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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005634 nucleus | IBA GO_REF:0000033 | KEEP AS NON CORE | 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. 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. Supporting Evidence: file:human/NPLOC4/NPLOC4-uniprot.txt Nucleus {ECO:0000250|UniProtKB:Q9ES54} |
| GO:0031625 ubiquitin protein ligase binding | IBA GO_REF:0000033 | KEEP AS NON CORE | 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. 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. Supporting Evidence: file:human/NPLOC4/NPLOC4-uniprot.txt recruits RNF125 to promote ubiquitination and degradation of RIGI |
| GO:0043130 ubiquitin binding | IBA GO_REF:0000033 | ACCEPT | 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. Reason: Directly supported; the RanBP2-type zinc finger binds ubiquitinated proteins, a defining function of NPL4. Supporting Evidence: file:human/NPLOC4/NPLOC4-uniprot.txt Binds ubiquitinated proteins via its RanBP2-type zinc finger |
| GO:0005634 nucleus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Electronic annotation of nuclear localization, redundant with the IBA/HDA nuclear annotations. Reason: Consistent with documented nuclear localization; non-core as the adaptor acts in multiple compartments. Supporting Evidence: file:human/NPLOC4/NPLOC4-uniprot.txt Nucleus {ECO:0000250|UniProtKB:Q9ES54} |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000044 | ACCEPT | Summary: ER localization, where the VCP-NPL4-UFD1 complex drives retrotranslocation of misfolded proteins during ERAD. Reason: ER association is documented and corresponds to a major site of NPL4 function (ERAD retrotranslocation). Supporting Evidence: file:human/NPLOC4/NPLOC4-uniprot.txt Endoplasmic reticulum {ECO:0000250|UniProtKB:Q9ES54} |
| GO:0005829 cytosol | IEA GO_REF:0000044 | ACCEPT | Summary: Cytosolic localization, the principal compartment where the p97-UFD1-NPL4 segregase operates and delivers extracted substrates to the proteasome. Reason: Cytosolic localization is well supported and is the major site of the adaptor function. Supporting Evidence: file:human/NPLOC4/NPLOC4-uniprot.txt Cytoplasm, cytosol |
| GO:0006511 ubiquitin-dependent protein catabolic process | IEA GO_REF:0000002 | ACCEPT | Summary: NPL4, as the p97 substrate-recruiting cofactor, is integral to ubiquitin-dependent proteasomal degradation. Reason: Core biological-process role; the UFD1-NPL4-VCP complex delivers ubiquitinated substrates for degradation by the proteasome. Supporting Evidence: file:human/NPLOC4/NPLOC4-uniprot.txt where they are degraded by the proteasome |
| GO:0030970 retrograde protein transport, ER to cytosol | IEA GO_REF:0000117 | ACCEPT | Summary: NPL4 (with UFD1/VCP) mediates the export (retrotranslocation) of misfolded proteins from the ER to the cytosol during ERAD. Reason: Directly supported by the UniProt function and by IMP evidence; this is a core process for the complex. Supporting Evidence: file:human/NPLOC4/NPLOC4-uniprot.txt necessary for the export of misfolded proteins from the ER to the cytoplasm |
| GO:0005515 protein binding | IPI PMID:17070805 The Polycomb-associated protein Rybp is a ubiquitin binding ... | KEEP AS NON CORE | Summary: High-throughput interaction with ubiquitin (UBC, P0CG48). Bare protein binding; reflects the ubiquitin-binding activity. Reason: Records a ubiquitin interaction but bare protein binding is uninformative; the specific ubiquitin-binding function is captured elsewhere. Supporting Evidence: file:human/NPLOC4/NPLOC4-goa.tsv UniProtKB:P0CG48 |
| GO:0005515 protein binding | IPI PMID:18775313 UBXD7 binds multiple ubiquitin ligases and implicates p97 in... | KEEP AS NON CORE | Summary: Interaction with VCP (P55072) and UFD1 (Q92890), the core partners of the segregase complex. Bare protein binding term. 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. Supporting Evidence: file:human/NPLOC4/NPLOC4-goa.tsv UniProtKB:P55072 |
