Existing Annotations Review

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 PMID:26389662
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 reticulum–associated 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 reticulum–associated 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 granule–specific interaction network
GO:0005515 protein binding	IPI PMID:31073040 LMBR1L regulates lymphopoiesis through Wnt/β-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

Core Functions

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:

ubiquitin binding

Supporting Evidence:

PMID:18775313
proteins that bind ubiquitin conjugates
PMID:34739333
ubiquitinated G3BP1 interacted with the endoplasmic reticulum–associated protein FAF2, which engaged the ubiquitin-dependent segregase p97/VCP

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:

protein-macromolecule adaptor activity

Directly Involved In:

ERAD pathway retrograde protein transport, ER to cytosol

Cellular Locations:

endoplasmic reticulum

Supporting Evidence:

PMID:18711132
We identified AUP1, UBXD8, UBC6e, and OS9 as functionally important
PMID:25660456
dislocation, also known as retrotranslocation, of those unwanted proteins from

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:

lipase inhibitor activity

Directly Involved In:

lipid droplet organization

Cellular Locations:

lipid droplet

Supporting Evidence:

PMID:23297223
UBXD8 binds directly to ATGL
PMID:23297223
recruitment of p97/VCP to LDs increases

References

GO_REF:0000033

Annotation inferences using phylogenetic trees

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000107

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

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

PMID:14741744

Identification of major proteins in the lipid droplet-enriched fraction isolated from the human hepatocyte cell line HuH7.

PMID:18711132

SEL1L nucleates a protein complex required for dislocation of misfolded glycoproteins.

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.

PMID:18775313

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

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.

PMID:19818707

The otubain YOD1 is a deubiquitinating enzyme that associates with p97 to facilitate protein dislocation from the ER.

PMID:22119785

Defining human ERAD networks through an integrative mapping strategy.

PMID:23297223

Spatial regulation of UBXD8 and p97/VCP controls ATGL-mediated lipid droplet turnover.

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.
Association of UBXD8 with the ER-resident rhomboid pseudoprotease UBAC2 restricts trafficking of UBXD8 from the ER to lipid droplets.

PMID:24215460

Pathogenic mutation of UBQLN2 impairs its interaction with UBXD8 and disrupts endoplasmic reticulum-associated protein degradation.

UBXD8/FAF2 is an ER membrane protein involved in translocation of ubiquitinated ERAD substrates; UBQLN2 cooperates with UBXD8 in ERAD.

PMID:25660456

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

ERAD requires dislocation/retrotranslocation of substrates such as NHK alpha-1-antitrypsin from the ER lumen to the cytosol for proteasomal degradation.

PMID:28514442

Architecture of the human interactome defines protein communities and disease networks.

PMID:28819009

The AAA+ ATPase p97, a cellular multitool.

p97/VCP recruits substrates through diverse cofactors and functions in ubiquitin-dependent processes including ERAD; FAF2 is one such cofactor.

PMID:29997244

LuTHy: a double-readout bioluminescence-based two-hybrid technology for quantitative mapping of protein-protein interactions in mammalian cells.

PMID:31073040

LMBR1L regulates lymphopoiesis through Wnt/β-catenin signaling.

PMID:34739333

Ubiquitination of G3BP1 mediates stress granule disassembly in a context-specific manner.

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.

PMID:35044719

Proteome-scale mapping of binding sites in the unstructured regions of the human proteome.

PMID:35271311

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

PMID:37776851

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

PMID:40205054

Multimodal cell maps as a foundation for structural and functional genomics.

Reactome:R-HSA-6798751

Exocytosis of azurophil granule lumen proteins

file:human/FAF2/FAF2-uniprot.txt

UniProt entry Q96CS3 (FAF2_HUMAN), FAS-associated factor 2 / UBXD8

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.

PMID:26389662

Systematic proteomics of the VCP-UBXD adaptor network identifies a role for UBXN10 in regulating ciliogenesis.

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.

PMID:35920641

Multiple UBX proteins reduce the ubiquitin threshold of the mammalian p97-UFD1-NPL4 unfoldase.

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.

PMID:36746962

The p97-UBXD8 complex regulates ER-Mitochondria contact sites by altering membrane lipid saturation and composition.

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.

PMID:39472561

AAA+ ATPase chaperone p97/VCP(FAF2) governs basal pexophagy.

