Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0036503 ERAD pathway	IBA GO_REF:0000033	ACCEPT	Summary: UFD1 (with NPL4/VCP) is a core component of ERAD, driving retrotranslocation of misfolded ER proteins. Reason: Core process supported by UniProt function and experimental evidence. Supporting Evidence: file:human/UFD1/UFD1-uniprot.txt necessary for the export of misfolded proteins from the ER to the
GO:0031593 polyubiquitin modification-dependent protein binding	IBA GO_REF:0000033	ACCEPT	Summary: UFD1 binds polyubiquitin chains, the core molecular function letting the UFD1-NPL4 heterodimer recognize ubiquitinated substrates for p97. Reason: Directly supported; UFD1 is a ubiquitin-recognition factor that binds ubiquitinated proteins. Supporting Evidence: file:human/UFD1/UFD1-uniprot.txt The ternary complex containing UFD1, VCP and NPLOC4 binds
GO:0034098 VCP-NPL4-UFD1 AAA ATPase complex	IBA GO_REF:0000033	ACCEPT	Summary: UFD1 is a defining subunit of the VCP-NPL4-UFD1 segregase complex. Reason: Core complex membership, well documented. Supporting Evidence: file:human/UFD1/UFD1-uniprot.txt VCP-NPL4-UFD1 AAA ATPase complex
GO:0005634 nucleus	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Nuclear localization, consistent with nuclear p97 functions. Reason: Documented nuclear localization; the adaptor acts in multiple compartments, so retained as non-core. Supporting Evidence: file:human/UFD1/UFD1-uniprot.txt SUBCELLULAR LOCATION: Nucleus
GO:0005829 cytosol	IEA GO_REF:0000044	ACCEPT	Summary: Cytosolic localization, the principal compartment where the p97 segregase operates. Reason: Cytosolic localization is well supported and is the major site of the adaptor function. Supporting Evidence: file:human/UFD1/UFD1-uniprot.txt Cytoplasm, cytosol
GO:0006511 ubiquitin-dependent protein catabolic process	IEA GO_REF:0000002	ACCEPT	Summary: UFD1 is integral to ubiquitin-dependent proteasomal degradation as the p97 substrate-recruiting cofactor. Reason: Core biological-process role. Supporting Evidence: file:human/UFD1/UFD1-uniprot.txt ubiquitin-dependent proteolytic
GO:0030970 retrograde protein transport, ER to cytosol	IEA GO_REF:0000117	ACCEPT	Summary: UFD1 (with NPL4/VCP) mediates retrotranslocation of misfolded proteins from the ER to the cytosol. Reason: Directly supported core process. Supporting Evidence: file:human/UFD1/UFD1-uniprot.txt necessary for the export of misfolded proteins from the ER to the
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 NPLOC4 (Q8TAT6), the core complex partners. Bare protein binding term. Reason: Central interactions but bare protein binding is uninformative; captured by the complex annotations. Supporting Evidence: file:human/UFD1/UFD1-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 NPLOC4 captured as bare protein binding. Reason: Central interactions but bare protein binding is uninformative. Supporting Evidence: file:human/UFD1/UFD1-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 NPLOC4 (Q8TAT6) captured as bare protein binding. Reason: Central interaction but bare protein binding is uninformative. Supporting Evidence: file:human/UFD1/UFD1-goa.tsv UniProtKB:Q8TAT6
GO:0005515 protein binding	IPI PMID:25959826 Quantitative interaction proteomics of neurodegenerative dis...	KEEP AS NON CORE	Summary: Interaction with huntingtin (HTT, P42858). Bare protein binding term. Reason: A documented interaction but bare protein binding is uninformative and not part of the core function. Supporting Evidence: file:human/UFD1/UFD1-goa.tsv UniProtKB:P42858
GO:0005515 protein binding	IPI PMID:26712280 Characterization of an Additional Binding Surface on the p97...	KEEP AS NON CORE	Summary: Interaction with VCP (P55072). Bare protein binding term. Reason: Central interaction but bare protein binding is uninformative. Supporting Evidence: file:human/UFD1/UFD1-goa.tsv UniProtKB:P55072
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	KEEP AS NON CORE	Summary: HuRI interactome interaction with NPLOC4 (Q8TAT6). Bare protein binding. Reason: High-throughput interaction; bare protein binding is uninformative. Supporting Evidence: file:human/UFD1/UFD1-goa.tsv UniProtKB:Q8TAT6
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	KEEP AS NON CORE	Summary: Neurodegeneration interactome interaction with HTT (P42858). Bare protein binding. Reason: High-throughput interaction; bare protein binding is uninformative. Supporting Evidence: file:human/UFD1/UFD1-goa.tsv UniProtKB:P42858
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	KEEP AS NON CORE	Summary: BioPlex interactome interactions (VCP, NPLOC4). Bare protein binding. Reason: High-throughput interactions; bare protein binding is uninformative. Supporting Evidence: file:human/UFD1/UFD1-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 interaction with VCP (P55072). Bare protein binding. Reason: High-throughput interaction; bare protein binding is uninformative. Supporting Evidence: file:human/UFD1/UFD1-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/UFD1/UFD1-goa.tsv UniProtKB:P55072
GO:0005737 cytoplasm	IEA GO_REF:0000107	ACCEPT	Summary: Cytoplasmic localization, consistent with the cytosolic site of segregase action. Reason: Cytoplasmic/cytosolic localization is well supported. Supporting Evidence: file:human/UFD1/UFD1-uniprot.txt Cytoplasm, cytosol
GO:0034098 VCP-NPL4-UFD1 AAA ATPase complex	IEA GO_REF:0000120	ACCEPT	Summary: UFD1 is part of the VCP-NPL4-UFD1 complex. Reason: Core complex membership. Supporting Evidence: file:human/UFD1/UFD1-uniprot.txt VCP-NPL4-UFD1 AAA ATPase complex
GO:0036435 K48-linked polyubiquitin modification-dependent protein binding	IEA GO_REF:0000107	ACCEPT	Summary: UFD1 (in UFD1-NPL4) recognizes K48-linked polyubiquitin, the canonical degradation signal presented to p97. Reason: Consistent with the well-established K48-linked polyubiquitin recognition by the UFD1-NPL4 cofactor. Supporting Evidence: file:human/UFD1/UFD1-uniprot.txt The ternary complex containing UFD1, VCP and NPLOC4 binds
GO:0036501 UFD1-NPL4 complex	IEA GO_REF:0000120	ACCEPT	Summary: UFD1 forms an obligate heterodimer with NPLOC4 (the UFD1-NPL4 complex). Reason: Core complex membership. Supporting Evidence: file:human/UFD1/UFD1-uniprot.txt Heterodimer with NPLOC4
GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process	IEA GO_REF:0000041	ACCEPT	Summary: UFD1-mediated substrate extraction feeds proteasomal degradation. Reason: Core process; the segregase delivers extracted substrates to the proteasome. Supporting Evidence: file:human/UFD1/UFD1-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: p97 review describing UFD1-NPL4 in ubiquitin-dependent degradation. Reason: Consistent with the core degradative role. Supporting Evidence: file:human/UFD1/UFD1-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 UFD1 in ubiquitin-dependent degradation. Reason: Consistent with the core degradative role of the p97 machinery. Supporting Evidence: file:human/UFD1/UFD1-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 UFD1 within the VCP-NPL4-UFD1 complex. Reason: Core complex membership supported by direct interaction evidence. Supporting Evidence: file:human/UFD1/UFD1-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 UFD1 within the VCP-NPL4-UFD1 complex. Reason: Core complex membership supported by direct interaction evidence. Supporting Evidence: file:human/UFD1/UFD1-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. Supporting Evidence: file:human/UFD1/UFD1-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 is well established. Reason: UFD1 is unambiguously part of the VCP-NPL4-UFD1 complex; the complex assertion is accepted while the attached reference is a wrong-identifier citation (flagged in reference_review). Supporting Evidence: file:human/UFD1/UFD1-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 UFD1-NPL4's role in ERAD. Reason: Core process. Supporting Evidence: file:human/UFD1/UFD1-uniprot.txt necessary for the export of misfolded proteins from the ER to the
