id: Q96CS3
gene_symbol: FAF2
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: FAF2 (also known as UBXD8, ETEA, UBXN3B) is a 445-residue, membrane-anchored cofactor of the AAA-ATPase p97/VCP. It contains an N-terminal UBA domain that binds ubiquitin conjugates, a central UAS (thioredoxin-like) domain implicated in unsaturated fatty-acid sensing, a coiled-coil region, and a C-terminal UBX domain that docks onto p97/VCP. By bridging ubiquitinated client proteins to the p97/VCP segregase, FAF2 functions as a substrate-recruiting adaptor at the endoplasmic reticulum membrane and on lipid droplets. At the ER it is a component of the SEL1L/HRD1-associated ER-associated degradation (ERAD) machinery, where it promotes the dislocation/retrotranslocation of misfolded ER proteins to the cytosol for proteasomal degradation. On lipid droplets, FAF2 recruits p97/VCP and binds directly to the lipase PNPLA2/ATGL, inhibiting it by displacing its coactivator ABHD5/CGI-58, thereby restraining triacylglycerol lipolysis and increasing lipid-droplet size; its partitioning between the ER and lipid droplets is controlled by the ER-resident rhomboid pseudoprotease UBAC2. FAF2 also links lipid metabolism through p97-dependent dislocation of Insig-1 (SREBP regulation) and, upon heat stress, binds ubiquitinated G3BP1 to recruit p97/VCP and drive stress-granule disassembly. FAF2 is broadly expressed.
existing_annotations:
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic inference of FAF2's role in ERAD, consistent with strong experimental evidence that FAF2/UBXD8 is part of the ER dislocation machinery.
    action: ACCEPT
    reason: Core biological process; FAF2 is a p97/VCP cofactor in ER-associated degradation, supported experimentally.
    supported_by:
    - reference_id: PMID:18711132
      supporting_text: We identified AUP1, UBXD8, UBC6e, and OS9 as functionally important
    - reference_id: PMID:26389662
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic transfer of cytoplasmic localization from the UniProt subcellular location; FAF2 is a membrane protein of the ER/lipid droplet, which are cytoplasmic structures.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the specific ER and lipid-droplet compartments capture FAF2's site of action more informatively.
    supported_by:
    - reference_id: file:human/FAF2/FAF2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic assignment of ER localization, consistent with direct experimental evidence that FAF2 is an ER membrane protein.
    action: ACCEPT
    reason: Correct core compartment; redundant with IDA evidence.
    supported_by:
    - reference_id: file:human/FAF2/FAF2-uniprot.txt
      supporting_text: Endoplasmic reticulum
- term:
    id: GO:0005811
    label: lipid droplet
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: Electronic assignment of lipid-droplet localization, consistent with direct experimental and proteomic evidence.
    action: ACCEPT
    reason: Correct core compartment; FAF2 partitions between ER and lipid droplets.
    supported_by:
    - reference_id: file:human/FAF2/FAF2-uniprot.txt
      supporting_text: Lipid droplet
- term:
    id: GO:0010498
    label: proteasomal protein catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: ARBA machine-learning assignment of proteasomal protein catabolism, a generic parent of FAF2's specific ERAD/proteasome-mediated degradation role.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; GO:0036503 (ERAD pathway) better captures the specific function.
    supported_by:
    - reference_id: PMID:18711132
      supporting_text: dislocation of misfolded
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18711132
  qualifier: enables
  review:
    summary: IntAct capture of FAF2 protein interaction (VCP). The bare protein binding term is uninformative; the VCP interaction is better captured by ubiquitin protein ligase binding and the VCP complex annotations.
    action: KEEP_AS_NON_CORE
    reason: Records a real interaction but bare protein binding is uninformative per curation guidelines.
    supported_by:
    - reference_id: file:human/FAF2/FAF2-uniprot.txt
      supporting_text: 'Q96CS3; P55072: VCP'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:18775313
  qualifier: enables
  review:
    summary: IntAct capture of FAF2-VCP interaction from the UBX-domain/p97 cofactor study. Bare protein binding is uninformative; better represented by the specific p97/ubiquitin-binding terms.
    action: KEEP_AS_NON_CORE
    reason: Real p97 interaction but uninformative GO term.