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.

PMID:41258083

A UBH-UBX module amplifies p97/VCP's unfolding power to facilitate protein extraction and degradation.

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.

Suggested Experiments

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.

Deep Research

Falcon

(FAF2-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 30 citations 2 artifacts 2026-06-12T04:53:41.800441

Edison artifact artifact-00 (text/markdown)

## Context ID: pqac-00000035 The figure panels showing ER–mitochondria contact assay results, rescue by oleic acid or SCD1, and lipidomics/membrane order quanti (image/png)

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Research report: Human FAF2 (UniProt: Q96CS3; aliases UBXD8, ETEA, UBXN3B)—functional annotation

0) Target verification (critical disambiguation)

The literature in this report specifically addresses the human protein referred to as FAF2/UBXD8 (and sometimes annotated with the alias UBXN3B in the retrieved texts). Multiple independent primary studies and a systematic VCP/p97 adaptor interactome consistently describe FAF2/UBXD8 as an ER-tethered UBX-domain adaptor of the AAA+ ATPase p97/VCP involved in ERAD, lipid droplet regulation, and organelle membrane protein quality control (raman2015systematicproteomicsof pages 4-6, koyano2024aaa+atpasechaperone pages 1-2). This matches the UniProt Q96CS3 description you provided.

1) Key concepts and current understanding

1.1 What FAF2 is (core definition)

FAF2 (UBXD8) is best understood as a membrane-tethered adaptor (“cofactor”) for p97/VCP, positioning p97 at specific membranes and helping it engage ubiquitinated substrates for extraction/unfolding prior to downstream outcomes (often proteasomal degradation). This adaptor role is consistent across:
- an unbiased VCP–UBXD adaptor network map (raman2015systematicproteomicsof pages 4-6, raman2015systematicproteomicsof pages 3-4), and
- mechanistic cell biology on peroxisomes/pexophagy and contacts (koyano2024aaa+atpasechaperone pages 1-2, ganji2023thep97ubxd8complex pages 1-2).

1.2 Relationship to p97/VCP “segregase/unfoldase” function

p97/VCP is an AAA+ ATPase that uses ATP hydrolysis to extract proteins from membranes or complexes. FAF2 provides substrate engagement and localization, and can also increase p97’s effective unfolding capacity and/or lower the ubiquitin “requirements” for productive processing depending on the system studied (fujisawa2022multipleubxproteins pages 7-9, huo2025aubhubxmodule pages 8-9).

1.3 Domains and functional modules (operational view)

Across the primary evidence base, FAF2 is repeatedly treated as a multi-domain adaptor with:
- a UBX domain (p97-binding),
- a UBA domain (ubiquitin-binding in some contexts),
- a hairpin (HP)/membrane-association element important for membrane embedding/tethering,
- a coiled-coil region implicated in stimulating p97-UFD1-NPL4 unfoldase activity,
with additional mechanistic work identifying a UBH-UBX module (a UBX-adjacent ubiquitin-binding helix) that amplifies p97-UFD1L-NPLOC4 activity in reconstituted extraction systems (fujisawa2022multipleubxproteins pages 10-11, koyano2024aaa+atpasechaperone pages 9-10, huo2025aubhubxmodule pages 8-9).

2) Subcellular localization and interaction partners

2.1 Localization

FAF2/UBXD8 is reported as a membrane-associated cofactor localizing to multiple organellar surfaces, with strong emphasis on:
- endoplasmic reticulum (ER) (ER-tethered adaptor; ERAD context) (raman2015systematicproteomicsof pages 4-6, koyano2024aaa+atpasechaperone pages 2-2),
- lipid droplets (LDs) (redistribution/partitioning ER↔LD; lipolysis regulation) (olzmann2013spatialregulationof pages 1-2, olzmann2013spatialregulationof pages 2-3),
- ER–mitochondria contact sites (ERMCS/MAMs) (enriched in MAM fractions; functional contact regulator) (ganji2023thep97ubxd8complex pages 3-4, ganji2023thep97ubxd8complex pages 1-2),
- peroxisomes (functional peroxisomal homeostasis via extraction of ubiquitinated PMPs) (koyano2024aaa+atpasechaperone pages 1-2, koyano2024aaa+atpasechaperone pages 9-10).