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, but the proteasomal degradation role is correct. Reason: UFD1 participates in proteasome-mediated degradation as a p97 cofactor; assertion accepted, reference flagged as wrong identifier. Supporting Evidence: file:human/UFD1/UFD1-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: UFD1 is part of an AAA+ ATPase (p97) complex. Reason: Generic parent of the specific VCP-NPL4-UFD1 complex annotation. Supporting Evidence: file:human/UFD1/UFD1-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: UFD1 is part of an AAA+ ATPase (p97) complex. Reason: Generic parent of the specific complex annotation. Supporting Evidence: file:human/UFD1/UFD1-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: UFD1 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/UFD1/UFD1-uniprot.txt VCP-NPL4-UFD1 AAA ATPase complex
GO:0005634 nucleus	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: Sequence-similarity-inferred nuclear localization. Reason: Consistent with documented nuclear localization; non-core. Supporting Evidence: file:human/UFD1/UFD1-uniprot.txt SUBCELLULAR LOCATION: Nucleus
GO:0072344 rescue of stalled cytosolic ribosome	NAS PMID:35452614 Ribosome-associated quality-control mechanisms from bacteria...	KEEP AS NON CORE	Summary: UFD1/p97 participates in ribosome-associated quality control, extracting ubiquitinated nascent chains/factors from stalled ribosomes. Reason: A genuine p97-dependent RQC role per the cited review, but one of many p97 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 UFD1 in the ribosome-associated quality-control (RQC) complex. Reason: p97-UFD1-NPL4 functions with RQC but is a recruited cofactor module rather than a constitutive core RQC subunit; 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: UFD1/p97 extracts ubiquitinated nascent chains for degradation in RQC. Reason: A genuine p97-dependent RQC process; non-core relative to the general adaptor function. Supporting Evidence: PMID:35452614 Ribosome-associated quality-control mechanisms from bacteria to humans
GO:0036503 ERAD pathway	IMP PMID:24089527 Caveolin-1 interacts with Derlin-1 and promotes ubiquitinati...	ACCEPT	Summary: UFD1 functions in ERAD, demonstrated in a p97-dependent degradation context (caveolin-1/Derlin-1/COX-2). Reason: Experimentally supported (IMP) core process. Supporting Evidence: file:human/UFD1/UFD1-uniprot.txt necessary for the export of misfolded proteins from the ER to the
GO:0071218 cellular response to misfolded protein	IMP PMID:24089527 Caveolin-1 interacts with Derlin-1 and promotes ubiquitinati...	ACCEPT	Summary: UFD1 participates in the cellular response to misfolded proteins as part of the p97 degradation machinery. Reason: Experimentally supported; consistent with UFD1's role in clearing misfolded proteins. Supporting Evidence: file:human/UFD1/UFD1-uniprot.txt necessary for the export of misfolded proteins from the ER to the
GO:0005829 cytosol	TAS Reactome:R-HSA-9755507	ACCEPT	Summary: Reactome cytosolic localization. Reason: Cytosol is a principal site of segregase function. Supporting Evidence: file:human/UFD1/UFD1-uniprot.txt Cytoplasm, cytosol
GO:0005829 cytosol	TAS Reactome:R-HSA-9758088	ACCEPT	Summary: Reactome cytosolic localization. Reason: Cytosol is a principal site of segregase function. Supporting Evidence: file:human/UFD1/UFD1-uniprot.txt Cytoplasm, cytosol
GO:0005829 cytosol	TAS Reactome:R-HSA-9758090	ACCEPT	Summary: Reactome cytosolic localization. Reason: Cytosol is a principal site of segregase function. Supporting Evidence: file:human/UFD1/UFD1-uniprot.txt Cytoplasm, cytosol
GO:0005829 cytosol	TAS Reactome:R-HSA-9948427	ACCEPT	Summary: Reactome cytosolic localization. Reason: Cytosol is a principal site of segregase function. Supporting Evidence: file:human/UFD1/UFD1-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: UFD1 (with NPLOC4/VCP) promotes ubiquitin-dependent degradation of RIG-I. Reason: Directly supported by IMP; the p97-UFD1-NPL4 complex drives ubiquitin-dependent RIG-I degradation. Supporting Evidence: file:human/UFD1/UFD1-uniprot.txt recruits RNF125 to promote ubiquitination and degradation of
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, UFD1/p97 negatively regulates type I interferon production. Reason: A genuine, experimentally supported signaling role, but specialized relative to the core p97 cofactor function. Supporting Evidence: file:human/UFD1/UFD1-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 UFD1 within the VCP-NPL4-UFD1 complex. Reason: Core complex membership supported by direct evidence. Supporting Evidence: file:human/UFD1/UFD1-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: UFD1/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/UFD1/UFD1-uniprot.txt Acts as a negative regulator of type I interferon
GO:0036501 UFD1-NPL4 complex	IPI PMID:11574150 Cloning and characterization of the gene encoding human NPL4...	ACCEPT	Summary: Original study demonstrating UFD1 interacts with NPL4 (the UFD1-NPL4 heterodimer). Reason: Core complex membership supported by direct interaction evidence. Supporting Evidence: file:human/UFD1/UFD1-uniprot.txt Heterodimer with NPLOC4
GO:0005515 protein binding	IPI PMID:11574150 Cloning and characterization of the gene encoding human NPL4...	KEEP AS NON CORE	Summary: Interaction with NPLOC4 (Q8TAT6). Bare protein binding term. Reason: The NPLOC4 interaction is central but bare protein binding is uninformative; captured by the UFD1-NPL4 complex annotation. Supporting Evidence: file:human/UFD1/UFD1-goa.tsv UniProtKB:Q8TAT6
GO:0030970 retrograde protein transport, ER to cytosol	IMP PMID:25660456 Identification of ERAD components essential for dislocation ...	ACCEPT	Summary: UFD1 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/UFD1/UFD1-uniprot.txt necessary for the export of misfolded proteins from the ER to the
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/UFD1/UFD1-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/UFD1/UFD1-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/UFD1/UFD1-uniprot.txt GO:0005654; C:nucleoplasm
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-6781922	KEEP AS NON CORE	Summary: Reactome nucleoplasmic localization. Reason: Consistent with nuclear p97 functions; non-core. Supporting Evidence: file:human/UFD1/UFD1-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/UFD1/UFD1-uniprot.txt SUBCELLULAR LOCATION: Nucleus
GO:0005515 protein binding	IPI PMID:17681147 Ufd1 is a cofactor of gp78 and plays a key role in cholester...	KEEP AS NON CORE	Summary: Interaction with USP13 (Q9UKV5), which couples the ER stress response to cell-cycle control. Bare protein binding term. Reason: A documented, functionally relevant interaction (USP13), but bare protein binding is uninformative. Supporting Evidence: file:human/UFD1/UFD1-goa.tsv UniProtKB:Q9UKV5
GO:0001501 skeletal system development	TAS PMID:10024240 A molecular pathway revealing a genetic basis for human card...	KEEP AS NON CORE	Summary: Legacy annotation linking UFD1L to skeletal/developmental phenotypes in the DiGeorge/22q11 deletion context. Reason: UFD1L lies in the 22q11/DiGeorge-associated region and is developmentally expressed; a developmental-phenotype association exists but is far removed from the gene's direct molecular function. Retained as non-core (developmental/disease context). Supporting Evidence: file:human/UFD1/UFD1-uniprot.txt developmentally expressed
GO:0004843 cysteine-type deubiquitinase activity	TAS PMID:9063746 UFD1L, a developmentally expressed ubiquitination gene, is d...	REMOVE	Summary: Legacy (2003 PINC, TAS) annotation asserting UFD1 has cysteine-type deubiquitinase activity. UFD1 is a ubiquitin-recognition adaptor with no catalytic protease domain and is not a deubiquitinase; this is a mis-annotation likely conflating the broader ubiquitin-fusion-degradation pathway with a catalytic DUB activity. Reason: UFD1 is a non-catalytic ubiquitin-binding cofactor of p97 (UFD1 family; no peptidase domain). No experimental evidence supports intrinsic deubiquitinase activity; the original UFD1L paper (PMID:9063746) characterizes a developmentally expressed ubiquitination-pathway gene, not a DUB. This molecular-function annotation is incorrect. Supporting Evidence: file:human/UFD1/UFD1-uniprot.txt Ubiquitin recognition factor in ER-associated degradation protein 1
GO:0006511 ubiquitin-dependent protein catabolic process	TAS PMID:9063746 UFD1L, a developmentally expressed ubiquitination gene, is d...	ACCEPT	Summary: UFD1L participates in ubiquitin-dependent protein degradation, the pathway for which it was named (ubiquitin fusion degradation). Reason: Correct core process; UFD1 is an essential component of the ubiquitin-dependent proteolytic pathway. Supporting Evidence: file:human/UFD1/UFD1-uniprot.txt ubiquitin-dependent proteolytic

