Interactome interaction with VCP (P55072). Bare protein binding. action: KEEP_AS_NON_CORE reason: High-throughput interaction; bare protein binding is uninformative. supported_by: - reference_id: file:human/NPLOC4/NPLOC4-goa.tsv supporting_text: UniProtKB:P55072 - term: id: GO:0007030 label: Golgi organization evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: The UFD1-NPL4-VCP complex participates in Golgi membrane reassembly; the heterodimer can inhibit Golgi membrane fusion. action: KEEP_AS_NON_CORE reason: Supported by the documented role of the heterodimer in Golgi membrane fusion, but this is one of many p97 processes and is non-core relative to the ubiquitin-binding adaptor function. supported_by: - reference_id: file:human/NPLOC4/NPLOC4-uniprot.txt supporting_text: the heterodimer binds to VCP and inhibits Golgi membrane fusion - term: id: GO:0031625 label: ubiquitin protein ligase binding evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: enables review: summary: Electronic annotation of ubiquitin ligase binding, consistent with RNF125 recruitment. action: KEEP_AS_NON_CORE reason: Plausible (RNF125 recruitment), but the informative core function is polyubiquitin binding rather than ligase binding. supported_by: - reference_id: file:human/NPLOC4/NPLOC4-uniprot.txt supporting_text: recruits RNF125 to promote ubiquitination and degradation of RIGI - term: id: GO:0034098 label: VCP-NPL4-UFD1 AAA ATPase complex evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: part_of review: summary: NPL4 is a defining subunit of the VCP-NPL4-UFD1 AAA ATPase (p97 segregase) complex. action: ACCEPT reason: Core complex membership, well documented (ComplexPortal CPX-137; IDA). supported_by: - reference_id: file:human/NPLOC4/NPLOC4-uniprot.txt supporting_text: VCP-NPL4-UFD1 AAA ATPase complex - term: id: GO:0036435 label: K48-linked polyubiquitin modification-dependent protein binding evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: contributes_to review: summary: The UFD1-NPL4 heterodimer recognizes K48-linked polyubiquitin chains, the canonical degradation signal it presents to p97. action: ACCEPT reason: Consistent with the well-established recognition of K48-linked polyubiquitin by the UFD1-NPL4 cofactor; contributes_to reflects the heterodimeric nature of binding. supported_by: - reference_id: file:human/NPLOC4/NPLOC4-uniprot.txt supporting_text: Binds ubiquitinated proteins via its RanBP2-type zinc finger - term: id: GO:0036501 label: UFD1-NPL4 complex evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: part_of review: summary: NPL4 forms an obligate heterodimer with UFD1, the UFD1-NPL4 complex. action: ACCEPT reason: Core complex membership; NPL4 heterodimerizes with UFD1. supported_by: - reference_id: file:human/NPLOC4/NPLOC4-uniprot.txt supporting_text: Heterodimer with UFD1 - term: id: GO:0036503 label: ERAD pathway evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: involved_in review: summary: NPL4 (with UFD1/VCP) is a core component of the ERAD pathway, driving retrotranslocation of misfolded ER proteins. action: ACCEPT reason: Core process for the complex, supported by UniProt function and IMP/ISO evidence. supported_by: - reference_id: file:human/NPLOC4/NPLOC4-uniprot.txt supporting_text: necessary for the export of misfolded proteins from the ER to the cytoplasm - term: id: GO:0043130 label: ubiquitin binding evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: enables review: summary: Ubiquitin binding via the RanBP2-type zinc finger, the core molecular function. action: ACCEPT reason: Directly supported core function. supported_by: - reference_id: file:human/NPLOC4/NPLOC4-uniprot.txt supporting_text: Binds ubiquitinated proteins via its RanBP2-type zinc finger - term: id: GO:0044877 label: protein-containing complex binding evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: enables review: summary: Generic protein-complex binding; NPL4 binds VCP and the