2.2 Interaction partners (supported by experimental evidence)

Key FAF2-associated proteins from systematic AP-MS and targeted immunoprecipitation include:
- p97/VCP and core module UFD1L–NPLOC4 (broad association in VCP adaptor datasets; peroxisome study shows complex with NPLOC4/UFD1) (raman2015systematicproteomicsof pages 3-4, koyano2024aaa+atpasechaperone pages 9-10),
- ERAD/membrane quality control factors such as AMFR, DERLIN2, AUP1, BAG6, UBAC2 (proteomic network; also UBAC2 regulates ER↔LD partitioning) (raman2015systematicproteomicsof pages 4-6, olzmann2013spatialregulationof pages 1-2),
- Peroxisomal membrane proteins PMP70 and PEX16 and deubiquitylase USP30 (co-IP evidence in pexophagy study) (koyano2024aaa+atpasechaperone pages 9-10).

3) Primary biological functions and pathways (evidence-based)

3.1 Lipid droplet biology: regulation of ATGL-mediated lipolysis (real-world metabolic relevance)

A major, well-established FAF2/UBXD8 function is regulation of lipid droplet turnover by acting at lipid droplets with p97/VCP.

Mechanistic model supported by experiments:
- UBXD8 traffics/partitions between ER and LDs; the ER protein UBAC2 restricts UBXD8 localization to LDs (olzmann2013spatialregulationof pages 1-2, olzmann2013spatialregulationof pages 2-3).
- LD-localized UBXD8 binds ATGL and reduces ATGL activity by promoting dissociation of ATGL from its coactivator CGI-58, a process requiring UBXD8’s ability to recruit p97/VCP via its UBX domain (olzmann2013spatialregulationof pages 3-4, olzmann2013spatialregulationof pages 5-6).

Representative quantitative findings:
- ATGL overexpression reduced lipid droplet content by ~3–4-fold, and this lipolytic effect was largely abrogated by co-overexpression of LD-localized UBXD8 (olzmann2013spatialregulationof pages 3-4).
- Split-YFP and biochemical assays showed UBXD8 modulates ATGL–CGI-58 interaction with statistically significant differences (P < 0.05 in cited experiments) (olzmann2013spatialregulationof pages 5-6, olzmann2013spatialregulationof pages 4-5).

Key primary source:
- Olzmann et al., PNAS (Jan 2013), https://doi.org/10.1073/pnas.1213738110 (olzmann2013spatialregulationof pages 3-4).

3.2 ER–mitochondria contact site regulation via membrane lipid saturation (major 2023 advance)

A central recent development (2023) is that the p97–UBXD8 complex regulates ER–mitochondria contact sites (ERMCS/MAMs) by controlling membrane lipid saturation/composition.

Core mechanism:
- p97–UBXD8 localizes to ERMCS and restricts excessive contacts, requiring p97 catalytic activity (ganji2023thep97ubxd8complex pages 1-2, ganji2023thep97ubxd8complex pages 2-3).
- Loss of UBXD8 (or p97 inhibition) impairs SREBP1 activation and reduces SCD1-linked desaturation output, shifting membranes toward higher saturation and increased order; more ordered membranes are proposed to stabilize contacts by reducing lateral mobility of key tethering proteins (ganji2023thep97ubxd8complex pages 11-12, ganji2023thep97ubxd8complex pages 9-10).

Quantitative/statistical evidence:
- Quantitative proteomics of isolated ERMCS identified 4,499 proteins and detected 102 enriched and 112 depleted proteins in UBXD8 KO MAM fractions under stated filtering criteria (ganji2023thep97ubxd8complex pages 3-4).
- Lipidomics showed that about two-thirds of measured PC/PE/LPC/LPE species were significantly increased in UBXD8 KO MAM fractions (example threshold: log2 KO:WT > 1, P < 0.05), with many elevated species consisting largely of saturated/monounsaturated tails (ganji2023thep97ubxd8complex pages 5-6).
- Multiple contact measurements had very strong significance (e.g., p-values reported down to ~10^-9) and rescue experiments supported causality (ganji2023thep97ubxd8complex pages 11-12, ganji2023thep97ubxd8complex pages 9-10).
- The paper reports rescue of contact phenotypes by oleic acid (monounsaturated) supplementation and by SCD1 overexpression, while saturated palmitate does not rescue (ganji2023thep97ubxd8complex pages 6-7, ganji2023thep97ubxd8complex pages 9-10).