Core Functions

Ubiquitin-recognition cofactor of the AAA+ ATPase VCP/p97 that, as part of the obligate UFD1-NPL4 heterodimer, binds (poly)ubiquitinated substrates and presents them to p97 for ATP-driven extraction and unfolding, after which they are degraded by the proteasome.

Molecular Function:

polyubiquitin modification-dependent protein binding

Cellular Locations:

cytosol

In Complex:

VCP-NPL4-UFD1 AAA ATPase complex

Supporting Evidence:

file:human/UFD1/UFD1-uniprot.txt
The ternary complex containing UFD1, VCP and NPLOC4 binds
file:human/UFD1/UFD1-uniprot.txt
Heterodimer with NPLOC4

Substrate-delivery subunit of the VCP-NPL4-UFD1 segregase essential for ERAD, driving retrotranslocation of misfolded proteins from the ER to the cytosol for proteasomal degradation and supporting the cellular response to misfolded proteins.

Molecular Function:

polyubiquitin modification-dependent protein binding

Cellular Locations:

cytosol

Supporting Evidence:

file:human/UFD1/UFD1-uniprot.txt
necessary for the export of misfolded proteins from the ER to the
file:human/UFD1/UFD1-uniprot.txt
Essential component of the ubiquitin-dependent proteolytic

References

GO_REF:0000002

Gene Ontology annotation through association of InterPro records with GO terms

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000041

Gene Ontology annotation based on UniPathway vocabulary mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB keywords

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:9063746

UFD1L, a developmentally expressed ubiquitination gene, is deleted in CATCH 22 syndrome.

Cloned UFD1L as a developmentally expressed ubiquitination-pathway gene deleted in CATCH22/DiGeorge syndrome.

PMID:10024240

A molecular pathway revealing a genetic basis for human cardiac and craniofacial defects.

PMID:11574150

Cloning and characterization of the gene encoding human NPL4, a protein interacting with the ubiquitin fusion-degradation protein (UFD1L).

UFD1L interacts with NPL4, forming the UFD1-NPL4 heterodimer.

PMID:17681147

Ufd1 is a cofactor of gp78 and plays a key role in cholesterol metabolism by regulating the stability of HMG-CoA reductase.

PMID:18775313

UBXD7 binds multiple ubiquitin ligases and implicates p97 in HIF1alpha turnover.

PMID:20414249

Imbalances in p97 co-factor interactions in human proteinopathy.

PMID:21630459

Proteomic characterization of the human sperm nucleus.

PMID:21645854

Hierarchical binding of cofactors to the AAA ATPase p97.

PMID:24089527

Caveolin-1 interacts with Derlin-1 and promotes ubiquitination and degradation of cyclooxygenase-2 via collaboration with p97 complex.

UFD1 (in the p97 complex) is required for ERAD-type degradation of COX-2, supporting its role in the cellular response to misfolded proteins.

PMID:25660456

Identification of ERAD components essential for dislocation of the null Hong Kong variant of α-1-antitrypsin (NHK).

UFD1 is required for ERAD dislocation (retrotranslocation) of the NHK alpha-1-antitrypsin substrate from the ER to the cytosol.

PMID:25959826

Quantitative interaction proteomics of neurodegenerative disease proteins.

PMID:26471729

A non-canonical role of the p97 complex in RIG-I antiviral signaling.

The VCP-UFD1-NPLOC4 complex binds RIG-I and recruits RNF125 to promote RIG-I ubiquitination and degradation, negatively regulating type I interferon production.

PMID:26712280

Characterization of an Additional Binding Surface on the p97 N-Terminal Domain Involved in Bipartite Cofactor Interactions.

PMID:28819009

The AAA+ ATPase p97, a cellular multitool.

Reviews the UFD1-NPL4 cofactor as the principal ubiquitin-recruiting adaptor of p97 in ubiquitin-dependent degradation and ERAD.

PMID:32296183

A reference map of the human binary protein interactome.

PMID:32814053

Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains.

PMID:33712450

The p97-UBXN1 complex regulates aggresome formation.

Studies p97 cofactor complexes in ubiquitin-dependent degradation and aggresome formation.

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.

PMID:35271311

OpenCell: Endogenous tagging for the cartography of human cellular organization.

PMID:35452614

Ribosome-associated quality-control mechanisms from bacteria to humans.

Reviews ribosome-associated quality control, in which p97 (with UFD1-NPL4) extracts ubiquitinated nascent chains/factors from stalled ribosomes.

PMID:37776851

Analysis of proteome-wide degradation dynamics in ALS SOD1 iPSC-derived patient neurons reveals disrupted VCP homeostasis.

PMID:39329031

Study of Clinical Characteristics of Intellectual Disability in Morocco.

Reactome:R-HSA-5654985

Reactome: nucleoplasm localization (signaling-related pathway)

Reactome:R-HSA-5654989

Reactome: nucleoplasm localization (signaling-related pathway)

Reactome:R-HSA-6781922

Reactome: nucleoplasm localization

Reactome:R-HSA-9755507

Reactome: KEAP1-NFE2L2 / cytosol localization

Reactome:R-HSA-9758088

Reactome: cytosol localization

Reactome:R-HSA-9758090

Reactome: cytosol localization

Reactome:R-HSA-9948427

Reactome: cytosol localization

Suggested Experiments

Experiment: Reconstituted ERAD/retrotranslocation assays with UFD1 ubiquitin-binding mutants to dissect its contribution (vs NPL4) to substrate engagement and extraction.

Experiment: Quantitative interaction proteomics across stress conditions to map UFD1-specific cofactor and substrate partners distinct from NPL4.

Experiment: Biochemical assay testing purified UFD1 for any intrinsic isopeptidase activity to formally confirm the absence of deubiquitinase function.

📚 Additional Documentation

Notes

(UFD1-notes.md)

UFD1 (Q92890) research notes

Summary

UFD1 (Ubiquitin recognition factor in ER-associated degradation protein 1; also UFD1L, ubiquitin fusion degradation protein 1) is an essential ubiquitin-binding cofactor of the AAA+ ATPase VCP/p97. It forms the obligate UFD1-NPL4 heterodimer, the principal substrate-recruiting adaptor of p97, and with VCP constitutes the VCP-NPL4-UFD1 segregase. UFD1 binds (poly)ubiquitin and, together with NPL4, recognizes ubiquitinated substrates and presents them to p97 for ATP-driven extraction and unfolding, after which they are degraded by the proteasome. The complex is central to endoplasmic-reticulum-associated degradation (ERAD), driving retrotranslocation of misfolded proteins from the ER to the cytosol, and participates in many other p97-dependent processes including the cellular response to misfolded proteins, ribosome-associated quality control, spindle disassembly and nuclear-envelope reformation at the end of mitosis, and Golgi membrane reassembly. UFD1 also contributes to a non-canonical p97 function in innate immunity, acting (with NPLOC4/VCP) as a negative regulator of type I interferon production by binding RIG-I (RIGI) and recruiting RNF125 for its degradation, and it couples the ER stress response to cell-cycle control via interaction with USP13. The gene lies within the 3q29 / DiGeorge (22q11)-associated genomic context and is developmentally expressed. UFD1 localizes to the cytosol, ER and nucleus.