UFD1-NPL4-VCP assembly. action: KEEP_AS_NON_CORE reason: Generic term; the informative functions are ubiquitin binding and ATPase binding within the segregase complex. supported_by: - reference_id: file:human/NPLOC4/NPLOC4-uniprot.txt supporting_text: The heterodimer binds to VCP - term: id: GO:0051117 label: ATPase binding evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: enables review: summary: NPL4 binds the AAA+ ATPase VCP/p97, the enzyme it serves as a cofactor. action: ACCEPT reason: Directly supported; NPL4 (with UFD1) binds VCP, the core of its adaptor role. supported_by: - reference_id: file:human/NPLOC4/NPLOC4-uniprot.txt supporting_text: The heterodimer binds to VCP - term: id: GO:0070530 label: K63-linked polyubiquitin modification-dependent protein binding evidence_type: IEA original_reference_id: GO_REF:0000107 qualifier: contributes_to review: summary: The UFD1-NPL4 cofactor can recognize K63-linked polyubiquitin in some contexts. action: KEEP_AS_NON_CORE reason: Plausible given the heterodimer's broad polyubiquitin recognition, but the canonical and best-supported signal is K48-linked; retained as non-core. supported_by: - reference_id: file:human/NPLOC4/NPLOC4-uniprot.txt supporting_text: Binds ubiquitinated proteins via its RanBP2-type zinc finger - term: id: GO:0043161 label: proteasome-mediated ubiquitin-dependent protein catabolic process evidence_type: IEA original_reference_id: GO_REF:0000041 qualifier: involved_in review: summary: NPL4-mediated substrate extraction feeds the proteasomal degradation pathway. action: ACCEPT reason: Core process; the segregase delivers extracted ubiquitinated substrates to the proteasome. supported_by: - reference_id: file:human/NPLOC4/NPLOC4-uniprot.txt supporting_text: where they are degraded by the proteasome - term: id: GO:0006511 label: ubiquitin-dependent protein catabolic process evidence_type: NAS original_reference_id: PMID:28819009 qualifier: involved_in review: summary: Review of p97 (Stach & Freemont) describing the UFD1-NPL4 cofactor in ubiquitin-dependent degradation. action: ACCEPT reason: Consistent with the core degradative role; supported by an authoritative p97 review. supported_by: - reference_id: file:human/NPLOC4/NPLOC4-uniprot.txt supporting_text: where they are degraded by the proteasome - term: id: GO:0006511 label: ubiquitin-dependent protein catabolic process evidence_type: NAS original_reference_id: PMID:33712450 qualifier: involved_in review: summary: p97-UBXN1 aggresome study placing NPL4 in ubiquitin-dependent degradation. action: ACCEPT reason: Consistent with the core degradative role of the p97-UFD1-NPL4 machinery. supported_by: - reference_id: file:human/NPLOC4/NPLOC4-uniprot.txt supporting_text: where they are degraded by the proteasome - term: id: GO:0034098 label: VCP-NPL4-UFD1 AAA ATPase complex evidence_type: IPI original_reference_id: PMID:18775313 qualifier: part_of review: summary: Experimental (IPI) demonstration of NPL4 within the VCP-NPL4-UFD1 complex. action: ACCEPT reason: Core complex membership supported by direct interaction evidence. supported_by: - reference_id: file:human/NPLOC4/NPLOC4-uniprot.txt supporting_text: VCP-NPL4-UFD1 AAA ATPase complex - term: id: GO:0034098 label: VCP-NPL4-UFD1 AAA ATPase complex evidence_type: IPI original_reference_id: PMID:20414249 qualifier: part_of review: summary: Experimental (IPI) demonstration of NPL4 within the VCP-NPL4-UFD1 complex. action: ACCEPT reason: Core complex membership supported by direct interaction evidence. supported_by: - reference_id: file:human/NPLOC4/NPLOC4-uniprot.txt supporting_text: VCP-NPL4-UFD1 AAA ATPase complex - term: id: GO:0034098 label: VCP-NPL4-UFD1 AAA ATPase complex evidence_type: NAS original_reference_id: PMID:28819009 qualifier: part_of review: summary: p97 review describing the VCP-NPL4-UFD1 complex. action: ACCEPT reason: Core complex membership; supported by an authoritative review. supported_by: - reference_id: file:human/NPLOC4/NPLOC4-uniprot.txt supporting_text: VCP-NPL4-UFD1 AAA ATPase complex - term: id: GO:0034098 label: VCP-NPL4-UFD1 AAA ATPase complex evidence_type: IPI original_reference_id: PMID:39329031 qualifier: part_of review: summary: ComplexPortal-curated complex membership. The cited PMID:39329031 (an intellectual-disability clinical study from Morocco) does not concern the p97 complex and appears to be a mis-citation, though the complex membership itself is well established. action: ACCEPT reason: NPL4 is unambiguously part of the VCP-NPL4-UFD1 complex (multiple independent lines of evidence). The complex assertion is accepted; the specific reference attached is a wrong-identifier citation (flagged in reference_review). supported_by: - reference_id: file:human/NPLOC4/NPLOC4-uniprot.txt supporting_text: VCP-NPL4-UFD1 AAA ATPase complex - term: id: GO:0036503 label: ERAD pathway evidence_type: NAS original_reference_id: PMID:28819009 qualifier: involved_in review: summary: p97 review describing the UFD1-NPL4 cofactor's role in ERAD. action: ACCEPT reason: Core process; supported by an authoritative review. supported_by: - reference_id: file:human/NPLOC4/NPLOC4-uniprot.txt supporting_text: necessary for the export of misfolded proteins from the ER to the cytoplasm - term: id: GO:0043161 label: proteasome-mediated ubiquitin-dependent protein catabolic process evidence_type: NAS original_reference_id: PMID:39329031 qualifier: involved_in review: summary: ComplexPortal-curated process annotation. The attached PMID:39329031 is a mis-citation (unrelated clinical study), but the proteasomal degradation role is correct. action: ACCEPT reason: NPL4 participates in proteasome-mediated degradation as a p97 cofactor; the assertion is accepted while the attached reference is flagged as wrong identifier. supported_by: - reference_id: file:human/NPLOC4/NPLOC4-uniprot.txt supporting_text: where they are degraded by the proteasome - term: id: GO:1904949 label: ATPase complex evidence_type: NAS original_reference_id: PMID:28819009 qualifier: part_of review: summary: NPL4 is part of an AAA+ ATPase (p97) complex. action: KEEP_AS_NON_CORE reason: Correct but a generic parent of the specific VCP-NPL4-UFD1 complex annotation. supported_by: - reference_id: file:human/NPLOC4/NPLOC4-uniprot.txt supporting_text: VCP-NPL4-UFD1 AAA ATPase complex - term: id: GO:1904949 label: ATPase complex evidence_type: NAS original_reference_id: PMID:33712450 qualifier: part_of review: summary: NPL4 is part of an AAA+ ATPase (p97) complex. action: KEEP_AS_NON_CORE reason: Generic parent of the specific VCP-NPL4-UFD1 complex annotation. supported_by: - reference_id: file:human/NPLOC4/NPLOC4-uniprot.txt supporting_text: VCP-NPL4-UFD1 AAA ATPase complex - term: id: GO:1904949 label: ATPase complex evidence_type: NAS original_reference_id: PMID:39329031 qualifier: part_of review: summary: NPL4 is part of an AAA+ ATPase complex; the attached PMID:39329031 is a mis-citation. action: KEEP_AS_NON_CORE reason: Generic parent of the specific complex annotation; reference flagged as wrong identifier. supported_by: - reference_id: file:human/NPLOC4/NPLOC4-uniprot.txt supporting_text: VCP-NPL4-UFD1 AAA ATPase complex - term: id: GO:0005654 label: nucleoplasm evidence_type: IDA original_reference_id: GO_REF:0000052 qualifier: located_in review: summary: Immunofluorescence nucleoplasmic localization. action: KEEP_AS_NON_CORE reason: Consistent with nuclear p97 functions; non-core as the adaptor acts in multiple compartments. supported_by: - reference_id: file:human/NPLOC4/NPLOC4-uniprot.txt supporting_text: GO:0005654; C:nucleoplasm - term: id: GO:0005634 label: nucleus evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: located_in review: summary: Sequence-similarity-inferred nuclear localization. action: KEEP_AS_NON_CORE reason: Consistent with other nuclear annotations; non-core. supported_by: - reference_id: file:human/NPLOC4/NPLOC4-uniprot.txt supporting_text: Nucleus {ECO:0000250|UniProtKB:Q9ES54} - term: id: GO:0005783 label: endoplasmic reticulum evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: located_in review: summary: Sequence-similarity-inferred ER localization. action: ACCEPT reason: ER association is a documented, functionally relevant localization (ERAD). supported_by: - reference_id: file:human/NPLOC4/NPLOC4-uniprot.txt supporting_text: Endoplasmic reticulum {ECO:0000250|UniProtKB:Q9ES54} - term: id: GO:0072344 label: rescue of stalled cytosolic ribosome evidence_type: NAS original_reference_id: PMID:35452614 qualifier: involved_in review: summary: NPL4/p97 participates in ribosome-associated quality control, where the segregase extracts ubiquitinated nascent chains/factors from stalled ribosomes. action: KEEP_AS_NON_CORE reason: Supported as part of RQC by the cited review, but it is one of many p97-dependent processes; non-core relative to the ubiquitin-binding adaptor function. supported_by: - reference_id: PMID:35452614 supporting_text: Ribosome-associated quality-control mechanisms from bacteria to humans - term: id: GO:1990112 label: RQC complex evidence_type: NAS original_reference_id: PMID:35452614 qualifier: part_of review: summary: Annotation placing NPL4 in the ribosome-associated quality-control (RQC) complex. action: KEEP_AS_NON_CORE reason: p97-UFD1-NPL4 functions with RQC but is a distinct cofactor module recruited to extract substrates rather than a constitutive core RQC subunit; retained as non-core. supported_by: - reference_id: PMID:35452614 supporting_text: Ribosome-associated quality-control mechanisms from bacteria to humans - term: id: GO:1990116 label: ribosome-associated ubiquitin-dependent protein catabolic process evidence_type: NAS original_reference_id: PMID:35452614 qualifier: involved_in review: summary: NPL4/p97 extracts ubiquitinated nascent chains for degradation in RQC. action: KEEP_AS_NON_CORE reason: A genuine p97-dependent RQC process, but non-core relative to the general ubiquitin-binding adaptor function. supported_by: - reference_id: PMID:35452614 supporting_text: Ribosome-associated quality-control mechanisms from bacteria to humans - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9755507 qualifier: located_in review: summary: Reactome cytosolic localization. action: ACCEPT reason: Cytosol is a principal site of the segregase function. supported_by: - reference_id: file:human/NPLOC4/NPLOC4-uniprot.txt supporting_text: Cytoplasm, cytosol - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9758088 qualifier: located_in review: summary: Reactome cytosolic localization. action: ACCEPT reason: Cytosol is a principal site of the segregase function. supported_by: - reference_id: file:human/NPLOC4/NPLOC4-uniprot.txt supporting_text: Cytoplasm, cytosol - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9758090 qualifier: located_in review: summary: Reactome cytosolic localization. action: ACCEPT reason: Cytosol is a principal site of the segregase function. supported_by: - reference_id: file:human/NPLOC4/NPLOC4-uniprot.txt supporting_text: Cytoplasm, cytosol - term: id: GO:0005829 label: cytosol evidence_type: TAS original_reference_id: Reactome:R-HSA-9948427 qualifier: located_in review: summary: Reactome cytosolic localization. action: ACCEPT reason: Cytosol is a principal site of the segregase function. supported_by: - reference_id: file:human/NPLOC4/NPLOC4-uniprot.txt supporting_text: Cytoplasm, cytosol - term: id: GO:0006511 label: ubiquitin-dependent protein catabolic process evidence_type: IMP original_reference_id: PMID:26471729 qualifier: involved_in review: summary: NPL4 (with UFD1/VCP) promotes ubiquitin-dependent degradation of RIG-I, demonstrated by mutagenesis (VCP-binding mutants). action: ACCEPT reason: Directly supported by IMP; the p97-UFD1-NPL4 complex drives ubiquitin-dependent RIG-I degradation. supported_by: - reference_id: file:human/NPLOC4/NPLOC4-uniprot.txt supporting_text: recruits RNF125 to promote ubiquitination and degradation of RIGI - term: id: GO:0032480 label: negative regulation of type I interferon production evidence_type: IMP original_reference_id: PMID:26471729 qualifier: involved_in review: summary: Through RIG-I degradation, NPL4/p97 negatively regulates type I interferon production. action: KEEP_AS_NON_CORE reason: A genuine, experimentally supported signaling role, but downstream/specialized relative to the core p97 cofactor function. supported_by: - reference_id: file:human/NPLOC4/NPLOC4-uniprot.txt supporting_text: Acts as a negative regulator of type I interferon production - term: id: GO:0034098 label: VCP-NPL4-UFD1 AAA ATPase complex evidence_type: IDA original_reference_id: PMID:26471729 qualifier: part_of review: summary: Direct demonstration of NPL4 within the VCP-NPL4-UFD1 complex. action: ACCEPT reason: Core complex membership supported by direct evidence. supported_by: - reference_id: file:human/NPLOC4/NPLOC4-uniprot.txt supporting_text: VCP-NPL4-UFD1 AAA ATPase complex - term: id: GO:0039536 label: negative regulation of RIG-I signaling pathway evidence_type: IMP original_reference_id: PMID:26471729 qualifier: involved_in review: summary: NPL4/p97 negatively regulates RIG-I signaling by promoting RIG-I degradation. action: KEEP_AS_NON_CORE reason: A genuine specialized signaling role; non-core relative to the general p97 cofactor function. supported_by: - reference_id: file:human/NPLOC4/NPLOC4-uniprot.txt supporting_text: which binds to RIGI and recruits RNF125 - term: id: GO:0036501 label: UFD1-NPL4 complex evidence_type: IPI original_reference_id: PMID:11574150 qualifier: part_of review: summary: Original cloning study demonstrating NPL4 interacts with UFD1 (the UFD1-NPL4 heterodimer). action: ACCEPT reason: Core complex membership supported by direct interaction evidence. supported_by: - reference_id: file:human/NPLOC4/NPLOC4-uniprot.txt supporting_text: Heterodimer with UFD1 - term: id: GO:0005515 label: protein binding evidence_type: IPI original_reference_id: PMID:11574150 qualifier: enables review: summary: Interaction with UFD1 (Q92890). Bare protein binding term. action: KEEP_AS_NON_CORE reason: The UFD1 interaction is central but bare protein binding is uninformative; captured by the UFD1-NPL4 complex annotation. supported_by: - reference_id: file:human/NPLOC4/NPLOC4-goa.tsv supporting_text: UniProtKB:Q92890 - term: id: GO:0030970 label: retrograde protein transport, ER to cytosol evidence_type: IMP original_reference_id: PMID:25660456 qualifier: involved_in review: summary: NPL4 is required for dislocation of an ERAD substrate (null Hong Kong alpha-1-antitrypsin) from the ER to the cytosol. action: ACCEPT reason: Directly supported by IMP in an ERAD dislocation assay; a core process. supported_by: - reference_id: file:human/NPLOC4/NPLOC4-uniprot.txt supporting_text: necessary for the export of misfolded proteins from the ER to the cytoplasm - term: id: GO:0034098 label: VCP-NPL4-UFD1 AAA ATPase complex evidence_type: ISS original_reference_id: GO_REF:0000024 qualifier: part_of review: summary: Sequence-similarity-inferred complex membership. action: ACCEPT reason: Core complex membership corroborated by direct evidence. supported_by: - reference_id: file:human/NPLOC4/NPLOC4-uniprot.txt supporting_text: VCP-NPL4-UFD1 AAA ATPase complex - term: id: GO:0005654 label: nucleoplasm evidence_type: TAS original_reference_id: Reactome:R-HSA-5654985 qualifier: located_in review: summary: Reactome nucleoplasmic localization. action: KEEP_AS_NON_CORE reason: Consistent with nuclear p97 functions; non-core. supported_by: - reference_id: file:human/NPLOC4/NPLOC4-uniprot.txt supporting_text: GO:0005654; C:nucleoplasm - term: id: GO:0005654 label: nucleoplasm evidence_type: TAS original_reference_id: Reactome:R-HSA-5654989 qualifier: located_in review: summary: Reactome nucleoplasmic localization. action: KEEP_AS_NON_CORE reason: Consistent with