    supported_by:
    - reference_id: PMID:18775313
      supporting_text: p97 assembles with all of the 13 mammalian UBX-domain proteins
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22119785
  qualifier: enables
  review:
    summary: IntAct interaction captured in an ERAD network mapping study (partners VCP and UBAC2). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real ERAD-network interactions but uninformative GO term.
    supported_by:
    - reference_id: file:human/FAF2/FAF2-uniprot.txt
      supporting_text: 'Q96CS3; Q8NBM4: UBAC2'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28514442
  qualifier: enables
  review:
    summary: High-throughput interactome capture (UBAC2). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real interaction from a large-scale interactome but uninformative GO term.
    supported_by:
    - reference_id: file:human/FAF2/FAF2-uniprot.txt
      supporting_text: 'Q96CS3; Q8NBM4: UBAC2'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:29997244
  qualifier: enables
  review:
    summary: LuTHy two-hybrid capture of FAF2-VCP interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real interaction but uninformative GO term.
    supported_by:
    - reference_id: file:human/FAF2/FAF2-uniprot.txt
      supporting_text: 'Q96CS3; P55072: VCP'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35044719
  qualifier: enables
  review:
    summary: Proteome-scale binding-site mapping capturing a FAF2 interaction (VASP). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real interaction but uninformative GO term.
    supported_by:
    - reference_id: file:human/FAF2/FAF2-uniprot.txt
      supporting_text: 'Q96CS3; P50552: VASP'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35271311
  qualifier: enables
  review:
    summary: OpenCell endogenous-tagging interactome capture (VCP). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real interaction but uninformative GO term.
    supported_by:
    - reference_id: file:human/FAF2/FAF2-uniprot.txt
      supporting_text: 'Q96CS3; P55072: VCP'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:37776851
  qualifier: enables
  review:
    summary: Interaction captured in an ALS SOD1 degradation-dynamics study implicating VCP homeostasis. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real interaction but uninformative GO term.
    supported_by:
    - reference_id: file:human/FAF2/FAF2-uniprot.txt
      supporting_text: 'Q96CS3; P55072: VCP'
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:40205054
  qualifier: enables
  review:
    summary: Multimodal cell-map interactome capture (UBAC2). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real interaction but uninformative GO term.
    supported_by:
    - reference_id: file:human/FAF2/FAF2-uniprot.txt
      supporting_text: 'Q96CS3; Q8NBM4: UBAC2'
- term:
    id: GO:0043161
    label: proteasome-mediated ubiquitin-dependent protein catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Orthology-based assignment of proteasome-mediated ubiquitin-dependent catabolism, consistent with FAF2's adaptor role in delivering ubiquitinated substrates to p97 for proteasomal degradation.
    action: KEEP_AS_NON_CORE
    reason: Correct but a generic parent of the specific ERAD process; retained as non-core.
    supported_by:
    - reference_id: PMID:18711132
      supporting_text: dislocation of misfolded
- term:
    id: GO:0034098
    label: VCP-NPL4-UFD1 AAA ATPase complex
  evidence_type: NAS
  original_reference_id: PMID:28819009
  qualifier: part_of
  review:
    summary: FAF2 is a substrate-recruiting cofactor that assembles with the core p97/VCP-NPL4-UFD1 segregase (ComplexPortal CPX-8104, VCP-NPL4-UFD1-FAF2 complex).
    action: ACCEPT
    reason: Correct; FAF2 forms a defined p97/VCP cofactor complex, also supported by direct evidence (PMID:18775313).
    supported_by:
    - reference_id: file:human/FAF2/FAF2-uniprot.txt
      supporting_text: VCP-NPL4-UFD1-FAF2 AAA ATPase complex
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: NAS
  original_reference_id: PMID:28819009
  qualifier: involved_in
  review:
    summary: ComplexPortal assertion of FAF2's ERAD role as a p97/VCP cofactor, consistent with experimental evidence.
    action: ACCEPT
    reason: Core biological process; redundant with experimental IMP/IBA ERAD annotations.
    supported_by:
    - reference_id: PMID:18711132
      supporting_text: We identified AUP1, UBXD8, UBC6e, and OS9 as functionally important
- term:
    id: GO:1904949
    label: ATPase complex
  evidence_type: NAS
  original_reference_id: PMID:28819009
  qualifier: part_of
  review:
    summary: Generic parent term for the p97/VCP ATPase complex to which FAF2 binds.