Core functions (from review)

GO:0031593 polyubiquitin modification-dependent protein binding — Ubiquitin-recognition cofactor of the AAA+ ATPase VCP/p97 that, as part of the obligate UFD1-NPL4 heterodimer, binds (poly)ubiquitinated substrates and presents them to p97 for ATP-driven extraction and unfolding, after which they are degraded by the proteasome.
GO:0031593 polyubiquitin modification-dependent protein binding — Substrate-delivery subunit of the VCP-NPL4-UFD1 segregase essential for ERAD, driving retrotranslocation of misfolded proteins from the ER to the cytosol for proteasomal degradation and supporting the cellular response to misfolded proteins.

Provenance

Research and verbatim supporting quotes are recorded inline in UFD1-ai-review.yaml (per-annotation supported_by and references findings). This notes file summarizes the completed review; see the YAML for evidence citations.

Pn Notes

(UFD1-pn-notes.md)

UFD1 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q92890
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-07c
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/UFD1/UFD1-ai-review.yaml
AIGR review HTML: present - genes/human/UFD1/UFD1-ai-review.html
Gene notes: present - genes/human/UFD1/UFD1-notes.md
GOA TSV: present - genes/human/UFD1/UFD1-goa.tsv
UniProt record: present - genes/human/UFD1/UFD1-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/UFD1.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/UFD1.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

No *-deep-research*.md file found in this gene directory.

AIGR Review Snapshot

Description: UFD1 (Ubiquitin recognition factor in ER-associated degradation protein 1; also UFD1L, ubiquitin fusion degradation protein 1) is an essential ubiquitin-binding cofactor of the AAA+ ATPase VCP/p97. It forms the obligate UFD1-NPL4 heterodimer, the principal substrate-recruiting adaptor of p97, and with VCP constitutes the VCP-NPL4-UFD1 segregase. UFD1 binds (poly)ubiquitin and, together with NPL4, recognizes ubiquitinated substrates and presents them to p97 for ATP-driven extraction and unfolding, after which they are degraded by the proteasome. The complex is central to endoplasmic-reticulum-associated degradation (ERAD), driving retrotranslocation of misfolded proteins from the ER to the cytosol, and participates in many other p97-dependent processes including the cellular response to misfolded proteins, ribosome-associated quality control, spindle disassembly and nuclear-envelope reformation at the end of mitosis, and Golgi membrane reassembly. UFD1 also contributes to a non-canonical p97 function in innate immunity, acting (with NPLOC4/VCP) as a negative regulator of type I interferon production by binding RIG-I (RIGI) and recruiting RNF125 for its degradation, and it couples the ER stress response to cell-cycle control via interaction with USP13. The gene lies within the 3q29 / DiGeorge (22q11)-associated genomic context and is developmentally expressed. UFD1 localizes to the cytosol, ER and nucleus.
Existing/core annotation action counts: ACCEPT: 31; KEEP_AS_NON_CORE: 27; REMOVE: 1

PN Consistency Summary

Consistency: Strong. Notes/review/PN agree UFD1 is the p97/VCP ubiquitin-binding cofactor (UFD1-NPL4 heterodimer; ERAD retrotranslocation; also RQC, mitosis, immunity). NOTE: UFD1 is NOT a UFMylation-cascade member despite the name similarity — it is "ubiquitin fusion degradation 1," a p97 adaptor. The review/PN both treat it correctly as a UPS/ERAD/VCP gene; no false UFM1 conflation. Review ACCEPTs GO:0036503, GO:0034098 (8x in GOA), GO:0031593, GO:0030970, GO:0036501 (UFD1-NPL4 complex), GO:0036435 (K48-polyUb binding). No contradictions.
PN story / NEW pressure: Well captured. GO:0036503 (ERAD) and GO:0034098 (complex) are in GOA/review. PN's GO:0097466 (ubiquitin-dependent glycoprotein ERAD pathway; verify before any add) is flagged more_specific_than_existing — UFD1 is a general ERAD adaptor, not glycoprotein-specific, so this projection over-reaches. PN RQC type is correctly no_mapping; review captures RQC via GO:0072344 (NAS) + GO:1990116 as KEEP_AS_NON_CORE. The MF core GO:0031593 (polyubiquitin-modification-dependent protein binding) is annotated. Conclusion: already captured; GO:0097466 over-reaches.
Evidence alignment: PN cites PMID:28451587 (SHP motif) and 36736315 (IPR055417 domain) — neither in review YAML (domain/signature citations); review uses UniProt + p97/ERAD literature. Divergence is benign; no shared functional PMID but no conflict.
Verdict: Consistent and complete; correctly handled as a p97/ERAD adaptor (not a UFMylation gene). PN GO:0036503/GO:0034098 match the review; PN's glycoprotein-specific GO:0097466 over-reaches — keep general ERAD.

Full Consistency Review

UniProt: Q92890 · batch: proteostasis-batch-2026-06-07c · review status: complete (2 core_functions, both GO:0031593; large protein-binding set triaged)
PN placement: ER proteostasis|...|ER associated degradation|VCP system for retrotranslocation in ERAD|VCP accessories; Translation|...|Ribosome-associated QC|VCP system for RQC; UPS|VCP and associated proteins|adaptors|SHP|UT3; UPS|Ubiquitin and UBL binding|protein quality control|ERAD cofactor|...UT3 ; PN-node mapping: ERAD group→GO:0036503 (exact); SHP/UT3 subtype→GO:0034098 (VCP-NPL4-UFD1 complex); ERAD-cofactor type→GO:0097466 (glycoprotein ERAD, more_specific_than_existing); RQC type→no_mapping.
Consistency: Strong. Notes/review/PN agree UFD1 is the p97/VCP ubiquitin-binding cofactor (UFD1-NPL4 heterodimer; ERAD retrotranslocation; also RQC, mitosis, immunity). NOTE: UFD1 is NOT a UFMylation-cascade member despite the name similarity — it is "ubiquitin fusion degradation 1," a p97 adaptor. The review/PN both treat it correctly as a UPS/ERAD/VCP gene; no false UFM1 conflation. Review ACCEPTs GO:0036503, GO:0034098 (8x in GOA), GO:0031593, GO:0030970, GO:0036501 (UFD1-NPL4 complex), GO:0036435 (K48-polyUb binding). No contradictions.
PN story / NEW pressure: Well captured. GO:0036503 (ERAD) and GO:0034098 (complex) are in GOA/review. PN's GO:0097466 (ubiquitin-dependent glycoprotein ERAD pathway; verify before any add) is flagged more_specific_than_existing — UFD1 is a general ERAD adaptor, not glycoprotein-specific, so this projection over-reaches. PN RQC type is correctly no_mapping; review captures RQC via GO:0072344 (NAS) + GO:1990116 as KEEP_AS_NON_CORE. The MF core GO:0031593 (polyubiquitin-modification-dependent protein binding) is annotated. Conclusion: already captured; GO:0097466 over-reaches.
Mapping strategy: PN node is sound: ERAD group→GO:0036503 exact and the SHP/UT3 subtype→GO:0034098 complex are precise and match the review. The only caution is the ERAD-cofactor type→GO:0097466 (glycoprotein-specific) being narrower/skewed vs UFD1's general adaptor role — keep ERAD at GO:0036503, do not propagate the glycoprotein-specific child. UFD1 does not change the node.
Evidence alignment: PN cites PMID:28451587 (SHP motif) and 36736315 (IPR055417 domain) — neither in review YAML (domain/signature citations); review uses UniProt + p97/ERAD literature. Divergence is benign; no shared functional PMID but no conflict.
Verdict: Consistent and complete; correctly handled as a p97/ERAD adaptor (not a UFMylation gene). PN GO:0036503/GO:0034098 match the review; PN's glycoprotein-specific GO:0097466 over-reaches — keep general ERAD.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-07c
review_yaml: genes/human/UFD1/UFD1-ai-review.yaml
PN workbook rows: 4

PN row 1: ER proteostasis | Organelle-specific protein degradation | ER associated degradation | VCP system for retrotranslocation in ERAD | VCP accessories

UniProt: Q92890
In branches: ER, TR, UPS
PN-node mapping records (path + ancestors):
- [subtype] ER proteostasis|Organelle-specific protein degradation|ER associated degradation|VCP system for retrotranslocation in ERAD|VCP accessories
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad PN category rather than a single GO class. The member genes span multiple activities, complexes, or contexts, so direct propagation from this node would overstate the shared biology.
- [type] ER proteostasis|Organelle-specific protein degradation|ER associated degradation|VCP system for retrotranslocation in ERAD
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0036503 ERAD pathway]
  rationale: This PN type captures the VCP/p97-dependent retrotranslocation machinery used in ERAD. It is not a separate process from ERAD, but a core mechanistic subsystem within it.
- [group] ER proteostasis|Organelle-specific protein degradation|ER associated degradation
  status=mapped scope=exact GO=[GO:0036503 ERAD pathway]
  rationale: The PN group "ER associated degradation" is a direct lexical and biological match to the GO ERAD pathway term. The additional branch and class context disambiguates the source string from any broader degradation language.
- [class] ER proteostasis|Organelle-specific protein degradation
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad PN category rather than a single GO class. The member genes span multiple activities, complexes, or contexts, so direct propagation from this node would overstate the shared biology.
- [branch] ER proteostasis
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a top-level PN branch. This is a systems/taxonomy umbrella, not a direct GO assertion; narrower child curations carry any propagating GO mappings.

