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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0036503 ERAD pathway | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of FAF2's role in ERAD, consistent with strong experimental evidence that FAF2/UBXD8 is part of the ER dislocation machinery. Reason: Core biological process; FAF2 is a p97/VCP cofactor in ER-associated degradation, supported experimentally. Supporting Evidence: PMID:18711132 We identified AUP1, UBXD8, UBC6e, and OS9 as functionally important |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | 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. Reason: Correct but generic; the specific ER and lipid-droplet compartments capture FAF2's site of action more informatively. Supporting Evidence: file:human/FAF2/FAF2-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic assignment of ER localization, consistent with direct experimental evidence that FAF2 is an ER membrane protein. Reason: Correct core compartment; redundant with IDA evidence. Supporting Evidence: file:human/FAF2/FAF2-uniprot.txt Endoplasmic reticulum |
| GO:0005811 lipid droplet | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic assignment of lipid-droplet localization, consistent with direct experimental and proteomic evidence. Reason: Correct core compartment; FAF2 partitions between ER and lipid droplets. Supporting Evidence: file:human/FAF2/FAF2-uniprot.txt Lipid droplet |
| GO:0010498 proteasomal protein catabolic process | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA machine-learning assignment of proteasomal protein catabolism, a generic parent of FAF2's specific ERAD/proteasome-mediated degradation role. Reason: Correct but generic; GO:0036503 (ERAD pathway) better captures the specific function. Supporting Evidence: PMID:18711132 dislocation of misfolded |
| GO:0005515 protein binding | IPI PMID:18711132 SEL1L nucleates a protein complex required for dislocation o... | KEEP AS NON CORE | 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. Reason: Records a real interaction but bare protein binding is uninformative per curation guidelines. Supporting Evidence: file:human/FAF2/FAF2-uniprot.txt Q96CS3; P55072: VCP |
| GO:0005515 protein binding | IPI PMID:18775313 UBXD7 binds multiple ubiquitin ligases and implicates p97 in... | KEEP AS NON CORE | 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. Reason: Real p97 interaction but uninformative GO term. Supporting Evidence: PMID:18775313 p97 assembles with all of the 13 mammalian UBX-domain proteins |
| GO:0005515 protein binding | IPI PMID:22119785 Defining human ERAD networks through an integrative mapping ... | KEEP AS NON CORE | Summary: IntAct interaction captured in an ERAD network mapping study (partners VCP and UBAC2). Bare protein binding is uninformative. Reason: Real ERAD-network interactions but uninformative GO term. Supporting Evidence: file:human/FAF2/FAF2-uniprot.txt Q96CS3; Q8NBM4: UBAC2 |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | KEEP AS NON CORE | Summary: High-throughput interactome capture (UBAC2). Bare protein binding is uninformative. Reason: Real interaction from a large-scale interactome but uninformative GO term. Supporting Evidence: file:human/FAF2/FAF2-uniprot.txt Q96CS3; Q8NBM4: UBAC2 |
| GO:0005515 protein binding | IPI PMID:29997244 LuTHy: a double-readout bioluminescence-based two-hybrid tec... | KEEP AS NON CORE | Summary: LuTHy two-hybrid capture of FAF2-VCP interaction. Bare protein binding is uninformative. Reason: Real interaction but uninformative GO term. Supporting Evidence: file:human/FAF2/FAF2-uniprot.txt Q96CS3; P55072: VCP |