Key primary source (2023):
- Ganji et al., Nature Communications (Feb 2023), https://doi.org/10.1038/s41467-023-36298-2 (ganji2023thep97ubxd8complex pages 1-2).

(Selected figure evidence from this paper is captured in the cropped figure panels.) (ganji2023thep97ubxd8complex media 5198145b).

3.3 Peroxisome quality control: FAF2–p97 suppresses basal pexophagy (major 2024 advance)

A second major recent development (2024) is that FAF2/UBXD8 functions with p97/VCP to maintain peroxisome homeostasis by extracting ubiquitinated peroxisomal membrane proteins, thereby preventing unnecessary basal pexophagy.

Core findings and mechanism:
- FAF2 is described as an ER membrane protein/cofactor of p97/VCP that contributes to peroxisomal membrane protein turnover (koyano2024aaa+atpasechaperone pages 2-2, koyano2024aaa+atpasechaperone pages 1-2).
- FAF2-/- cells showed altered peroxisomal protein levels and accelerated pexophagy; the study proposes FAF2–p97 extracts ubiquitylated PMPs (example: PMP70, also PEX16), preventing recruitment of the autophagy adaptor OPTN and basal pexophagy (koyano2024aaa+atpasechaperone pages 10-11, koyano2024aaa+atpasechaperone pages 1-2).
- Biochemical data show FAF2 forms complexes with p97/VCP, NPLOC4, UFD1 and physically associates with PMP70/PEX16 and USP30 (koyano2024aaa+atpasechaperone pages 9-10).

Quantitative findings:
- The FACS-based pexophagy assay shows a strong FAF2 dependence; in one quantified dataset, basal pexophagy increased from 3.9% to 15.5 ± 0.5% in FAF2 KO and was rescued by FAF2 re-expression (huo2025aubhubxmodule pages 10-11).
- Multiple comparisons in figures included significant p-values (e.g., p = 1.25E-04; p = 6.46E-03) (koyano2024aaa+atpasechaperone pages 10-11).

Key primary source (2024):
- Koyano et al., Nature Communications (Oct 2024), https://doi.org/10.1038/s41467-024-53558-x (koyano2024aaa+atpasechaperone pages 1-2).

4) Mechanistic/biochemical framework: how FAF2 tunes p97 substrate processing

Even beyond specific organelle contexts, FAF2 appears to enhance p97 substrate processing efficiency in multiple in vitro and cellular systems.

4.1 Lowering the ubiquitin threshold of the mammalian p97-UFD1-NPL4 unfoldase (2022)

In reconstituted CMG helicase disassembly, FAF2 (studied as a soluble FAF2ΔM construct lacking membrane tethering) functions as a UBX cofactor that reduces the ubiquitin chain-length threshold required for p97-UFD1-NPL4 to unfold/disassemble substrates.
- In the presence of UBX cofactors (including FAF2), disassembly could proceed when substrates carried ≥5 ubiquitins (approaching yeast-like thresholds) (fujisawa2022multipleubxproteins pages 7-9, fujisawa2022multipleubxproteins pages 9-10).
- Domain mapping indicated FAF2’s UBX is required but its UBA is dispensable; a coiled-coil plus UBX fragment was sufficient whereas UBX alone was inactive (fujisawa2022multipleubxproteins pages 10-11).

Key primary source:
- Fujisawa et al., eLife (Aug 2022), https://doi.org/10.7554/eLife.76763 (fujisawa2022multipleubxproteins pages 10-11).

4.2 UBH-UBX module and amplified “power output” (2025 mechanistic detail; included for completeness)

Mechanistic reconstitution work (2025) proposes an additional ubiquitin-binding element (UBH) adjacent to UBX that increases p97-UFD1L-NPLOC4 ATPase and unfolding output and supports membrane extraction.
- p97-UN ATPase rate increased from ~2.7 s^-1 to ~4.3 s^-1 with FAF2; unfolding signals increased about 2-fold (huo2025aubhubxmodule pages 8-9).
- FAF2 knockout stabilized CD4 (ERAD client) by ~10-fold in that system (huo2025aubhubxmodule pages 1-2).

Key primary source:
- Huo et al., Nature Communications (Nov 2025), https://doi.org/10.1038/s41467-025-65166-4 (huo2025aubhubxmodule pages 1-2).