PN row 2: Translation | Cytosolic translation | Ribosome-associated QC | VCP system for RQC

UniProt: Q92890
In branches: ER, TR, UPS
PN-node mapping records (path + ancestors):
- [type] Translation|Cytosolic translation|Ribosome-associated QC|VCP system for RQC
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad PN category rather than a single GO class. The member genes span multiple activities, complexes, or contexts, so direct propagation from this node would overstate the shared biology.
- [group] Translation|Cytosolic translation|Ribosome-associated QC
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0006515 protein quality control for misfolded or incompletely synthesized proteins]
  rationale: The PN ribosome-associated quality-control group covers surveillance and disposal of stalled or defective nascent-chain translation products. GO lacks a dedicated ribosome-associated QC term in the local cache, so the broader protein-quality-control process is the best supported target.
- [class] Translation|Cytosolic translation
  status=context_only scope=too_broad_to_propagate GO=[GO:0002181 cytoplasmic translation]
  rationale: The PN class Cytosolic translation is centered on the cytoplasmic translation apparatus and process, but it also houses supporting machinery such as ribosome biogenesis factors. The GO process term is a useful high-level label for the class, but propagating it to all members would over-annotate genes whose PN placement is through assembly or maturation context rather than core cytoplasmic translation.
- [branch] Translation
  status=context_only scope=too_broad_to_propagate GO=[GO:0006412 translation]
  rationale: The PN Translation branch is organized around the translation apparatus and immediately associated cotranslational quality-control systems. GO translation is the closest high-level process label, but the PN branch also contains adjacent machinery such as ribosome biogenesis and nascent-chain handling. Keeping this relationship is useful for interpretation, but it is too broad to project safely onto every member.

PN row 3: Ubiquitin Proteasome System | VCP and associated proteins | adaptors | SHP | UT3

UniProt: Q92890
In branches: ER, TR, UPS
Signature domains: PMID: 28451587 (SHP)
Auxiliary domains: IPR042299
PN references (titles):
- 28451587
PN-node mapping records (path + ancestors):
- [subtype] Ubiquitin Proteasome System|VCP and associated proteins|adaptors|SHP|UT3
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0034098 VCP-NPL4-UFD1 AAA ATPase complex]
  rationale: This PN subtype identifies UFD1 in the canonical VCP-NPL4-UFD1 adaptor complex. The matching GO cellular-component term is VCP-NPL4-UFD1 AAA ATPase complex.
- [type] Ubiquitin Proteasome System|VCP and associated proteins|adaptors|SHP
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a VCP-adaptor motif or architecture subdivision. The label is useful taxonomy but too indirect for direct GO propagation without gene-level evidence.
- [group] Ubiquitin Proteasome System|VCP and associated proteins|adaptors
  status=context_only scope=too_broad_to_propagate GO=[GO:0034098 VCP-NPL4-UFD1 AAA ATPase complex]
  rationale: This PN group records VCP adaptor context, but it mixes UBX, SHP, VIM, VBM, membrane, and other adaptor classes. Direct propagation should come only from narrower complex-specific nodes or gene-level review.
- [class] Ubiquitin Proteasome System|VCP and associated proteins
  status=context_only scope=too_broad_to_propagate GO=[GO:0043335 protein unfolding]
  rationale: This class records the VCP segregase branch context, but descendants include VCP, substrate adaptors, DUBs, E3 ligases, channels, and unrelated associated enzymes. Direct propagation is restricted to narrower nodes.
- [branch] Ubiquitin Proteasome System
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.

PN row 4: Ubiquitin Proteasome System | Ubiquitin and UBL binding | protein quality control | ERAD cofactor | idiosyncratic Ub binding / UT3

UniProt: Q92890
In branches: ER, TR, UPS
Signature domains: PMID: 36736315 (IPR055417)
Auxiliary domains: (none)
PN references (titles):
- 36736315
PN-node mapping records (path + ancestors):
- [subtype] Ubiquitin Proteasome System|Ubiquitin and UBL binding|protein quality control|ERAD cofactor|idiosyncratic Ub binding / UT3
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a family, domain, architecture, or residual subdivision. The label is useful for PN taxonomy navigation but is not itself a GO annotation target; any functional assertion should come from a curated parent role or gene-level evidence.
- [type] Ubiquitin Proteasome System|Ubiquitin and UBL binding|protein quality control|ERAD cofactor
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0097466 ubiquitin-dependent glycoprotein ERAD pathway]
  rationale: This PN type groups ubiquitin/UBL-binding factors that act as ERAD cofactors in protein-quality-control contexts. The best available GO target in the local cache is ubiquitin-dependent glycoprotein ERAD pathway, used here at propagation scope.
- [group] Ubiquitin Proteasome System|Ubiquitin and UBL binding|protein quality control
  status=context_only scope=too_broad_to_propagate GO=[GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process]
  rationale: This PN group is a protein-quality-control context bucket, but its descendants include ERAD cofactors, HSP70 cochaperone context, stalled-chain recognition, and other mixed roles. Direct propagation should come from narrower nodes such as ERAD cofactor.
- [class] Ubiquitin Proteasome System|Ubiquitin and UBL binding
  status=context_only scope=too_broad_to_propagate GO=[GO:0140036 ubiquitin-modified protein reader activity]
  rationale: This class records ubiquitin/UBL-reader context, but the subtree mixes ubiquitin, SUMO, UBL-domain, domain-architecture, catalytic, signaling, trafficking, and nucleic-acid process buckets. It is useful context, not a safe direct propagation.
- [branch] Ubiquitin Proteasome System
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.

Projected GO annotations (5)

GO:0036503 ERAD pathway | scope=exact | goa_status=already_in_goa_exact | from=ER proteostasis|Organelle-specific protein degradation|ER associated degradation
GO:0036503 ERAD pathway | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=ER proteostasis|Organelle-specific protein degradation|ER associated degradation|VCP system for retrotranslocation in ERAD
GO:0006515 protein quality control for misfolded or incompletely synthesized proteins | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Translation|Cytosolic translation|Ribosome-associated QC
GO:0034098 VCP-NPL4-UFD1 AAA ATPase complex | scope=ok_for_propagation_to_go | goa_status=already_in_goa_exact | from=Ubiquitin Proteasome System|VCP and associated proteins|adaptors|SHP|UT3
GO:0097466 ubiquitin-dependent glycoprotein ERAD pathway | scope=ok_for_propagation_to_go | goa_status=more_specific_than_existing_goa | from=Ubiquitin Proteasome System|Ubiquitin and UBL binding|protein quality control|ERAD cofactor

Note

This file is generated from the current PROTEOSTASIS phase-1 dossier and local gene-review artifacts. Edit the source review, PN mapping, or dossier rather than this generated note when correcting the underlying curation.