| GO:0005515 protein binding | IPI PMID:35044719 Proteome-scale mapping of binding sites in the unstructured ... | KEEP AS NON CORE | Summary: Proteome-scale binding-site mapping capturing a FAF2 interaction (VASP). Bare protein binding is uninformative. Reason: Real interaction but uninformative GO term. Supporting Evidence: file:human/FAF2/FAF2-uniprot.txt Q96CS3; P50552: VASP |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | KEEP AS NON CORE | Summary: OpenCell endogenous-tagging interactome capture (VCP). Bare protein binding is uninformative. Reason: Real interaction but uninformative GO term. Supporting Evidence: file:human/FAF2/FAF2-uniprot.txt Q96CS3; P55072: VCP |
| GO:0005515 protein binding | IPI PMID:37776851 Analysis of proteome-wide degradation dynamics in ALS SOD1 i... | KEEP AS NON CORE | Summary: Interaction captured in an ALS SOD1 degradation-dynamics study implicating VCP homeostasis. Bare protein binding is uninformative. Reason: Real interaction but uninformative GO term. Supporting Evidence: file:human/FAF2/FAF2-uniprot.txt Q96CS3; P55072: VCP |
| GO:0005515 protein binding | IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func... | KEEP AS NON CORE | Summary: Multimodal cell-map interactome capture (UBAC2). Bare protein binding is uninformative. Reason: Real interaction but uninformative GO term. Supporting Evidence: file:human/FAF2/FAF2-uniprot.txt Q96CS3; Q8NBM4: UBAC2 |
| GO:0043161 proteasome-mediated ubiquitin-dependent protein catabolic process | IEA GO_REF:0000107 | KEEP AS NON CORE | 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. Reason: Correct but a generic parent of the specific ERAD process; retained as non-core. Supporting Evidence: PMID:18711132 dislocation of misfolded |
| GO:0034098 VCP-NPL4-UFD1 AAA ATPase complex | NAS PMID:28819009 The AAA+ ATPase p97, a cellular multitool. | ACCEPT | 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). Reason: Correct; FAF2 forms a defined p97/VCP cofactor complex, also supported by direct evidence (PMID:18775313). Supporting Evidence: file:human/FAF2/FAF2-uniprot.txt VCP-NPL4-UFD1-FAF2 AAA ATPase complex |
| GO:0036503 ERAD pathway | NAS PMID:28819009 The AAA+ ATPase p97, a cellular multitool. | ACCEPT | Summary: ComplexPortal assertion of FAF2's ERAD role as a p97/VCP cofactor, consistent with experimental evidence. Reason: Core biological process; redundant with experimental IMP/IBA ERAD annotations. Supporting Evidence: PMID:18711132 We identified AUP1, UBXD8, UBC6e, and OS9 as functionally important |
| GO:1904949 ATPase complex | NAS PMID:28819009 The AAA+ ATPase p97, a cellular multitool. | KEEP AS NON CORE | Summary: Generic parent term for the p97/VCP ATPase complex to which FAF2 binds. Reason: Correct but generic; the specific VCP-NPL4-UFD1 complex term is more informative. Supporting Evidence: file:human/FAF2/FAF2-uniprot.txt VCP-NPL4-UFD1-FAF2 AAA ATPase complex |
| GO:0005783 endoplasmic reticulum | IDA GO_REF:0000052 | ACCEPT | Summary: Direct immunofluorescence (HPA) evidence for ER localization, consistent with FAF2's role as an ER membrane protein. Reason: Core compartment; FAF2 acts at the ER membrane. Supporting Evidence: file:human/FAF2/FAF2-uniprot.txt Endoplasmic reticulum |
| GO:0005811 lipid droplet | IDA GO_REF:0000052 | ACCEPT | Summary: Direct immunofluorescence (HPA) evidence for lipid-droplet localization, consistent with FAF2's lipid-droplet function. Reason: Core compartment; FAF2 traffics to lipid droplets to recruit p97/VCP. Supporting Evidence: file:human/FAF2/FAF2-uniprot.txt Lipid droplet |
| GO:0005783 endoplasmic reticulum | IDA PMID:34739333 Ubiquitination of G3BP1 mediates stress granule disassembly ... | ACCEPT | Summary: FAF2 is active at the ER, where it engages ubiquitinated G3BP1 and recruits p97/VCP during heat-stress stress-granule disassembly. Reason: Correct site of action; directly demonstrated. Supporting Evidence: PMID:34739333 the endoplasmic reticulumβassociated protein FAF2 |
| GO:0030674 protein-macromolecule adaptor activity | IDA PMID:34739333 Ubiquitination of G3BP1 mediates stress granule disassembly ... | ACCEPT | 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. Reason: Core molecular function; FAF2 couples ubiquitinated clients to p97/VCP. Supporting Evidence: PMID:34739333 ubiquitinated G3BP1 interacted with the endoplasmic reticulumβassociated protein FAF2, which engaged the ubiquitin-dependent segregase p97/VCP |