| GO:0005515 protein binding | IPI PMID:20414249 Imbalances in p97 co-factor interactions in human proteinopa... | KEEP AS NON CORE | Summary: Interaction with VCP and UFD1 captured as bare protein binding. Reason: Central interactions but bare protein binding is uninformative; captured by complex/ATPase-binding annotations. Supporting Evidence: file:human/NPLOC4/NPLOC4-goa.tsv UniProtKB:P55072 |
| GO:0005515 protein binding | IPI PMID:21645854 Hierarchical binding of cofactors to the AAA ATPase p97. | KEEP AS NON CORE | Summary: Interaction with VCP and UFD1 captured as bare protein binding. Reason: Central interactions but bare protein binding is uninformative. Supporting Evidence: file:human/NPLOC4/NPLOC4-goa.tsv UniProtKB:P55072 |
| GO:0005515 protein binding | IPI PMID:26471729 A non-canonical role of the p97 complex in RIG-I antiviral s... | KEEP AS NON CORE | Summary: Interactions with VCP (P55072) and RIG-I/RIGI (O95786), the latter underlying the antiviral-signaling role. 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. Supporting Evidence: file:human/NPLOC4/NPLOC4-goa.tsv UniProtKB:O95786 |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: HuRI interactome interactions (e.g. VPS26B Q4G0F5, UFD1). Bare protein binding. Reason: High-throughput interactions; bare protein binding is uninformative. Supporting Evidence: file:human/NPLOC4/NPLOC4-goa.tsv UniProtKB:Q4G0F5 |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | KEEP AS NON CORE | Summary: Neurodegeneration interactome interactions (e.g. VCP, TGFBR2 P37173). Bare protein binding. Reason: High-throughput interactions; bare protein binding is uninformative. Supporting Evidence: file:human/NPLOC4/NPLOC4-goa.tsv UniProtKB:P55072 |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: BioPlex interactome interactions (VCP, UFD1, TMEM62). Bare protein binding. Reason: High-throughput interactions; bare protein binding is uninformative; the central partners are captured by complex annotations. Supporting Evidence: file:human/NPLOC4/NPLOC4-goa.tsv UniProtKB:P55072 |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | KEEP AS NON CORE | Summary: Interactome interactions including VCP (P55072) and ubiquitin (P0CG48). Bare protein binding. Reason: High-throughput interactions; bare protein binding is uninformative. Supporting Evidence: file:human/NPLOC4/NPLOC4-goa.tsv UniProtKB:P55072 |
| GO:0005515 protein binding | IPI PMID:37776851 Analysis of proteome-wide degradation dynamics in ALS SOD1 i... | KEEP AS NON CORE | Summary: Interactome interaction with VCP (P55072). Bare protein binding. Reason: High-throughput interaction; bare protein binding is uninformative. Supporting Evidence: file:human/NPLOC4/NPLOC4-goa.tsv UniProtKB:P55072 |
| GO:0007030 Golgi organization | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The UFD1-NPL4-VCP complex participates in Golgi membrane reassembly; the heterodimer can inhibit Golgi membrane fusion. 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. Supporting Evidence: file:human/NPLOC4/NPLOC4-uniprot.txt the heterodimer binds to VCP and inhibits Golgi membrane fusion |
| GO:0031625 ubiquitin protein ligase binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Electronic annotation of ubiquitin ligase binding, consistent with RNF125 recruitment. Reason: Plausible (RNF125 recruitment), but the informative core function is polyubiquitin binding rather than ligase binding. Supporting Evidence: file:human/NPLOC4/NPLOC4-uniprot.txt recruits RNF125 to promote ubiquitination and degradation of RIGI |
| GO:0034098 VCP-NPL4-UFD1 AAA ATPase complex | IEA GO_REF:0000107 | ACCEPT | Summary: NPL4 is a defining subunit of the VCP-NPL4-UFD1 AAA ATPase (p97 segregase) complex. Reason: Core complex membership, well documented (ComplexPortal CPX-137; IDA). Supporting Evidence: file:human/NPLOC4/NPLOC4-uniprot.txt VCP-NPL4-UFD1 AAA ATPase complex |
| GO:0036435 K48-linked polyubiquitin modification-dependent protein binding | IEA GO_REF:0000107 | ACCEPT | Summary: The UFD1-NPL4 heterodimer recognizes K48-linked polyubiquitin chains, the canonical degradation signal it presents to p97. Reason: Consistent with the well-established recognition of K48-linked polyubiquitin by the UFD1-NPL4 cofactor; contributes_to reflects the heterodimeric nature of binding. Supporting Evidence: file:human/NPLOC4/NPLOC4-uniprot.txt Binds ubiquitinated proteins via its RanBP2-type zinc finger |