5) Current applications and real-world implementations

5.1 Metabolic and lipid storage phenotypes (LD turnover)

FAF2/UBXD8’s demonstrated control of ATGL-mediated lipolysis positions it as a mechanistic node relevant to fat storage phenotypes and diseases characterized by altered lipolysis and triglyceride handling (e.g., steatosis), via a concrete molecular mechanism (ATGL–CGI-58 disassembly by UBXD8–p97) (olzmann2013spatialregulationof pages 3-4).

5.2 Organelle contact sites as therapeutic-relevant biology (ERMCS and lipid saturation)

The 2023 work links p97–UBXD8 regulation of ERMCS to lipid desaturation control (SREBP1–SCD1 axis), and further connects impairment of this axis to brains of p97 mutant mouse models associated with neurodegeneration (ganji2023thep97ubxd8complex pages 1-2). While this is not yet a FAF2-targeted clinical intervention, it supports the idea that FAF2-linked p97 biology has in vivo disease relevance (ganji2023thep97ubxd8complex pages 1-2).

5.3 Peroxisome homeostasis and selective autophagy modulation

The 2024 pexophagy study provides a mechanistic basis for manipulating peroxisome abundance via the FAF2–p97 axis and suggests FAF2 may be a useful handle for studying peroxisome maintenance vs autophagic removal in cell models (koyano2024aaa+atpasechaperone pages 1-2, koyano2024aaa+atpasechaperone pages 9-10).

6) Expert/authoritative analysis (what leading sources emphasize)

A high-confidence view emerging from systematic network mapping and mechanistic organelle-specific studies is that FAF2/UBXD8 is not a “single-pathway” protein but rather a location-defining p97 adaptor whose functional output depends on where it recruits/activates p97 and what ubiquitinated substrates are present.
- The VCP adaptor network emphasizes modularity and shared recruitment modules (UFD1L/NPLOC4 frequently co-associated), while assigning FAF2 to ER/membrane quality control and lipid droplet biology with defined ERAD interactors (AMFR, DERLIN2, AUP1, BAG6, UBAC2) (raman2015systematicproteomicsof pages 4-6, raman2015systematicproteomicsof pages 3-4).
- The 2023–2024 work extends this model to contact-site lipid homeostasis and peroxisomal membrane protein surveillance, respectively, consistent with a broader “organelle-proximal proteostasis and lipid regulation” role for FAF2 (ganji2023thep97ubxd8complex pages 1-2, koyano2024aaa+atpasechaperone pages 1-2).

7) Evidence map (summary table)

The following table consolidates the highest-value mechanistic and quantitative findings for FAF2/UBXD8 across major pathways.