    action: KEEP_AS_NON_CORE
    reason: Correct but generic; the specific VCP-NPL4-UFD1 complex term is more informative.
    supported_by:
    - reference_id: file:human/FAF2/FAF2-uniprot.txt
      supporting_text: VCP-NPL4-UFD1-FAF2 AAA ATPase complex
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Direct immunofluorescence (HPA) evidence for ER localization, consistent with FAF2's role as an ER membrane protein.
    action: ACCEPT
    reason: Core compartment; FAF2 acts at the ER membrane.
    supported_by:
    - reference_id: file:human/FAF2/FAF2-uniprot.txt
      supporting_text: Endoplasmic reticulum
- term:
    id: GO:0005811
    label: lipid droplet
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Direct immunofluorescence (HPA) evidence for lipid-droplet localization, consistent with FAF2's lipid-droplet function.
    action: ACCEPT
    reason: Core compartment; FAF2 traffics to lipid droplets to recruit p97/VCP.
    supported_by:
    - reference_id: file:human/FAF2/FAF2-uniprot.txt
      supporting_text: Lipid droplet
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:34739333
  qualifier: is_active_in
  review:
    summary: FAF2 is active at the ER, where it engages ubiquitinated G3BP1 and recruits p97/VCP during heat-stress stress-granule disassembly.
    action: ACCEPT
    reason: Correct site of action; directly demonstrated.
    supported_by:
    - reference_id: PMID:34739333
      supporting_text: the endoplasmic reticulum–associated protein FAF2
- term:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  evidence_type: IDA
  original_reference_id: PMID:34739333
  qualifier: enables
  review:
    summary: FAF2 acts as an adaptor that bridges ubiquitinated G3BP1 to the p97/VCP segregase, an informative molecular function reflecting its general p97-cofactor adaptor role.
    action: ACCEPT
    reason: Core molecular function; FAF2 couples ubiquitinated clients to p97/VCP.
    supported_by:
    - reference_id: PMID:34739333
      supporting_text: ubiquitinated G3BP1 interacted with the endoplasmic reticulum–associated protein FAF2, which engaged the ubiquitin-dependent segregase p97/VCP
- term:
    id: GO:0035617
    label: stress granule disassembly
  evidence_type: IDA
  original_reference_id: PMID:34739333
  qualifier: involved_in
  review:
    summary: FAF2 promotes heat-stress-induced stress-granule disassembly by recruiting p97/VCP to ubiquitinated G3BP1, extracting it from the granule.
    action: ACCEPT
    reason: Directly demonstrated biological process; a distinct (non-ERAD) role of FAF2 as a p97 adaptor.
    supported_by:
    - reference_id: PMID:34739333
      supporting_text: targeting of G3BP1 weakened the stress granule–specific interaction network
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:31073040
  qualifier: enables
  review:
    summary: IPI capture of FAF2-LMBR1L interaction. Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real interaction (LMBR1L) but uninformative GO term.
    supported_by:
    - reference_id: file:human/FAF2/FAF2-uniprot.txt
      supporting_text: Interacts with LMBR1L
- term:
    id: GO:0005576
    label: extracellular region
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798751
  qualifier: located_in
  review:
    summary: Reactome neutrophil-degranulation pathway annotation placing FAF2 in the extracellular region via azurophil-granule exocytosis. This derives from bulk granule proteomics and does not reflect FAF2's characterized ER/lipid-droplet membrane function.
    action: MARK_AS_OVER_ANNOTATED
    reason: FAF2 is an integral ER/lipid-droplet membrane protein; extracellular localization is an over-annotation from neutrophil-granule proteomics, not its biological site of action.
    supported_by:
    - reference_id: file:human/FAF2/FAF2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0035578
    label: azurophil granule lumen
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-6798751
  qualifier: located_in
  review:
    summary: Reactome neutrophil-degranulation annotation placing FAF2 in the azurophil granule lumen, from bulk neutrophil-granule proteomics; inconsistent with FAF2 being an integral cytoplasmic-facing ER/lipid-droplet membrane protein.
    action: MARK_AS_OVER_ANNOTATED
    reason: Over-annotation from granule proteomics; not the characterized ER/lipid-droplet function.