📄 View Raw YAML

id: Q92890
gene_symbol: UFD1
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  UFD1 (Ubiquitin recognition factor in ER-associated degradation protein 1;
  also UFD1L, ubiquitin fusion degradation protein 1) is an essential
  ubiquitin-binding cofactor of the AAA+ ATPase VCP/p97. It forms the obligate
  UFD1-NPL4 heterodimer, the principal substrate-recruiting adaptor of p97, and
  with VCP constitutes the VCP-NPL4-UFD1 segregase. UFD1 binds (poly)ubiquitin
  and, together with NPL4, recognizes ubiquitinated substrates and presents them
  to p97 for ATP-driven extraction and unfolding, after which they are degraded
  by the proteasome. The complex is central to endoplasmic-reticulum-associated
  degradation (ERAD), driving retrotranslocation of misfolded proteins from the
  ER to the cytosol, and participates in many other p97-dependent processes
  including the cellular response to misfolded proteins, ribosome-associated
  quality control, spindle disassembly and nuclear-envelope reformation at the
  end of mitosis, and Golgi membrane reassembly. UFD1 also contributes to a
  non-canonical p97 function in innate immunity, acting (with NPLOC4/VCP) as a
  negative regulator of type I interferon production by binding RIG-I (RIGI) and
  recruiting RNF125 for its degradation, and it couples the ER stress response
  to cell-cycle control via interaction with USP13. The gene lies within the
  3q29 / DiGeorge (22q11)-associated genomic context and is developmentally
  expressed. UFD1 localizes to the cytosol, ER and nucleus.
existing_annotations:
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: UFD1 (with NPL4/VCP) is a core component of ERAD, driving retrotranslocation of misfolded ER proteins.
    action: ACCEPT
    reason: Core process supported by UniProt function and experimental evidence.
    supported_by:
    - reference_id: file:human/UFD1/UFD1-uniprot.txt
      supporting_text: necessary for the export of misfolded proteins from the ER to the
- term:
    id: GO:0031593
    label: polyubiquitin modification-dependent protein binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: UFD1 binds polyubiquitin chains, the core molecular function letting the UFD1-NPL4 heterodimer recognize ubiquitinated substrates for p97.
    action: ACCEPT
    reason: Directly supported; UFD1 is a ubiquitin-recognition factor that binds ubiquitinated proteins.
    supported_by:
    - reference_id: file:human/UFD1/UFD1-uniprot.txt
      supporting_text: The ternary complex containing UFD1, VCP and NPLOC4 binds
- term:
    id: GO:0034098
    label: VCP-NPL4-UFD1 AAA ATPase complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: UFD1 is a defining subunit of the VCP-NPL4-UFD1 segregase complex.
    action: ACCEPT
    reason: Core complex membership, well documented.
    supported_by:
    - reference_id: file:human/UFD1/UFD1-uniprot.txt
      supporting_text: VCP-NPL4-UFD1 AAA ATPase complex
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Nuclear localization, consistent with nuclear p97 functions.
    action: KEEP_AS_NON_CORE
    reason: Documented nuclear localization; the adaptor acts in multiple compartments, so retained as non-core.
    supported_by:
    - reference_id: file:human/UFD1/UFD1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
- 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 segregase operates.
    action: ACCEPT
    reason: Cytosolic localization is well supported and is the major site of the adaptor function.
    supported_by:
    - reference_id: file:human/UFD1/UFD1-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: UFD1 is integral to ubiquitin-dependent proteasomal degradation as the p97 substrate-recruiting cofactor.
    action: ACCEPT
    reason: Core biological-process role.
    supported_by:
    - reference_id: file:human/UFD1/UFD1-uniprot.txt
      supporting_text: ubiquitin-dependent proteolytic
- 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: UFD1 (with NPL4/VCP) mediates retrotranslocation of misfolded proteins from the ER to the cytosol.
    action: ACCEPT
    reason: Directly supported core process.
    supported_by:
    - reference_id: file:human/UFD1/UFD1-uniprot.txt
      supporting_text: necessary for the export of misfolded proteins from the ER to the
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18775313
  qualifier: enables
  review:
    summary: Interaction with VCP (P55072) and NPLOC4 (Q8TAT6), the core complex partners. Bare protein binding term.
    action: KEEP_AS_NON_CORE
    reason: Central interactions but bare protein binding is uninformative; captured by the complex annotations.
    supported_by:
    - reference_id: file:human/UFD1/UFD1-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 NPLOC4 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/UFD1/UFD1-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 NPLOC4 (Q8TAT6) captured as bare protein binding.
    action: KEEP_AS_NON_CORE
    reason: Central interaction but bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/UFD1/UFD1-goa.tsv
      supporting_text: UniProtKB:Q8TAT6
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25959826
  qualifier: enables
  review:
    summary: Interaction with huntingtin (HTT, P42858). Bare protein binding term.
    action: KEEP_AS_NON_CORE
    reason: A documented interaction but bare protein binding is uninformative and not part of the core function.
    supported_by:
    - reference_id: file:human/UFD1/UFD1-goa.tsv
      supporting_text: UniProtKB:P42858
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:26712280
  qualifier: enables
  review:
    summary: Interaction with VCP (P55072). Bare protein binding term.
    action: KEEP_AS_NON_CORE
    reason: Central interaction but bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/UFD1/UFD1-goa.tsv
      supporting_text: UniProtKB:P55072
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: HuRI interactome interaction with NPLOC4 (Q8TAT6). Bare protein binding.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interaction; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/UFD1/UFD1-goa.tsv
      supporting_text: UniProtKB:Q8TAT6
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32814053
  qualifier: enables
  review:
    summary: Neurodegeneration interactome interaction with HTT (P42858). Bare protein binding.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interaction; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/UFD1/UFD1-goa.tsv
      supporting_text: UniProtKB:P42858
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:33961781
  qualifier: enables
  review:
    summary: BioPlex interactome interactions (VCP, NPLOC4). Bare protein binding.
    action: KEEP_AS_NON_CORE
    reason: High-throughput interactions; bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/UFD1/UFD1-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 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/UFD1/UFD1-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/UFD1/UFD1-goa.tsv
      supporting_text: UniProtKB:P55072
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Cytoplasmic localization, consistent with the cytosolic site of segregase action.
    action: ACCEPT
    reason: Cytoplasmic/cytosolic localization is well supported.
    supported_by:
    - reference_id: file:human/UFD1/UFD1-uniprot.txt
      supporting_text: Cytoplasm, cytosol
- term:
    id: GO:0034098
    label: VCP-NPL4-UFD1 AAA ATPase complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: part_of
  review:
    summary: UFD1 is part of the VCP-NPL4-UFD1 complex.
    action: ACCEPT
    reason: Core complex membership.
    supported_by:
    - reference_id: file:human/UFD1/UFD1-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: enables
  review:
    summary: UFD1 (in UFD1-NPL4) recognizes K48-linked polyubiquitin, the canonical degradation signal presented to p97.
    action: ACCEPT
    reason: Consistent with the well-established K48-linked polyubiquitin recognition by the UFD1-NPL4 cofactor.
    supported_by:
    - reference_id: file:human/UFD1/UFD1-uniprot.txt
      supporting_text: The ternary complex containing UFD1, VCP and NPLOC4 binds
- term:
    id: GO:0036501
    label: UFD1-NPL4 complex
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: part_of
  review:
    summary: UFD1 forms an obligate heterodimer with NPLOC4 (the UFD1-NPL4 complex).
    action: ACCEPT
    reason: Core complex membership.
    supported_by:
    - reference_id: file:human/UFD1/UFD1-uniprot.txt
      supporting_text: Heterodimer with NPLOC4
- 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: UFD1-mediated substrate extraction feeds proteasomal degradation.
    action: ACCEPT
    reason: Core process; the segregase delivers extracted substrates to the proteasome.
    supported_by:
    - reference_id: file:human/UFD1/UFD1-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: p97 review describing UFD1-NPL4 in ubiquitin-dependent degradation.
    action: ACCEPT
    reason: Consistent with the core degradative role.
    supported_by:
    - reference_id: file:human/UFD1/UFD1-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 UFD1 in ubiquitin-dependent degradation.
    action: ACCEPT
    reason: Consistent with the core degradative role of the p97 machinery.
    supported_by:
    - reference_id: file:human/UFD1/UFD1-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 UFD1 within the VCP-NPL4-UFD1 complex.
    action: ACCEPT
    reason: Core complex membership supported by direct interaction evidence.
    supported_by:
    - reference_id: file:human/UFD1/UFD1-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 UFD1 within the VCP-NPL4-UFD1 complex.
    action: ACCEPT
    reason: Core complex membership supported by direct interaction evidence.
    supported_by:
    - reference_id: file:human/UFD1/UFD1-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:
    - reference_id: file:human/UFD1/UFD1-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 is well established.
    action: ACCEPT
    reason: UFD1 is unambiguously part of the VCP-NPL4-UFD1 complex; the complex assertion is accepted while the attached reference is a wrong-identifier citation (flagged in reference_review).
    supported_by:
    - reference_id: file:human/UFD1/UFD1-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 UFD1-NPL4's role in ERAD.
    action: ACCEPT
    reason: Core process.
    supported_by:
    - reference_id: file:human/UFD1/UFD1-uniprot.txt
      supporting_text: necessary for the export of misfolded proteins from the ER to the
- 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, but the proteasomal degradation role is correct.
    action: ACCEPT
    reason: UFD1 participates in proteasome-mediated degradation as a p97 cofactor; assertion accepted, reference flagged as wrong identifier.
    supported_by:
    - reference_id: file:human/UFD1/UFD1-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: UFD1 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/UFD1/UFD1-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: UFD1 is part of an AAA+ ATPase (p97) complex.
    action: KEEP_AS_NON_CORE
    reason: Generic parent of the specific complex annotation.
    supported_by:
    - reference_id: file:human/UFD1/UFD1-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: UFD1 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/UFD1/UFD1-uniprot.txt
      supporting_text: VCP-NPL4-UFD1 AAA ATPase complex
- 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 documented nuclear localization; non-core.
    supported_by:
    - reference_id: file:human/UFD1/UFD1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
- term:
    id: GO:0072344
    label: rescue of stalled cytosolic ribosome
  evidence_type: NAS
  original_reference_id: PMID:35452614
  qualifier: involved_in
  review:
    summary: UFD1/p97 participates in ribosome-associated quality control, extracting ubiquitinated nascent chains/factors from stalled ribosomes.
    action: KEEP_AS_NON_CORE
    reason: A genuine p97-dependent RQC role per the cited review, but one of many p97 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 UFD1 in the ribosome-associated quality-control (RQC) complex.
    action: KEEP_AS_NON_CORE
    reason: p97-UFD1-NPL4 functions with RQC but is a recruited cofactor module rather than a constitutive core RQC subunit; 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: UFD1/p97 extracts ubiquitinated nascent chains for degradation in RQC.
    action: KEEP_AS_NON_CORE
    reason: A genuine p97-dependent RQC process; non-core relative to the general adaptor function.
    supported_by:
    - reference_id: PMID:35452614
      supporting_text: Ribosome-associated quality-control mechanisms from bacteria to humans
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IMP
  original_reference_id: PMID:24089527
  qualifier: involved_in
  review:
    summary: UFD1 functions in ERAD, demonstrated in a p97-dependent degradation context (caveolin-1/Derlin-1/COX-2).
    action: ACCEPT