Biological process/pathway	Localization	Molecular role/mechanism	Key experimental evidence (assays/models)	Quantitative/statistical highlights	Key reference with publication date and URL
ER-associated degradation (ERAD) and membrane protein extraction	ER membrane; also reported at mitochondrial outer membrane and peroxisomes	FAF2 is an ER-tethered p97/VCP adaptor. Its UBX domain binds p97, and a UBH-UBX module enhances p97-UFD1L-NPLOC4 engagement with ubiquitinated substrates, boosting mechanical unfolding/extraction; FAF2 forms ternary complexes with p97 and ubiquitinated clients such as CD4. UBA is less important than UBH/UBX for extraction in these assays. (huo2025aubhubxmodule pages 1-2, huo2025aubhubxmodule pages 8-9)	Reconstituted extraction of ubiquitinated mCD4 from microsomes; tandem IP showing CD4–FAF2–p97 complex; FAF2 knockout/depletion assays monitoring CD4, TCRα, mTAP2, ABCG2-F208S degradation; ATPase and unfolding assays with purified p97-UN ± FAF2 constructs. (huo2025aubhubxmodule pages 1-2, huo2025aubhubxmodule pages 8-9)	FAF2 knockout increased steady-state CD4 by ~10-fold; FAF2 UBH-UBX raised p97 ATPase from ~2.7 s^-1 to ~4.3 s^-1 and increased unfolding ~2-fold; UBH mutants abolished/strongly impaired stimulation. (huo2025aubhubxmodule pages 1-2, huo2025aubhubxmodule pages 8-9)	Huo et al., Nature Communications (Nov 2025). https://doi.org/10.1038/s41467-025-65166-4
Lipid droplet turnover / lipolysis control	ER and lipid droplets	LD-localized FAF2/UBXD8 recruits p97/VCP to lipid droplets, binds ATGL, and restrains ATGL-mediated triacylglycerol hydrolysis by promoting dissociation of ATGL from its activator CGI-58; UBAC2 restricts FAF2 trafficking from ER to LDs. (olzmann2013spatialregulationof pages 1-2, olzmann2013spatialregulationof pages 3-4, olzmann2013spatialregulationof pages 2-3)	Immunolocalization and LD fractionation after oleate loading; UBAC2 overexpression or knockdown to alter FAF2 partitioning; LD size/number quantification by BODIPY; ^14C-oleate pulse-chase TAG turnover; co-IP of UBXD8 with ATGL; split-YFP complementation for ATGL–CGI-58 interaction; ATGL-null MEFs. (olzmann2013spatialregulationof pages 5-6, olzmann2013spatialregulationof pages 4-5, olzmann2013spatialregulationof pages 3-4, olzmann2013spatialregulationof pages 2-3)	ATGL overexpression reduced LD content ~3- to 4-fold, largely abrogated by UBXD8-S; ATGL half-life ~45 min and >12 h with MG132, but UBXD8 did not change ATGL stability; dominant-negative p97/VCP and UBX deletion blocked UBXD8 LD effects; significance typically P < 0.05, with ~500–600 droplets quantified in some analyses. (olzmann2013spatialregulationof pages 3-4, olzmann2013spatialregulationof pages 2-3)	Olzmann et al., PNAS (Jan 2013). https://doi.org/10.1073/pnas.1213738110
ER–mitochondria contact site regulation and lipid saturation control	ER–mitochondria contact sites / MAMs	The p97–UBXD8 complex localizes to ERMCS and limits excessive contacts by promoting INSIG1 turnover, enabling SREBP1 activation and SCD1-dependent lipid desaturation. Loss of the complex increases membrane saturation/order, stabilizing contacts; unsaturated fatty acids or SCD1 rescue the phenotype. (ganji2023thep97ubxd8complex pages 1-2, ganji2023thep97ubxd8complex pages 2-3, ganji2023thep97ubxd8complex pages 9-10)	Split-luciferase and SPLICS/split-GFP contact reporters; MAM fractionation; TMT proteomics of WT vs UBXD8 KO ERMCS; lipidomics of MAM fractions; pyrene-based membrane order assays; rescue with wild-type p97/UBXD8, SCD1 overexpression, oleic acid, or palmitic acid control; TEM/confocal contact measurements. (ganji2023thep97ubxd8complex pages 1-2, ganji2023thep97ubxd8complex pages 9-10, ganji2023thep97ubxd8complex pages 5-6, ganji2023thep97ubxd8complex pages 3-4, ganji2023thep97ubxd8complex media 5198145b)	Proteomics identified 4,499 proteins in ERMCS fractions, with 102 enriched and 112 depleted in UBXD8 KO; ~two-thirds of measured PC/PE/LPC/LPE species increased in UBXD8 KO ([log2 KO:WT] > 1, P < 0.05); many TG and DG species were ≥2-fold elevated; rescue comparisons showed strong significance (e.g., p = 7.46 × 10^-10; other panels p = 9 × 10^-9 to 1.89 × 10^-7). Oleic acid, but not palmitic acid, rescued increased contacts. (ganji2023thep97ubxd8complex pages 11-12, ganji2023thep97ubxd8complex pages 6-7, ganji2023thep97ubxd8complex pages 9-10, ganji2023thep97ubxd8complex pages 5-6, ganji2023thep97ubxd8complex pages 3-4)	Ganji et al., Nature Communications (Feb 2023). https://doi.org/10.1038/s41467-023-36298-2