    supported_by:
    - reference_id: file:human/FAF2/FAF2-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0030970
    label: retrograde protein transport, ER to cytosol
  evidence_type: IMP
  original_reference_id: PMID:25660456
  qualifier: involved_in
  review:
    summary: FAF2/UBXD8 was experimentally required for dislocation (retrotranslocation) of the NHK alpha-1-antitrypsin ERAD substrate from the ER lumen to the cytosol.
    action: ACCEPT
    reason: Directly supported (IMP); captures the dislocation/retrotranslocation step of ERAD in which FAF2 participates.
    supported_by:
    - reference_id: PMID:25660456
      supporting_text: dislocation, also known as retrotranslocation, of those unwanted proteins from
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24215460
  qualifier: enables
  review:
    summary: IPI capture of FAF2-UBQLN2 interaction. Bare protein binding is uninformative; the functional cooperation in ERAD is captured by the ERAD process annotation.
    action: KEEP_AS_NON_CORE
    reason: Real interaction (UBQLN2) but uninformative GO term.
    supported_by:
    - reference_id: file:human/FAF2/FAF2-uniprot.txt
      supporting_text: Interacts (via N-terminus) with UBQLN2
- term:
    id: GO:0036503
    label: ERAD pathway
  evidence_type: IMP
  original_reference_id: PMID:24215460
  qualifier: involved_in
  review:
    summary: Loss/disruption of FAF2/UBXD8 interaction with UBQLN2 impaired ERAD, demonstrating FAF2's functional requirement in the pathway.
    action: ACCEPT
    reason: Core biological process with direct mutant/perturbation (IMP) support.
    supported_by:
    - reference_id: PMID:24215460
      supporting_text: disrupts endoplasmic reticulum-associated protein degradation
- term:
    id: GO:0005783
    label: endoplasmic reticulum
  evidence_type: IDA
  original_reference_id: PMID:23297223
  qualifier: located_in
  review:
    summary: Direct evidence for ER localization of FAF2/UBXD8, the compartment from which it traffics to lipid droplets.
    action: ACCEPT
    reason: Core compartment; directly demonstrated.
    supported_by:
    - reference_id: PMID:23297223
      supporting_text: UBXD8 with the ER-resident rhomboid pseudoprotease UBAC2
- term:
    id: GO:0005811
    label: lipid droplet
  evidence_type: IDA
  original_reference_id: PMID:23297223
  qualifier: located_in
  review:
    summary: Direct evidence that FAF2/UBXD8 localizes to lipid droplets, where it recruits p97/VCP and regulates ATGL.
    action: ACCEPT
    reason: Core compartment; directly demonstrated.
    supported_by:
    - reference_id: PMID:23297223
      supporting_text: UBXD8-mediated recruitment of p97/VCP to LDs
- term:
    id: GO:0034389
    label: lipid droplet organization
  evidence_type: IMP
  original_reference_id: PMID:23297223
  qualifier: acts_upstream_of_or_within
  review:
    summary: FAF2/UBXD8 controls lipid-droplet size by recruiting p97/VCP and inhibiting ATGL-mediated triacylglycerol hydrolysis, regulating lipid-droplet organization.
    action: ACCEPT
    reason: Directly supported biological process; FAF2 governs lipid-droplet dynamics via ATGL regulation.
    supported_by:
    - reference_id: PMID:23297223
      supporting_text: recruitment of p97/VCP to LDs increases
- term:
    id: GO:0035473
    label: lipase binding
  evidence_type: IDA
  original_reference_id: PMID:23297223
  qualifier: enables
  review:
    summary: FAF2/UBXD8 binds directly to the lipase ATGL/PNPLA2, a specific and informative molecular function.
    action: ACCEPT
    reason: Directly demonstrated specific binding; supports the lipase-inhibitor and lipid-droplet roles.
    supported_by:
    - reference_id: PMID:23297223
      supporting_text: UBXD8 binds directly to ATGL
- term:
    id: GO:0055102
    label: lipase inhibitor activity
  evidence_type: IDA
  original_reference_id: PMID:23297223
  qualifier: enables
  review:
    summary: FAF2/UBXD8 inhibits ATGL/PNPLA2 lipase activity by promoting dissociation of its coactivator CGI-58/ABHD5, a specific molecular function.
    action: ACCEPT
    reason: Directly demonstrated lipase-inhibitor activity; a defining lipid-metabolic function of FAF2.