nuclear p97 functions; non-core. supported_by: - reference_id: file:human/NPLOC4/NPLOC4-uniprot.txt supporting_text: GO:0005654; C:nucleoplasm - term: id: GO:0005634 label: nucleus evidence_type: HDA original_reference_id: PMID:21630459 qualifier: located_in review: summary: High-throughput direct-assay nuclear localization. action: KEEP_AS_NON_CORE reason: Consistent with documented nuclear localization; non-core. supported_by: - reference_id: file:human/NPLOC4/NPLOC4-uniprot.txt supporting_text: Nucleus {ECO:0000250|UniProtKB:Q9ES54} - term: id: GO:0007030 label: Golgi organization evidence_type: ISS original_reference_id: PMID:11574150 qualifier: involved_in review: summary: The UFD1-NPL4 heterodimer (with VCP) influences Golgi membrane fusion/organization. action: KEEP_AS_NON_CORE reason: Supported by the documented inhibition of Golgi membrane fusion by the heterodimer; one of many p97 processes, non-core. supported_by: - reference_id: file:human/NPLOC4/NPLOC4-uniprot.txt supporting_text: the heterodimer binds to VCP and inhibits Golgi membrane fusion - term: id: GO:0005783 label: endoplasmic reticulum evidence_type: ISS original_reference_id: PMID:11574150 qualifier: located_in review: summary: ER localization inferred by similarity. action: ACCEPT reason: ER association is documented and functionally relevant (ERAD). supported_by: - reference_id: file:human/NPLOC4/NPLOC4-uniprot.txt supporting_text: Endoplasmic reticulum {ECO:0000250|UniProtKB:Q9ES54} - term: id: GO:0042175 label: nuclear outer membrane-endoplasmic reticulum membrane network evidence_type: ISS original_reference_id: PMID:11574150 qualifier: located_in review: summary: Localization to the nuclear-envelope/ER membrane network, consistent with ER association and nuclear-envelope reformation roles. action: KEEP_AS_NON_CORE reason: Consistent with ER/nuclear-envelope functions; a specific localization retained as non-core. supported_by: - reference_id: file:human/NPLOC4/NPLOC4-uniprot.txt supporting_text: Associated with the endoplasmic reticulum and nuclear references: - id: GO_REF:0000002 title: Gene Ontology annotation through association of InterPro records with GO terms findings: [] - id: GO_REF:0000024 title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity findings: [] - id: GO_REF:0000033 title: Annotation inferences using phylogenetic trees findings: [] - id: GO_REF:0000041 title: Gene Ontology annotation based on UniPathway vocabulary mapping findings: [] - id: GO_REF:0000044 title: Gene Ontology annotation based on UniProtKB keywords findings: [] - id: GO_REF:0000052 title: Gene Ontology annotation based on curation of immunofluorescence data findings: [] - id: GO_REF:0000107 title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara findings: [] - id: GO_REF:0000117 title: Electronic Gene Ontology annotations created by ARBA machine learning models findings: [] - id: PMID:11574150 title: Cloning and characterization of the gene encoding human NPL4, a protein interacting with the ubiquitin fusion-degradation protein (UFD1L). findings: - statement: NPL4 interacts with the ubiquitin fusion-degradation protein UFD1L, forming the UFD1-NPL4 heterodimer. reference_section_type: ABSTRACT reference_review: relevance: HIGH correctness: VERIFIED review_notes: Cached; establishes the UFD1-NPL4 interaction. - id: PMID:17070805 title: The Polycomb-associated protein Rybp is a ubiquitin binding protein. findings: [] reference_review: relevance: LOW correctness: UNVERIFIED review_notes: Not cached; high-throughput protein-binding (ubiquitin/UBC) interaction. - id: PMID:18775313 title: UBXD7 binds multiple ubiquitin ligases and implicates p97 in HIF1alpha turnover. findings: [] reference_review: relevance: MEDIUM correctness: UNVERIFIED review_notes: Captures NPLOC4-VCP and NPLOC4-UFD1 interactions (the core complex). - id: PMID:20414249 title: Imbalances in p97 co-factor interactions in human proteinopathy. findings: [] reference_review: relevance: MEDIUM correctness: UNVERIFIED review_notes: Captures NPLOC4-VCP/UFD1 complex interactions. - id: PMID:21630459 title: Proteomic characterization of the human sperm nucleus. findings: [] reference_review: relevance: LOW correctness: UNVERIFIED review_notes: HDA nuclear localization. - id: PMID:21645854 title: Hierarchical binding of cofactors to the AAA ATPase p97. findings: [] reference_review: relevance: MEDIUM correctness: UNVERIFIED review_notes: Captures NPLOC4-VCP/UFD1 complex interactions. - id: PMID:25660456 title: Identification of ERAD components essential for dislocation of the null Hong Kong variant of α-1-antitrypsin (NHK). findings: - statement: NPLOC4 is required for ERAD dislocation (retrotranslocation) of the NHK alpha-1-antitrypsin substrate from the ER to the cytosol. reference_section_type: RESULTS reference_review: relevance: HIGH correctness: VERIFIED review_notes: Cached; supports the ERAD retrotranslocation role. - id: PMID:26471729 title: A non-canonical role of the p97 complex in RIG-I antiviral signaling. findings: - statement: The VCP-UFD1-NPLOC4 complex binds RIG-I and recruits RNF125 to promote RIG-I ubiquitination and degradation, negatively regulating type I interferon production. reference_section_type: RESULTS reference_review: relevance: HIGH correctness: VERIFIED review_notes: Cached; establishes the RIG-I/interferon regulatory role and complex membership. - id: PMID:28819009 title: The AAA+ ATPase p97, a cellular multitool. findings: - statement: Reviews the UFD1-NPL4 cofactor as the principal ubiquitin-recruiting adaptor of p97 in ubiquitin-dependent degradation and ERAD. reference_section_type: RESULTS reference_review: relevance: HIGH correctness: VERIFIED review_notes: Cached; authoritative p97 review. - id: PMID:32296183 title: A reference map of the human binary protein interactome. findings: [] reference_review: relevance: LOW correctness: UNVERIFIED review_notes: High-throughput interactome; bare protein-binding partners. - id: PMID:32814053 title: Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains. findings: [] reference_review: relevance: LOW correctness: UNVERIFIED review_notes: Neurodegeneration interactome; bare protein-binding partners. - id: PMID:33712450 title: The p97-UBXN1 complex regulates aggresome formation. findings: - statement: Studies p97 cofactor complexes (including UFD1-NPL4 context) in ubiquitin-dependent degradation and aggresome formation. reference_section_type: RESULTS reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Cached; p97 cofactor degradation context. - id: PMID:33961781 title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. findings: [] reference_review: relevance: LOW correctness: UNVERIFIED review_notes: BioPlex interactome; bare protein-binding partners (VCP/UFD1/TMEM62). - id: PMID:35271311 title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.' findings: [] reference_review: relevance: LOW correctness: UNVERIFIED review_notes: Interactome; bare protein-binding partners (VCP/ubiquitin). - id: PMID:35452614 title: Ribosome-associated quality-control mechanisms from bacteria to humans. findings: - statement: Reviews ribosome-associated quality control, in which p97 (with UFD1-NPL4) extracts ubiquitinated nascent chains/factors from stalled ribosomes. reference_section_type: RESULTS reference_review: relevance: MEDIUM correctness: VERIFIED review_notes: Cached; RQC review supporting the NAS RQC annotations. - id: PMID:37776851 title: Analysis of proteome-wide degradation dynamics in ALS SOD1 iPSC-derived patient neurons reveals disrupted VCP homeostasis. findings: [] reference_review: relevance: LOW correctness: UNVERIFIED review_notes: Interactome; bare protein-binding partner (VCP). - id: PMID:39329031 title: Study of Clinical Characteristics of Intellectual Disability in Morocco. findings: [] reference_review: relevance: NONE correctness: WRONG_IDENTIFIER review_notes: PMID:39329031 is a