| GO:0035617 stress granule disassembly | IDA PMID:34739333 Ubiquitination of G3BP1 mediates stress granule disassembly ... | ACCEPT | Summary: FAF2 promotes heat-stress-induced stress-granule disassembly by recruiting p97/VCP to ubiquitinated G3BP1, extracting it from the granule. Reason: Directly demonstrated biological process; a distinct (non-ERAD) role of FAF2 as a p97 adaptor. Supporting Evidence: PMID:34739333 targeting of G3BP1 weakened the stress granuleβspecific interaction network |
| GO:0005515 protein binding | IPI PMID:31073040 LMBR1L regulates lymphopoiesis through Wnt/Ξ²-catenin signali... | KEEP AS NON CORE | Summary: IPI capture of FAF2-LMBR1L interaction. Bare protein binding is uninformative. Reason: Real interaction (LMBR1L) but uninformative GO term. Supporting Evidence: file:human/FAF2/FAF2-uniprot.txt Interacts with LMBR1L |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-6798751 | MARK AS OVER ANNOTATED | 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. 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. Supporting Evidence: file:human/FAF2/FAF2-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0035578 azurophil granule lumen | TAS Reactome:R-HSA-6798751 | MARK AS OVER ANNOTATED | 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. Reason: Over-annotation from granule proteomics; not the characterized ER/lipid-droplet function. Supporting Evidence: file:human/FAF2/FAF2-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm |
| GO:0030970 retrograde protein transport, ER to cytosol | IMP PMID:25660456 Identification of ERAD components essential for dislocation ... | ACCEPT | Summary: FAF2/UBXD8 was experimentally required for dislocation (retrotranslocation) of the NHK alpha-1-antitrypsin ERAD substrate from the ER lumen to the cytosol. Reason: Directly supported (IMP); captures the dislocation/retrotranslocation step of ERAD in which FAF2 participates. Supporting Evidence: PMID:25660456 dislocation, also known as retrotranslocation, of those unwanted proteins from |
| GO:0005515 protein binding | IPI PMID:24215460 Pathogenic mutation of UBQLN2 impairs its interaction with U... | KEEP AS NON CORE | Summary: IPI capture of FAF2-UBQLN2 interaction. Bare protein binding is uninformative; the functional cooperation in ERAD is captured by the ERAD process annotation. Reason: Real interaction (UBQLN2) but uninformative GO term. Supporting Evidence: file:human/FAF2/FAF2-uniprot.txt Interacts (via N-terminus) with UBQLN2 |
| GO:0036503 ERAD pathway | IMP PMID:24215460 Pathogenic mutation of UBQLN2 impairs its interaction with U... | ACCEPT | Summary: Loss/disruption of FAF2/UBXD8 interaction with UBQLN2 impaired ERAD, demonstrating FAF2's functional requirement in the pathway. Reason: Core biological process with direct mutant/perturbation (IMP) support. Supporting Evidence: PMID:24215460 disrupts endoplasmic reticulum-associated protein degradation |
| GO:0005783 endoplasmic reticulum | IDA PMID:23297223 Spatial regulation of UBXD8 and p97/VCP controls ATGL-mediat... | ACCEPT | Summary: Direct evidence for ER localization of FAF2/UBXD8, the compartment from which it traffics to lipid droplets. Reason: Core compartment; directly demonstrated. Supporting Evidence: PMID:23297223 UBXD8 with the ER-resident rhomboid pseudoprotease UBAC2 |
| GO:0005811 lipid droplet | IDA PMID:23297223 Spatial regulation of UBXD8 and p97/VCP controls ATGL-mediat... | ACCEPT | Summary: Direct evidence that FAF2/UBXD8 localizes to lipid droplets, where it recruits p97/VCP and regulates ATGL. Reason: Core compartment; directly demonstrated. Supporting Evidence: PMID:23297223 UBXD8-mediated recruitment of p97/VCP to LDs |