    supported_by:
    - reference_id: PMID:23297223
      supporting_text: promotes dissociation of its endogenous coactivator, CGI-58
- term:
    id: GO:0005811
    label: lipid droplet
  evidence_type: IDA
  original_reference_id: PMID:14741744
  qualifier: located_in
  review:
    summary: Lipid-droplet proteomic identification of FAF2/UBXD8 in the LD-enriched fraction of HuH7 hepatocytes, corroborating its lipid-droplet localization.
    action: ACCEPT
    reason: Independent IDA support for the lipid-droplet compartment.
    supported_by:
    - reference_id: file:human/FAF2/FAF2-uniprot.txt
      supporting_text: Lipid droplet
- term:
    id: GO:0031625
    label: ubiquitin protein ligase binding
  evidence_type: IDA
  original_reference_id: PMID:18775313
  qualifier: enables
  review:
    summary: As a UBX-domain p97 cofactor, FAF2/UBXD8 binds E3 ubiquitin ligases, linking ubiquitinated substrates to p97/VCP. This is an informative molecular function reflecting its adaptor role.
    action: ACCEPT
    reason: Directly demonstrated; UBX-domain p97 cofactors that bind ubiquitin conjugates also interact with E3 ubiquitin ligases.
    supported_by:
    - reference_id: PMID:18775313
      supporting_text: also interact with dozens of E3
- term:
    id: GO:0034098
    label: VCP-NPL4-UFD1 AAA ATPase complex
  evidence_type: IDA
  original_reference_id: PMID:18775313
  qualifier: part_of
  review:
    summary: FAF2/UBXD8 directly assembles with the p97/VCP-NPL4-UFD1 segregase as a substrate-recruiting cofactor.
    action: ACCEPT
    reason: Core complex membership with direct (IDA) support.
    supported_by:
    - reference_id: file:human/FAF2/FAF2-uniprot.txt
      supporting_text: VCP-NPL4-UFD1-FAF2 AAA ATPase complex
- term:
    id: GO:0043130
    label: ubiquitin binding
  evidence_type: IDA
  original_reference_id: PMID:18775313
  qualifier: enables
  review:
    summary: FAF2/UBXD8 binds ubiquitin/ubiquitin conjugates through its N-terminal UBA domain, the molecular basis for recognizing ubiquitinated p97 clients.
    action: ACCEPT
    reason: Core informative molecular function; the UBA domain binds polyubiquitinated substrates for delivery to p97/VCP.
    supported_by:
    - reference_id: PMID:18775313
      supporting_text: proteins that bind ubiquitin conjugates
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:19818707
  qualifier: enables
  review:
    summary: IPI capture of FAF2-YOD1 interaction (a p97-associated deubiquitinase in ER dislocation). Bare protein binding is uninformative.
    action: KEEP_AS_NON_CORE
    reason: Real interaction (YOD1) but uninformative GO term.
    supported_by:
    - reference_id: file:human/FAF2/FAF2-uniprot.txt
      supporting_text: Interacts with YOD1
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: PMID:14741744
  title: Identification of major proteins in the lipid droplet-enriched fraction isolated
    from the human hepatocyte cell line HuH7.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Lipid-droplet proteomics identifying UBXD8/FAF2; supports the lipid-droplet localization.
- id: PMID:18711132
  title: SEL1L nucleates a protein complex required for dislocation of misfolded glycoproteins.
  findings:
  - statement: FAF2/UBXD8 was identified together with AUP1, UBC6e and OS9 as a functionally important component of the SEL1L-nucleated ER dislocation complex for misfolded glycoproteins.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes FAF2/UBXD8 as part of the SEL1L/HRD1 ERAD dislocation machinery.
- id: PMID:18775313
  title: UBXD7 binds multiple ubiquitin ligases and implicates p97 in HIF1alpha turnover.
  findings:
  - statement: p97 assembles with all 13 mammalian UBX-domain proteins (including UBXD8/FAF2); UBX proteins that bind ubiquitin conjugates also interact with many E3 ubiquitin ligases.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Source of the ubiquitin binding, ubiquitin-protein-ligase binding and VCP-complex annotations for the UBX-domain cofactor family.