| GO:0036501 UFD1-NPL4 complex | IEA GO_REF:0000107 | ACCEPT | Summary: NPL4 forms an obligate heterodimer with UFD1, the UFD1-NPL4 complex. Reason: Core complex membership; NPL4 heterodimerizes with UFD1. Supporting Evidence: file:human/NPLOC4/NPLOC4-uniprot.txt Heterodimer with UFD1 |
| GO:0036503 ERAD pathway | IEA GO_REF:0000107 | ACCEPT | Summary: NPL4 (with UFD1/VCP) is a core component of the ERAD pathway, driving retrotranslocation of misfolded ER proteins. Reason: Core process for the complex, supported by UniProt function and IMP/ISO evidence. Supporting Evidence: file:human/NPLOC4/NPLOC4-uniprot.txt necessary for the export of misfolded proteins from the ER to the cytoplasm |
| GO:0043130 ubiquitin binding | IEA GO_REF:0000107 | ACCEPT | Summary: Ubiquitin binding via the RanBP2-type zinc finger, the core molecular function. Reason: Directly supported core function. Supporting Evidence: file:human/NPLOC4/NPLOC4-uniprot.txt Binds ubiquitinated proteins via its RanBP2-type zinc finger |
| GO:0044877 protein-containing complex binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Generic protein-complex binding; NPL4 binds VCP and the UFD1-NPL4-VCP assembly. Reason: Generic term; the informative functions are ubiquitin binding and ATPase binding within the segregase complex. Supporting Evidence: file:human/NPLOC4/NPLOC4-uniprot.txt The heterodimer binds to VCP |
| GO:0051117 ATPase binding | IEA GO_REF:0000107 | ACCEPT | Summary: NPL4 binds the AAA+ ATPase VCP/p97, the enzyme it serves as a cofactor. Reason: Directly supported; NPL4 (with UFD1) binds VCP, the core of its adaptor role. Supporting Evidence: file:human/NPLOC4/NPLOC4-uniprot.txt The heterodimer binds to VCP |
| GO:0070530 K63-linked polyubiquitin modification-dependent protein binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: The UFD1-NPL4 cofactor can recognize K63-linked polyubiquitin in some contexts. Reason: Plausible given the heterodimer's broad polyubiquitin recognition, but the canonical and best-supported signal is K48-linked; retained as non-core. Supporting Evidence: file:human/NPLOC4/NPLOC4-uniprot.txt Binds ubiquitinated proteins via its RanBP2-type zinc finger |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | IEA GO_REF:0000041 | ACCEPT | Summary: NPL4-mediated substrate extraction feeds the proteasomal degradation pathway. Reason: Core process; the segregase delivers extracted ubiquitinated substrates to the proteasome. Supporting Evidence: file:human/NPLOC4/NPLOC4-uniprot.txt where they are degraded by the proteasome |
| GO:0006511 ubiquitin-dependent protein catabolic process | NAS PMID:28819009 The AAA+ ATPase p97, a cellular multitool. | ACCEPT | Summary: Review of p97 (Stach & Freemont) describing the UFD1-NPL4 cofactor in ubiquitin-dependent degradation. Reason: Consistent with the core degradative role; supported by an authoritative p97 review. Supporting Evidence: file:human/NPLOC4/NPLOC4-uniprot.txt where they are degraded by the proteasome |
| GO:0006511 ubiquitin-dependent protein catabolic process | NAS PMID:33712450 The p97-UBXN1 complex regulates aggresome formation. | ACCEPT | Summary: p97-UBXN1 aggresome study placing NPL4 in ubiquitin-dependent degradation. Reason: Consistent with the core degradative role of the p97-UFD1-NPL4 machinery. Supporting Evidence: file:human/NPLOC4/NPLOC4-uniprot.txt where they are degraded by the proteasome |
| GO:0034098 VCP-NPL4-UFD1 AAA ATPase complex | IPI PMID:18775313 UBXD7 binds multiple ubiquitin ligases and implicates p97 in... | ACCEPT | Summary: Experimental (IPI) demonstration of NPL4 within the VCP-NPL4-UFD1 complex. Reason: Core complex membership supported by direct interaction evidence. Supporting Evidence: file:human/NPLOC4/NPLOC4-uniprot.txt VCP-NPL4-UFD1 AAA ATPase complex |
| GO:0034098 VCP-NPL4-UFD1 AAA ATPase complex | IPI PMID:20414249 Imbalances in p97 co-factor interactions in human proteinopa... | ACCEPT | Summary: Experimental (IPI) demonstration of NPL4 within the VCP-NPL4-UFD1 complex. Reason: Core complex membership supported by direct interaction evidence. Supporting Evidence: file:human/NPLOC4/NPLOC4-uniprot.txt VCP-NPL4-UFD1 AAA ATPase complex |