| GO:0034389 lipid droplet organization | IMP PMID:23297223 Spatial regulation of UBXD8 and p97/VCP controls ATGL-mediat... | ACCEPT | Summary: FAF2/UBXD8 controls lipid-droplet size by recruiting p97/VCP and inhibiting ATGL-mediated triacylglycerol hydrolysis, regulating lipid-droplet organization. Reason: Directly supported biological process; FAF2 governs lipid-droplet dynamics via ATGL regulation. Supporting Evidence: PMID:23297223 recruitment of p97/VCP to LDs increases |
| GO:0035473 lipase binding | IDA PMID:23297223 Spatial regulation of UBXD8 and p97/VCP controls ATGL-mediat... | ACCEPT | Summary: FAF2/UBXD8 binds directly to the lipase ATGL/PNPLA2, a specific and informative molecular function. Reason: Directly demonstrated specific binding; supports the lipase-inhibitor and lipid-droplet roles. Supporting Evidence: PMID:23297223 UBXD8 binds directly to ATGL |
| GO:0055102 lipase inhibitor activity | IDA PMID:23297223 Spatial regulation of UBXD8 and p97/VCP controls ATGL-mediat... | ACCEPT | Summary: FAF2/UBXD8 inhibits ATGL/PNPLA2 lipase activity by promoting dissociation of its coactivator CGI-58/ABHD5, a specific molecular function. Reason: Directly demonstrated lipase-inhibitor activity; a defining lipid-metabolic function of FAF2. Supporting Evidence: PMID:23297223 promotes dissociation of its endogenous coactivator, CGI-58 |
| GO:0005811 lipid droplet | IDA PMID:14741744 Identification of major proteins in the lipid droplet-enrich... | ACCEPT | Summary: Lipid-droplet proteomic identification of FAF2/UBXD8 in the LD-enriched fraction of HuH7 hepatocytes, corroborating its lipid-droplet localization. Reason: Independent IDA support for the lipid-droplet compartment. Supporting Evidence: file:human/FAF2/FAF2-uniprot.txt Lipid droplet |
| GO:0031625 ubiquitin protein ligase binding | IDA PMID:18775313 UBXD7 binds multiple ubiquitin ligases and implicates p97 in... | ACCEPT | 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. Reason: Directly demonstrated; UBX-domain p97 cofactors that bind ubiquitin conjugates also interact with E3 ubiquitin ligases. Supporting Evidence: PMID:18775313 also interact with dozens of E3 |
| GO:0034098 VCP-NPL4-UFD1 AAA ATPase complex | IDA PMID:18775313 UBXD7 binds multiple ubiquitin ligases and implicates p97 in... | ACCEPT | Summary: FAF2/UBXD8 directly assembles with the p97/VCP-NPL4-UFD1 segregase as a substrate-recruiting cofactor. Reason: Core complex membership with direct (IDA) support. Supporting Evidence: file:human/FAF2/FAF2-uniprot.txt VCP-NPL4-UFD1-FAF2 AAA ATPase complex |
| GO:0043130 ubiquitin binding | IDA PMID:18775313 UBXD7 binds multiple ubiquitin ligases and implicates p97 in... | ACCEPT | Summary: FAF2/UBXD8 binds ubiquitin/ubiquitin conjugates through its N-terminal UBA domain, the molecular basis for recognizing ubiquitinated p97 clients. Reason: Core informative molecular function; the UBA domain binds polyubiquitinated substrates for delivery to p97/VCP. Supporting Evidence: PMID:18775313 proteins that bind ubiquitin conjugates |
| GO:0005515 protein binding | IPI PMID:19818707 The otubain YOD1 is a deubiquitinating enzyme that associate... | KEEP AS NON CORE | Summary: IPI capture of FAF2-YOD1 interaction (a p97-associated deubiquitinase in ER dislocation). Bare protein binding is uninformative. Reason: Real interaction (YOD1) but uninformative GO term. Supporting Evidence: file:human/FAF2/FAF2-uniprot.txt Interacts with YOD1 |
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Download this section (compressed HTML)Q: 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?
Q: Is FAF2's role in p97-dependent dislocation of Insig-1 (SREBP regulation) mechanistically separable from its general ERAD substrate-extraction adaptor activity?
Experiment: 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.
Experiment: 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.
Experiment: 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.
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