    reason: Experimentally supported (IMP) core process.
    supported_by:
    - reference_id: file:human/UFD1/UFD1-uniprot.txt
      supporting_text: necessary for the export of misfolded proteins from the ER to the
- term:
    id: GO:0071218
    label: cellular response to misfolded protein
  evidence_type: IMP
  original_reference_id: PMID:24089527
  qualifier: involved_in
  review:
    summary: UFD1 participates in the cellular response to misfolded proteins as part of the p97 degradation machinery.
    action: ACCEPT
    reason: Experimentally supported; consistent with UFD1's role in clearing misfolded proteins.
    supported_by:
    - reference_id: file:human/UFD1/UFD1-uniprot.txt
      supporting_text: necessary for the export of misfolded proteins from the ER to the
- 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 segregase function.
    supported_by:
    - reference_id: file:human/UFD1/UFD1-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 segregase function.
    supported_by:
    - reference_id: file:human/UFD1/UFD1-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 segregase function.
    supported_by:
    - reference_id: file:human/UFD1/UFD1-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 segregase function.
    supported_by:
    - reference_id: file:human/UFD1/UFD1-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: UFD1 (with NPLOC4/VCP) promotes ubiquitin-dependent degradation of RIG-I.
    action: ACCEPT
    reason: Directly supported by IMP; the p97-UFD1-NPL4 complex drives ubiquitin-dependent RIG-I degradation.
    supported_by:
    - reference_id: file:human/UFD1/UFD1-uniprot.txt
      supporting_text: recruits RNF125 to promote ubiquitination and degradation of
- 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, UFD1/p97 negatively regulates type I interferon production.
    action: KEEP_AS_NON_CORE
    reason: A genuine, experimentally supported signaling role, but specialized relative to the core p97 cofactor function.
    supported_by:
    - reference_id: file:human/UFD1/UFD1-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 UFD1 within the VCP-NPL4-UFD1 complex.
    action: ACCEPT
    reason: Core complex membership supported by direct evidence.
    supported_by:
    - reference_id: file:human/UFD1/UFD1-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: UFD1/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/UFD1/UFD1-uniprot.txt
      supporting_text: Acts as a negative regulator of type I interferon
- term:
    id: GO:0036501
    label: UFD1-NPL4 complex
  evidence_type: IPI
  original_reference_id: PMID:11574150
  qualifier: part_of
  review:
    summary: Original study demonstrating UFD1 interacts with NPL4 (the UFD1-NPL4 heterodimer).
    action: ACCEPT
    reason: Core complex membership supported by direct interaction evidence.
    supported_by:
    - reference_id: file:human/UFD1/UFD1-uniprot.txt
      supporting_text: Heterodimer with NPLOC4
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11574150
  qualifier: enables
  review:
    summary: Interaction with NPLOC4 (Q8TAT6). Bare protein binding term.
    action: KEEP_AS_NON_CORE
    reason: The NPLOC4 interaction is central but bare protein binding is uninformative; captured by the UFD1-NPL4 complex annotation.
    supported_by:
    - reference_id: file:human/UFD1/UFD1-goa.tsv
      supporting_text: UniProtKB:Q8TAT6
- term:
    id: GO:0030970
    label: retrograde protein transport, ER to cytosol
  evidence_type: IMP
  original_reference_id: PMID:25660456
  qualifier: involved_in
  review:
    summary: UFD1 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/UFD1/UFD1-uniprot.txt
      supporting_text: necessary for the export of misfolded proteins from the ER to the
- 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/UFD1/UFD1-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/UFD1/UFD1-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/UFD1/UFD1-uniprot.txt
      supporting_text: GO:0005654; C:nucleoplasm
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6781922
  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/UFD1/UFD1-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/UFD1/UFD1-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Nucleus'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17681147
  qualifier: enables
  review:
    summary: Interaction with USP13 (Q9UKV5), which couples the ER stress response to cell-cycle control. Bare protein binding term.
    action: KEEP_AS_NON_CORE
    reason: A documented, functionally relevant interaction (USP13), but bare protein binding is uninformative.
    supported_by:
    - reference_id: file:human/UFD1/UFD1-goa.tsv
      supporting_text: UniProtKB:Q9UKV5
- term:
    id: GO:0001501
    label: skeletal system development
  evidence_type: TAS
  original_reference_id: PMID:10024240
  qualifier: involved_in
  review:
    summary: Legacy annotation linking UFD1L to skeletal/developmental phenotypes in the DiGeorge/22q11 deletion context.
    action: KEEP_AS_NON_CORE
    reason: UFD1L lies in the 22q11/DiGeorge-associated region and is developmentally expressed; a developmental-phenotype association exists but is far removed from the gene's direct molecular function. Retained as non-core (developmental/disease context).
    supported_by:
    - reference_id: file:human/UFD1/UFD1-uniprot.txt
      supporting_text: developmentally expressed
- term:
    id: GO:0004843
    label: cysteine-type deubiquitinase activity
  evidence_type: TAS
  original_reference_id: PMID:9063746
  qualifier: enables
  review:
    summary: Legacy (2003 PINC, TAS) annotation asserting UFD1 has cysteine-type deubiquitinase activity. UFD1 is a ubiquitin-recognition adaptor with no catalytic protease domain and is not a deubiquitinase; this is a mis-annotation likely conflating the broader ubiquitin-fusion-degradation pathway with a catalytic DUB activity.
    action: REMOVE
    reason: UFD1 is a non-catalytic ubiquitin-binding cofactor of p97 (UFD1 family; no peptidase domain). No experimental evidence supports intrinsic deubiquitinase activity; the original UFD1L paper (PMID:9063746) characterizes a developmentally expressed ubiquitination-pathway gene, not a DUB. This molecular-function annotation is incorrect.
    supported_by:
    - reference_id: file:human/UFD1/UFD1-uniprot.txt
      supporting_text: Ubiquitin recognition factor in ER-associated degradation protein 1
- term:
    id: GO:0006511
    label: ubiquitin-dependent protein catabolic process
  evidence_type: TAS
  original_reference_id: PMID:9063746
  qualifier: involved_in
  review:
    summary: UFD1L participates in ubiquitin-dependent protein degradation, the pathway for which it was named (ubiquitin fusion degradation).
    action: ACCEPT
    reason: Correct core process; UFD1 is an essential component of the ubiquitin-dependent proteolytic pathway.
    supported_by:
    - reference_id: file:human/UFD1/UFD1-uniprot.txt
      supporting_text: ubiquitin-dependent proteolytic
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:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:9063746
  title: UFD1L, a developmentally expressed ubiquitination gene, is deleted in CATCH 22 syndrome.
  findings:
  - statement: Cloned UFD1L as a developmentally expressed ubiquitination-pathway gene deleted in CATCH22/DiGeorge syndrome.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: MISCITED
    review_notes: Title from UniProt reference list; not cached. Correctly supports the ubiquitin-dependent catabolic-process and developmental/22q11 context, but it is mis-cited for the cysteine-type deubiquitinase activity annotation (UFD1 is not a DUB).
- id: PMID:10024240
  title: 'A molecular pathway revealing a genetic basis for human cardiac and craniofacial defects.'
  findings: []
  reference_review:
    relevance: LOW
    correctness: UNVERIFIED
    review_notes: Not cached; legacy TAS source for the skeletal/developmental annotation tied to the 22q11/DiGeorge context.
- 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: UFD1L interacts with NPL4, 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:17681147
  title: Ufd1 is a cofactor of gp78 and plays a key role in cholesterol metabolism by regulating the stability of HMG-CoA reductase.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: UNVERIFIED
    review_notes: Captures UFD1-USP13 interaction (ER stress / cell-cycle coupling).
- 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 UFD1-VCP and UFD1-NPLOC4 interactions (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 UFD1-VCP/NPLOC4 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 UFD1-NPLOC4 complex interaction.
- id: PMID:24089527
  title: Caveolin-1 interacts with Derlin-1 and promotes ubiquitination and degradation of cyclooxygenase-2 via collaboration with p97 complex.
  findings:
  - statement: UFD1 (in the p97 complex) is required for ERAD-type degradation of COX-2, supporting its role in the cellular response to misfolded proteins.
    reference_section_type: RESULTS
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Cached; supports ERAD / misfolded-protein response roles.
- id: PMID:25660456
  title: Identification of ERAD components essential for dislocation of the null Hong Kong variant of α-1-antitrypsin (NHK).
  findings:
  - statement: UFD1 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:25959826
  title: Quantitative interaction proteomics of neurodegenerative disease proteins.
  findings: []
  reference_review:
    relevance: LOW
    correctness: UNVERIFIED
    review_notes: Captures a UFD1-HTT interaction; bare protein binding.
- 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:26712280
  title: Characterization of an Additional Binding Surface on the p97 N-Terminal Domain Involved in Bipartite Cofactor Interactions.
  findings: []
  reference_review:
    relevance: LOW
    correctness: UNVERIFIED
    review_notes: Captures a UFD1-VCP interaction; bare protein binding.
- 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 partner (NPLOC4).
- 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 partner (HTT).
- id: PMID:33712450
  title: The p97-UBXN1 complex regulates aggresome formation.
  findings:
  - statement: Studies p97 cofactor complexes 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/NPLOC4).
- 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 partner (VCP).
- 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-6781922
  title: 'Reactome: nucleoplasm localization'
  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: []
core_functions:
- description: Ubiquitin-recognition cofactor of the AAA+ ATPase VCP/p97 that, as part of the obligate UFD1-NPL4 heterodimer, binds (poly)ubiquitinated substrates and presents them to p97 for ATP-driven extraction and unfolding, after which they are degraded by the proteasome.
  molecular_function:
    id: GO:0031593
    label: polyubiquitin modification-dependent protein binding
  locations:
  - id: GO:0005829
    label: cytosol
  in_complex:
    id: GO:0034098
    label: VCP-NPL4-UFD1 AAA ATPase complex
  supported_by:
  - reference_id: file:human/UFD1/UFD1-uniprot.txt
    supporting_text: The ternary complex containing UFD1, VCP and NPLOC4 binds
  - reference_id: file:human/UFD1/UFD1-uniprot.txt
    supporting_text: Heterodimer with NPLOC4
- description: Substrate-delivery subunit of the VCP-NPL4-UFD1 segregase essential for ERAD, driving retrotranslocation of misfolded proteins from the ER to the cytosol for proteasomal degradation and supporting the cellular response to misfolded proteins.
  molecular_function:
    id: GO:0031593
    label: polyubiquitin modification-dependent protein binding
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: file:human/UFD1/UFD1-uniprot.txt
    supporting_text: necessary for the export of misfolded proteins from the ER to the
  - reference_id: file:human/UFD1/UFD1-uniprot.txt
    supporting_text: Essential component of the ubiquitin-dependent proteolytic
proposed_new_terms: []
suggested_questions:
- question: How do UFD1 and NPL4 cooperate to unfold the initiating ubiquitin and engage the p97 pore, and what is the division of labor between the two subunits in substrate selection?
- question: Does the USP13 interaction reflect a regulated deubiquitination step that edits UFD1-bound substrates, coupling ER stress to cell-cycle control?
- question: What is the basis of the historical cysteine-type deubiquitinase annotation, and should related UFD1 orthologs carrying it be corrected?
suggested_experiments:
- description: Reconstituted ERAD/retrotranslocation assays with UFD1 ubiquitin-binding mutants to dissect its contribution (vs NPL4) to substrate engagement and extraction.
- description: Quantitative interaction proteomics across stress conditions to map UFD1-specific cofactor and substrate partners distinct from NPL4.
- description: Biochemical assay testing purified UFD1 for any intrinsic isopeptidase activity to formally confirm the absence of deubiquitinase function.