| GO:0034098 VCP-NPL4-UFD1 AAA ATPase complex | NAS PMID:28819009 The AAA+ ATPase p97, a cellular multitool. | ACCEPT | Summary: p97 review describing the VCP-NPL4-UFD1 complex. Reason: Core complex membership; supported by an authoritative review. Supporting Evidence: file:human/NPLOC4/NPLOC4-uniprot.txt VCP-NPL4-UFD1 AAA ATPase complex |
| GO:0034098 VCP-NPL4-UFD1 AAA ATPase complex | IPI PMID:39329031 Study of Clinical Characteristics of Intellectual Disability... | ACCEPT | 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. 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). Supporting Evidence: file:human/NPLOC4/NPLOC4-uniprot.txt VCP-NPL4-UFD1 AAA ATPase complex |
| GO:0036503 ERAD pathway | NAS PMID:28819009 The AAA+ ATPase p97, a cellular multitool. | ACCEPT | Summary: p97 review describing the UFD1-NPL4 cofactor's role in ERAD. Reason: Core process; supported by an authoritative review. Supporting Evidence: file:human/NPLOC4/NPLOC4-uniprot.txt necessary for the export of misfolded proteins from the ER to the cytoplasm |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | NAS PMID:39329031 Study of Clinical Characteristics of Intellectual Disability... | ACCEPT | Summary: ComplexPortal-curated process annotation. The attached PMID:39329031 is a mis-citation (unrelated clinical study), but the proteasomal degradation role is correct. Reason: NPL4 participates in proteasome-mediated degradation as a p97 cofactor; the assertion is accepted while the attached reference is flagged as wrong identifier. Supporting Evidence: file:human/NPLOC4/NPLOC4-uniprot.txt where they are degraded by the proteasome |
| GO:1904949 ATPase complex | NAS PMID:28819009 The AAA+ ATPase p97, a cellular multitool. | KEEP AS NON CORE | Summary: NPL4 is part of an AAA+ ATPase (p97) complex. Reason: Correct but a generic parent of the specific VCP-NPL4-UFD1 complex annotation. Supporting Evidence: file:human/NPLOC4/NPLOC4-uniprot.txt VCP-NPL4-UFD1 AAA ATPase complex |
| GO:1904949 ATPase complex | NAS PMID:33712450 The p97-UBXN1 complex regulates aggresome formation. | KEEP AS NON CORE | Summary: NPL4 is part of an AAA+ ATPase (p97) complex. Reason: Generic parent of the specific VCP-NPL4-UFD1 complex annotation. Supporting Evidence: file:human/NPLOC4/NPLOC4-uniprot.txt VCP-NPL4-UFD1 AAA ATPase complex |
| GO:1904949 ATPase complex | NAS PMID:39329031 Study of Clinical Characteristics of Intellectual Disability... | KEEP AS NON CORE | Summary: NPL4 is part of an AAA+ ATPase complex; the attached PMID:39329031 is a mis-citation. Reason: Generic parent of the specific complex annotation; reference flagged as wrong identifier. Supporting Evidence: file:human/NPLOC4/NPLOC4-uniprot.txt VCP-NPL4-UFD1 AAA ATPase complex |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: Immunofluorescence nucleoplasmic localization. Reason: Consistent with nuclear p97 functions; non-core as the adaptor acts in multiple compartments. Supporting Evidence: file:human/NPLOC4/NPLOC4-uniprot.txt GO:0005654; C:nucleoplasm |
| GO:0005634 nucleus | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Sequence-similarity-inferred nuclear localization. Reason: Consistent with other nuclear annotations; non-core. Supporting Evidence: file:human/NPLOC4/NPLOC4-uniprot.txt Nucleus {ECO:0000250|UniProtKB:Q9ES54} |
| GO:0005783 endoplasmic reticulum | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity-inferred ER localization. Reason: ER association is a documented, functionally relevant localization (ERAD). Supporting Evidence: file:human/NPLOC4/NPLOC4-uniprot.txt Endoplasmic reticulum {ECO:0000250|UniProtKB:Q9ES54} |
| GO:0072344 rescue of stalled cytosolic ribosome | NAS PMID:35452614 Ribosome-associated quality-control mechanisms from bacteria... | KEEP AS NON CORE | Summary: NPL4/p97 participates in ribosome-associated quality control, where the segregase extracts ubiquitinated nascent chains/factors from stalled ribosomes. 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. Supporting Evidence: PMID:35452614 Ribosome-associated quality-control mechanisms from bacteria to humans |
