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.