UFD1

Gene Description

Existing Annotations Review

Core Functions

Ubiquitin-recognition cofactor of the AAA+ ATPase VCP/p97 that, as part of the obligate UFD1-NPL4 heterodimer, binds (poly)ubiquitinated substrates and presents them to p97 for ATP-driven extraction and unfolding, after which they are degraded by the proteasome.

Substrate-delivery subunit of the VCP-NPL4-UFD1 segregase essential for ERAD, driving retrotranslocation of misfolded proteins from the ER to the cytosol for proteasomal degradation and supporting the cellular response to misfolded proteins.

References

Suggested Questions for Experts

Suggested Experiments

📚 Additional Documentation

Notes

UFD1 (Q92890) research notes

Summary

Core functions (from review)

Provenance

Pn Notes

UFD1 PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

PN row 1: ER proteostasis | Organelle-specific protein degradation | ER associated degradation | VCP system for retrotranslocation in ERAD | VCP accessories

PN row 2: Translation | Cytosolic translation | Ribosome-associated QC | VCP system for RQC

PN row 3: Ubiquitin Proteasome System | VCP and associated proteins | adaptors | SHP | UT3

PN row 4: Ubiquitin Proteasome System | Ubiquitin and UBL binding | protein quality control | ERAD cofactor | idiosyncratic Ub binding / UT3

Projected GO annotations (5)

Note

📄 View Raw YAML