| GO:1990112 RQC complex | NAS PMID:35452614 Ribosome-associated quality-control mechanisms from bacteria... | KEEP AS NON CORE | Summary: Annotation placing NPL4 in the ribosome-associated quality-control (RQC) complex. 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. Supporting Evidence: PMID:35452614 Ribosome-associated quality-control mechanisms from bacteria to humans |
| GO:1990116 ribosome-associated ubiquitin-dependent protein catabolic process | NAS PMID:35452614 Ribosome-associated quality-control mechanisms from bacteria... | KEEP AS NON CORE | Summary: NPL4/p97 extracts ubiquitinated nascent chains for degradation in RQC. Reason: A genuine p97-dependent RQC process, but non-core relative to the general ubiquitin-binding adaptor function. Supporting Evidence: PMID:35452614 Ribosome-associated quality-control mechanisms from bacteria to humans |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9755507 | ACCEPT | Summary: Reactome cytosolic localization. Reason: Cytosol is a principal site of the segregase function. Supporting Evidence: file:human/NPLOC4/NPLOC4-uniprot.txt Cytoplasm, cytosol |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9758088 | ACCEPT | Summary: Reactome cytosolic localization. Reason: Cytosol is a principal site of the segregase function. Supporting Evidence: file:human/NPLOC4/NPLOC4-uniprot.txt Cytoplasm, cytosol |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9758090 | ACCEPT | Summary: Reactome cytosolic localization. Reason: Cytosol is a principal site of the segregase function. Supporting Evidence: file:human/NPLOC4/NPLOC4-uniprot.txt Cytoplasm, cytosol |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9948427 | ACCEPT | Summary: Reactome cytosolic localization. Reason: Cytosol is a principal site of the segregase function. Supporting Evidence: file:human/NPLOC4/NPLOC4-uniprot.txt Cytoplasm, cytosol |
| GO:0006511 ubiquitin-dependent protein catabolic process | IMP PMID:26471729 A non-canonical role of the p97 complex in RIG-I antiviral s... | ACCEPT | Summary: NPL4 (with UFD1/VCP) promotes ubiquitin-dependent degradation of RIG-I, demonstrated by mutagenesis (VCP-binding mutants). Reason: Directly supported by IMP; the p97-UFD1-NPL4 complex drives ubiquitin-dependent RIG-I degradation. Supporting Evidence: file:human/NPLOC4/NPLOC4-uniprot.txt recruits RNF125 to promote ubiquitination and degradation of RIGI |
| GO:0032480 negative regulation of type I interferon production | IMP PMID:26471729 A non-canonical role of the p97 complex in RIG-I antiviral s... | KEEP AS NON CORE | Summary: Through RIG-I degradation, NPL4/p97 negatively regulates type I interferon production. Reason: A genuine, experimentally supported signaling role, but downstream/specialized relative to the core p97 cofactor function. Supporting Evidence: file:human/NPLOC4/NPLOC4-uniprot.txt Acts as a negative regulator of type I interferon production |
| GO:0034098 VCP-NPL4-UFD1 AAA ATPase complex | IDA PMID:26471729 A non-canonical role of the p97 complex in RIG-I antiviral s... | ACCEPT | Summary: Direct demonstration of NPL4 within the VCP-NPL4-UFD1 complex. Reason: Core complex membership supported by direct evidence. Supporting Evidence: file:human/NPLOC4/NPLOC4-uniprot.txt VCP-NPL4-UFD1 AAA ATPase complex |
| GO:0039536 negative regulation of RIG-I signaling pathway | IMP PMID:26471729 A non-canonical role of the p97 complex in RIG-I antiviral s... | KEEP AS NON CORE | Summary: NPL4/p97 negatively regulates RIG-I signaling by promoting RIG-I degradation. Reason: A genuine specialized signaling role; non-core relative to the general p97 cofactor function. Supporting Evidence: file:human/NPLOC4/NPLOC4-uniprot.txt which binds to RIGI and recruits RNF125 |
| GO:0036501 UFD1-NPL4 complex | IPI PMID:11574150 Cloning and characterization of the gene encoding human NPL4... | ACCEPT | Summary: Original cloning study demonstrating NPL4 interacts with UFD1 (the UFD1-NPL4 heterodimer). Reason: Core complex membership supported by direct interaction evidence. Supporting Evidence: file:human/NPLOC4/NPLOC4-uniprot.txt Heterodimer with UFD1 |