- id: PMID:19818707
  title: The otubain YOD1 is a deubiquitinating enzyme that associates with p97 to
    facilitate protein dislocation from the ER.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: FAF2 interacts with the p97-associated DUB YOD1 in ER dislocation; source of an IPI protein-binding annotation.
- id: PMID:22119785
  title: Defining human ERAD networks through an integrative mapping strategy.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: ERAD interaction-network mapping; source of FAF2-VCP/UBAC2 IPI annotations.
- id: PMID:23297223
  title: Spatial regulation of UBXD8 and p97/VCP controls ATGL-mediated lipid droplet
    turnover.
  findings:
  - statement: UBXD8/FAF2 recruits p97/VCP to lipid droplets, binds directly to ATGL and promotes dissociation of its coactivator CGI-58, inhibiting lipolysis and increasing lipid-droplet size.
    reference_section_type: ABSTRACT
  - statement: Association of UBXD8 with the ER-resident rhomboid pseudoprotease UBAC2 restricts trafficking of UBXD8 from the ER to lipid droplets.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Key study for FAF2's lipid-droplet/ATGL regulation and the UBAC2 partitioning mechanism.
- id: PMID:24215460
  title: Pathogenic mutation of UBQLN2 impairs its interaction with UBXD8 and disrupts
    endoplasmic reticulum-associated protein degradation.
  findings:
  - statement: UBXD8/FAF2 is an ER membrane protein involved in translocation of ubiquitinated ERAD substrates; UBQLN2 cooperates with UBXD8 in ERAD.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Supports FAF2's ERAD role and the UBQLN2 interaction.
- id: PMID:25660456
  title: Identification of ERAD components essential for dislocation of the null Hong
    Kong variant of α-1-antitrypsin (NHK).
  findings:
  - statement: ERAD requires dislocation/retrotranslocation of substrates such as NHK alpha-1-antitrypsin from the ER lumen to the cytosol for proteasomal degradation.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Source of the retrograde-protein-transport IMP annotation; FAF2 was among ERAD dislocation components assayed.
- id: PMID:28514442
  title: Architecture of the human interactome defines protein communities and disease
    networks.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput interactome; source of a FAF2-UBAC2 IPI annotation.
- id: PMID:28819009
  title: The AAA+ ATPase p97, a cellular multitool.
  findings:
  - statement: p97/VCP recruits substrates through diverse cofactors and functions in ubiquitin-dependent processes including ERAD; FAF2 is one such cofactor.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Review used by ComplexPortal for the VCP-complex and ERAD NAS annotations.
- id: PMID:29997244
  title: 'LuTHy: a double-readout bioluminescence-based two-hybrid technology for
    quantitative mapping of protein-protein interactions in mammalian cells.'
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Two-hybrid technology paper; source of a FAF2-VCP IPI annotation.
- id: PMID:31073040
  title: LMBR1L regulates lymphopoiesis through Wnt/β-catenin signaling.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: FAF2 interacts with LMBR1L; peripheral to its core ERAD/lipid-droplet function.
- id: PMID:34739333
  title: Ubiquitination of G3BP1 mediates stress granule disassembly in a context-specific
    manner.
  findings:
  - statement: Ubiquitinated G3BP1 interacts with the ER-associated protein FAF2, which engages the p97/VCP segregase to extract G3BP1 and drive heat-stress stress-granule disassembly.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Establishes FAF2 as a p97 adaptor in stress-granule disassembly; source of the adaptor-activity and stress-granule-disassembly annotations.
- id: PMID:35044719
  title: Proteome-scale mapping of binding sites in the unstructured regions of the
    human proteome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Proteome-scale binding-site mapping; source of a FAF2-VASP IPI annotation.
- id: PMID:35271311
  title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Endogenous-tagging interactome; source of a FAF2-VCP IPI annotation.
- 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: VERIFIED
    review_notes: ALS SOD1 degradation-dynamics study; source of a FAF2-VCP IPI annotation.
- id: PMID:40205054
  title: Multimodal cell maps as a foundation for structural and functional genomics.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Multimodal cell-map interactome; source of a FAF2-UBAC2 IPI annotation.
- id: Reactome:R-HSA-6798751
  title: Exocytosis of azurophil granule lumen proteins
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Neutrophil-degranulation pathway; source of the over-annotated extracellular/azurophil-granule localizations from bulk granule proteomics.