clinical study of intellectual disability in Morocco and does not concern the VCP-NPL4-UFD1 complex. It is mis-attached to ComplexPortal complex/process annotations. The underlying complex membership is correct, but this citation is a wrong identifier and should be replaced. - id: Reactome:R-HSA-5654985 title: 'Reactome: nucleoplasm localization (signaling-related pathway)' findings: [] - id: Reactome:R-HSA-5654989 title: 'Reactome: nucleoplasm localization (signaling-related pathway)' findings: [] - id: Reactome:R-HSA-9755507 title: 'Reactome: KEAP1-NFE2L2 / cytosol localization' findings: [] - id: Reactome:R-HSA-9758088 title: 'Reactome: cytosol localization' findings: [] - id: Reactome:R-HSA-9758090 title: 'Reactome: cytosol localization' findings: [] - id: Reactome:R-HSA-9948427 title: 'Reactome: cytosol localization' findings: [] - id: file:human/NPLOC4/NPLOC4-hypotheses/pseudodub-mpn-catalytic-check/openscientist.md title: 'OpenScientist hypothesis run: NPLOC4 pseudo-DUB MPN catalytic check' findings: - statement: Confirms NPL4's MPN domain is a catalytically inactive pseudo-DUB - it lacks the JAMM/MPN+ zinc-metalloprotease motif and adversarial checks rule out all six DUB mechanistic families - so deubiquitinase activity (GO:0004843) is correctly absent and should not be annotated (the term is also mechanistically wrong, as MPN DUBs are zinc metalloproteases, not cysteine-type proteases). supporting_text: NPLOC4 has no deubiquitinase activity of any type core_functions: - description: Polyubiquitin-binding cofactor of the AAA+ ATPase VCP/p97 that, as part of the obligate UFD1-NPL4 heterodimer, recognizes (notably K48-linked) polyubiquitinated substrates via its RanBP2-type zinc finger and presents them to p97 for ATP-driven extraction/unfolding. molecular_function: id: GO:0043130 label: ubiquitin binding locations: - id: GO:0005829 label: cytosol - id: GO:0005783 label: endoplasmic reticulum supported_by: - reference_id: file:human/NPLOC4/NPLOC4-uniprot.txt supporting_text: Binds ubiquitinated proteins via its RanBP2-type zinc finger - reference_id: file:human/NPLOC4/NPLOC4-uniprot.txt supporting_text: The heterodimer binds ubiquitinated proteins - description: Substrate-recruiting adaptor subunit of the VCP-NPL4-UFD1 segregase that binds the p97 ATPase and drives ubiquitin-dependent extraction of substrates from membranes and complexes, including ER-to-cytosol retrotranslocation of misfolded proteins during ERAD, delivering them for proteasomal degradation. molecular_function: id: GO:0051117 label: ATPase binding in_complex: id: GO:0034098 label: VCP-NPL4-UFD1 AAA ATPase complex locations: - id: GO:0005783 label: endoplasmic reticulum supported_by: - reference_id: file:human/NPLOC4/NPLOC4-uniprot.txt supporting_text: The heterodimer binds to VCP - reference_id: file:human/NPLOC4/NPLOC4-uniprot.txt supporting_text: necessary for the export of misfolded proteins from the ER to the cytoplasm proposed_new_terms: [] suggested_questions: - question: How do UFD1 and NPL4 together unfold the initiating ubiquitin to engage the p97 pore, and what determines substrate polyubiquitin linkage preference (K48 vs K63 vs branched)? - question: Which p97 cofactor combinations (UBXD adaptors) direct NPL4-bearing complexes to specific processes (ERAD vs RQC vs chromatin vs RIG-I), and how is this regulated? - question: Is NPLOC4 haploinsufficiency phenotypically relevant, analogous to UFD1L in the 22q11 region? suggested_experiments: - description: Reconstituted single-molecule unfolding assays with VCP, UFD1 and NPL4 variants (RanBP2 zinc-finger mutants) on defined K48- vs K63-linked substrates to dissect substrate engagement. - description: Proximity-labeling (BioID/TurboID) of NPLOC4 across stress conditions to map compartment- and process-specific cofactor partners. - description: Acute degron depletion of NPLOC4 with quantitative proteomics to define the endogenous substrate set extracted by the UFD1-NPL4-p97 complex.