| GO:0005515 protein binding | IPI PMID:11574150 Cloning and characterization of the gene encoding human NPL4... | KEEP AS NON CORE | Summary: Interaction with UFD1 (Q92890). Bare protein binding term. Reason: The UFD1 interaction is central but bare protein binding is uninformative; captured by the UFD1-NPL4 complex annotation. Supporting Evidence: file:human/NPLOC4/NPLOC4-goa.tsv UniProtKB:Q92890 |
| GO:0030970 retrograde protein transport, ER to cytosol | IMP PMID:25660456 Identification of ERAD components essential for dislocation ... | ACCEPT | Summary: NPL4 is required for dislocation of an ERAD substrate (null Hong Kong alpha-1-antitrypsin) from the ER to the cytosol. Reason: Directly supported by IMP in an ERAD dislocation assay; a core process. Supporting Evidence: file:human/NPLOC4/NPLOC4-uniprot.txt necessary for the export of misfolded proteins from the ER to the cytoplasm |
| GO:0034098 VCP-NPL4-UFD1 AAA ATPase complex | ISS GO_REF:0000024 | ACCEPT | Summary: Sequence-similarity-inferred complex membership. Reason: Core complex membership corroborated by direct evidence. Supporting Evidence: file:human/NPLOC4/NPLOC4-uniprot.txt VCP-NPL4-UFD1 AAA ATPase complex |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5654985 | KEEP AS NON CORE | Summary: Reactome nucleoplasmic localization. Reason: Consistent with nuclear p97 functions; non-core. Supporting Evidence: file:human/NPLOC4/NPLOC4-uniprot.txt GO:0005654; C:nucleoplasm |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-5654989 | KEEP AS NON CORE | Summary: Reactome nucleoplasmic localization. Reason: Consistent with nuclear p97 functions; non-core. Supporting Evidence: file:human/NPLOC4/NPLOC4-uniprot.txt GO:0005654; C:nucleoplasm |
| GO:0005634 nucleus | HDA PMID:21630459 Proteomic characterization of the human sperm nucleus. | KEEP AS NON CORE | Summary: High-throughput direct-assay nuclear localization. Reason: Consistent with documented nuclear localization; non-core. Supporting Evidence: file:human/NPLOC4/NPLOC4-uniprot.txt Nucleus {ECO:0000250|UniProtKB:Q9ES54} |
| GO:0007030 Golgi organization | ISS PMID:11574150 Cloning and characterization of the gene encoding human NPL4... | KEEP AS NON CORE | Summary: The UFD1-NPL4 heterodimer (with VCP) influences Golgi membrane fusion/organization. Reason: Supported by the documented inhibition of Golgi membrane fusion by the heterodimer; one of many p97 processes, non-core. Supporting Evidence: file:human/NPLOC4/NPLOC4-uniprot.txt the heterodimer binds to VCP and inhibits Golgi membrane fusion |
| GO:0005783 endoplasmic reticulum | ISS PMID:11574150 Cloning and characterization of the gene encoding human NPL4... | ACCEPT | Summary: ER localization inferred by similarity. Reason: ER association is documented and functionally relevant (ERAD). Supporting Evidence: file:human/NPLOC4/NPLOC4-uniprot.txt Endoplasmic reticulum {ECO:0000250|UniProtKB:Q9ES54} |
| GO:0042175 nuclear outer membrane-endoplasmic reticulum membrane network | ISS PMID:11574150 Cloning and characterization of the gene encoding human NPL4... | KEEP AS NON CORE | Summary: Localization to the nuclear-envelope/ER membrane network, consistent with ER association and nuclear-envelope reformation roles. Reason: Consistent with ER/nuclear-envelope functions; a specific localization retained as non-core. Supporting Evidence: file:human/NPLOC4/NPLOC4-uniprot.txt Associated with the endoplasmic reticulum and nuclear |
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Download this section (compressed HTML)Q: 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)?
Q: 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?
Q: Is NPLOC4 haploinsufficiency phenotypically relevant, analogous to UFD1L in the 22q11 region?
Experiment: 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.
Experiment: Proximity-labeling (BioID/TurboID) of NPLOC4 across stress conditions to map compartment- and process-specific cofactor partners.
Experiment: Acute degron depletion of NPLOC4 with quantitative proteomics to define the endogenous substrate set extracted by the UFD1-NPL4-p97 complex.
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