- id: file:human/FAF2/FAF2-uniprot.txt
  title: UniProt entry Q96CS3 (FAF2_HUMAN), FAS-associated factor 2 / UBXD8
  findings:
  - statement: FAF2/UBXD8 is a UBA-UAS-UBX p97/VCP cofactor at the ER membrane and lipid droplets, functioning in ERAD substrate dislocation, ATGL inhibition/lipid-droplet regulation, and stress-granule disassembly.
    reference_section_type: OTHER
- id: PMID:26389662
  title: Systematic proteomics of the VCP-UBXD adaptor network identifies a role for UBXN10 in regulating ciliogenesis.
  findings:
  - statement: Systematic AP-MS of the human VCP/p97-UBXD adaptor network places FAF2/UBXD8 among the membrane-tethered UBXD adaptors linked to ERAD and lipid-droplet homeostasis, recovering interactors such as AMFR, DERLIN2, AUP1, BAG6 and UBAC2 and the shared UFD1L/NPLOC4 module.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified (Nat Cell Biol 2015;17(10):1356-69; DOI 10.1038/ncb3238; PMC4610257). Falcon deep-research finding. Systematic VCP-UBXD adaptor interactome that classifies FAF2/UBXD8 as a membrane-tethered p97 adaptor with ERAD/lipid-droplet interactors; corroborates the p97-cofactor/adaptor core function. Not cached in publications/, so no verbatim supporting_text added to annotations.
- id: PMID:35920641
  title: Multiple UBX proteins reduce the ubiquitin threshold of the mammalian p97-UFD1-NPL4 unfoldase.
  findings:
  - statement: In reconstituted CMG-helicase disassembly assays, FAF2 (together with UBXN7 and FAF1) acts as a UBX cofactor that lowers the high ubiquitin-chain-length threshold of mammalian p97-UFD1-NPL4, stabilising productive interactions between UFD1-NPL4 and K48-linked chains of at least five ubiquitins; FAF1/FAF2 use a previously uncharacterised coiled-coil domain rather than the UBA domain.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified (eLife 2022;11:e76763; DOI 10.7554/eLife.76763). Falcon deep-research finding. Mechanistic in vitro demonstration that FAF2 stimulates p97-UFD1-NPL4 unfoldase activity (UBX-dependent, UBA-dispensable, coiled-coil required), supporting the p97-cofactor/adaptor core function. Not cached in publications/, so no verbatim supporting_text added to annotations.
- id: PMID:36746962
  title: The p97-UBXD8 complex regulates ER-Mitochondria contact sites by altering membrane lipid saturation and composition.
  findings:
  - statement: The p97-UBXD8/FAF2 complex localises to ER-mitochondria contact sites (ERMCS) and limits excessive contacts in a p97-catalytic-activity-dependent manner; loss of UBXD8 increases membrane lipid saturation via the SREBP1-SCD1 axis, and aberrant contacts are rescued by unsaturated fatty acids or SCD1 overexpression.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified (Nat Commun 2023;14:638; DOI 10.1038/s41467-023-36298-2). Falcon deep-research finding. New 2023 function — FAF2/UBXD8 with p97 regulates ER-mitochondria contact sites and membrane lipid saturation (SREBP1-SCD1); not represented in current GOA. Not cached in publications/, so no verbatim supporting_text added to annotations.
- id: PMID:39472561
  title: 'AAA+ ATPase chaperone p97/VCP(FAF2) governs basal pexophagy.'
  findings:
  - statement: FAF2/UBXD8, with p97/VCP (NPLOC4/UFD1), maintains peroxisome homeostasis by extracting ubiquitylated peroxisomal membrane proteins such as PMP70; in FAF2-deficient cells PMP70 accumulates, recruiting the autophagy adaptor OPTN to peroxisomes and inducing basal pexophagy, so FAF2-p97 negatively regulates pexophagy rather than acting in peroxisome biogenesis.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified (Nat Commun 2024;15:9347; DOI 10.1038/s41467-024-53558-x). Falcon deep-research finding. New 2024 function — FAF2/UBXD8 with p97 extracts ubiquitylated peroxisomal membrane proteins (PMP70) to suppress basal pexophagy; not represented in current GOA. Not cached in publications/, so no verbatim supporting_text added to annotations.
- id: PMID:41258083
  title: A UBH-UBX module amplifies p97/VCP's unfolding power to facilitate protein extraction and degradation.
  findings:
  - statement: FAF2 contains a conserved ubiquitin-binding helix (UBH) adjacent to its UBX domain; the UBH-UBX module enhances engagement of ubiquitinated substrates with p97-UFD1L-NPLOC4 and boosts the motor's ATPase and unfolding activities ~2-fold, with reconstituted p97-UFD1L-NPLOC4-FAF2 sufficient to extract membrane proteins from the ER and mitochondria. FAF2 knockout stabilised the ERAD client CD4.
    reference_section_type: ABSTRACT
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified (Nat Commun 2025;16:10162; DOI 10.1038/s41467-025-65166-4). Falcon deep-research finding. Identifies a UBH ubiquitin-binding element in FAF2 that amplifies p97 unfolding power for membrane-protein extraction, refining the ubiquitin-binding/adaptor core function. Not cached in publications/, so no verbatim supporting_text added to annotations.
core_functions:
- description: Ubiquitin-binding adaptor (via its N-terminal UBA domain) that recognizes polyubiquitinated client proteins and, through its C-terminal UBX domain, recruits the p97/VCP segregase, coupling ubiquitinated substrates to ATP-driven extraction.
  molecular_function:
    id: GO:0043130
    label: ubiquitin binding
  supported_by:
  - reference_id: PMID:18775313
    supporting_text: proteins that bind ubiquitin conjugates
  - reference_id: PMID:34739333
    supporting_text: ubiquitinated G3BP1 interacted with the endoplasmic reticulum–associated protein FAF2, which engaged the ubiquitin-dependent segregase p97/VCP
- description: ER-membrane p97/VCP cofactor in the SEL1L/HRD1 ER-associated degradation machinery that promotes dislocation/retrotranslocation of misfolded ER proteins to the cytosol for proteasomal degradation.
  molecular_function:
    id: GO:0030674
    label: protein-macromolecule adaptor activity
  locations:
  - id: GO:0005783
    label: endoplasmic reticulum
  directly_involved_in:
  - id: GO:0036503
    label: ERAD pathway
  - id: GO:0030970
    label: retrograde protein transport, ER to cytosol
  supported_by:
  - reference_id: PMID:18711132
    supporting_text: We identified AUP1, UBXD8, UBC6e, and OS9 as functionally important
  - reference_id: PMID:25660456
    supporting_text: dislocation, also known as retrotranslocation, of those unwanted proteins from
- description: Lipid-droplet regulator that recruits p97/VCP and binds directly to the lipase ATGL/PNPLA2, inhibiting it by displacing the coactivator CGI-58/ABHD5, thereby restraining triacylglycerol lipolysis and controlling lipid-droplet size.
  molecular_function:
    id: GO:0055102
    label: lipase inhibitor activity
  locations:
  - id: GO:0005811
    label: lipid droplet
  directly_involved_in:
  - id: GO:0034389
    label: lipid droplet organization
  supported_by:
  - reference_id: PMID:23297223
    supporting_text: UBXD8 binds directly to ATGL
  - reference_id: PMID:23297223
    supporting_text: recruitment of p97/VCP to LDs increases
proposed_new_terms: []
suggested_questions:
- question: To what extent does FAF2's UAS-domain unsaturated-fatty-acid sensing directly gate its ER-to-lipid-droplet partitioning and ATGL inhibition under different metabolic states?
- question: Is FAF2's role in p97-dependent dislocation of Insig-1 (SREBP regulation) mechanistically separable from its general ERAD substrate-extraction adaptor activity?
suggested_experiments:
- description: Reconstitute p97/VCP-dependent extraction of a defined ubiquitinated ERAD substrate with purified FAF2, UFD1-NPL4 and p97 to test whether FAF2 is sufficient as the substrate-recruiting cofactor and to map its UBA-dependence.
- description: Use proximity labeling (BioID/TurboID) of FAF2 in cells shifted between fed and lipolytic states to define how the ER versus lipid-droplet interactomes (including UBAC2, ATGL, CGI-58) change with metabolic condition.
- description: Quantitative degradation assays of endogenous ERAD substrates (e.g. NHK alpha-1-antitrypsin) and lipid-droplet ATGL turnover in FAF2 UBA-domain and UBX-domain point mutants to dissociate the ubiquitin-binding from the p97-recruiting contributions.