Peroxisomal membrane protein quality control and suppression of basal pexophagy	Peroxisomes; also ER/lipid droplets/mitochondria reported	FAF2 partners with p97/VCP, UFD1, and NPLOC4 to extract ubiquitylated peroxisomal membrane proteins such as PMP70/PEX16, thereby preventing OPTN recruitment and inappropriate basal pexophagy. HP/membrane-association is critical; UBA is dispensable in this context. (koyano2024aaa+atpasechaperone pages 10-11, koyano2024aaa+atpasechaperone pages 1-2, koyano2024aaa+atpasechaperone pages 9-10)	FAF2 knockout HCT116 cells; mKeima-SKL FACS pexophagy assay; IP of 3HA-FAF2 with PMP70, PEX16, USP30, p97/VCP, NPLOC4, UFD1; proximity ligation assay with PMP70; p97 inhibition (NMS-873); domain-mutant reconstitution; PMP70 knockdown rescue experiments. (koyano2024aaa+atpasechaperone pages 10-11, koyano2024aaa+atpasechaperone pages 15-16, koyano2024aaa+atpasechaperone pages 9-10)	FAF2 loss significantly accelerated pexophagy; one assay showed basal pexophagy rising from 3.9% to 15.5 ± 0.5% in FAF2 KO, rescued to 3.2 ± 0.2% by WT FAF2 but only to 7.0 ± 0.4% by a UBH mutant; reported statistics included p = 1.25E-04 and p = 6.46E-03, with multiple panels at p < 0.0001. (koyano2024aaa+atpasechaperone pages 10-11, huo2025aubhubxmodule pages 10-11, koyano2024aaa+atpasechaperone pages 9-10)	Koyano et al., Nature Communications (Oct 2024). https://doi.org/10.1038/s41467-024-53558-x
General stimulation of mammalian p97-UFD1-NPL4 unfoldase	Membrane-associated sites including ER, lipid droplets, and nuclear outer membrane/peripheral membranes	FAF2 is a UBX-family cofactor that lowers the ubiquitin-chain threshold required for mammalian p97-UFD1-NPL4 substrate processing. Its UBX domain is essential, the UBA domain is dispensable, and a coiled-coil region is required/sufficient together with UBX to stimulate unfoldase activity. (fujisawa2022multipleubxproteins pages 7-9, fujisawa2022multipleubxproteins pages 10-11, fujisawa2022multipleubxproteins pages 1-2, fujisawa2022multipleubxproteins pages 9-10)	In vitro CMG helicase disassembly assays with soluble FAF2ΔM; truncation/domain mutants; tests of dependence on UFD1-NPL4 and NPL4 groove; genetic interaction analyses with related UBX proteins. (fujisawa2022multipleubxproteins pages 7-9, fujisawa2022multipleubxproteins pages 10-11, fujisawa2022multipleubxproteins pages 9-10, fujisawa2022multipleubxproteins pages 14-15)	In the presence of FAF2/FAF1/UBXN7, human p97-UFD1-NPL4 could process substrates bearing ≥5 ubiquitins, reducing the otherwise high ubiquitin threshold toward the yeast-like minimum. (fujisawa2022multipleubxproteins pages 7-9, fujisawa2022multipleubxproteins pages 1-2, fujisawa2022multipleubxproteins pages 14-15)	Fujisawa et al., eLife (Aug 2022). https://doi.org/10.7554/eLife.76763
Interaction network / adaptor classification	ER-tethered adaptor with links to mitochondria and membrane-trafficking systems	Systematic proteomics places FAF2/UBXD8 within the membrane-tethered UBXD adaptors of the VCP/p97 network, associated with ERAD, lipid droplet homeostasis, and possible mitochondrial/mitophagy-related functions. Interactors include AMFR, DERLIN2, AUP1, BAG6, UBAC2, and shared VCP-network components; UFD1L/NPLOC4 broadly associate with UBXD adaptors. (raman2015systematicproteomicsof pages 4-6, raman2015systematicproteomicsof pages 3-4, raman2015systematicproteomicsof pages 1-3)	Comparative AP-MS of VCP and 13 UBXD adaptors in human cells with CompPASS filtering, reciprocal validation, and localization analyses. (raman2015systematicproteomicsof pages 4-6, raman2015systematicproteomicsof pages 3-4, raman2015systematicproteomicsof pages 11-13)	Network study identified 169 high-confidence interacting proteins under stringent criteria and showed UFD1L/NPLOC4 association with 11/14 UBXD proteins in the dataset; FAF2 clustered with membrane/ERAD factors and partially colocalized with mitochondria. (raman2015systematicproteomicsof pages 4-6, raman2015systematicproteomicsof pages 3-4)	Raman et al., Nature Cell Biology (Sep 2015). https://doi.org/10.1038/ncb3238

Table: This table summarizes experimentally supported functions, localizations, mechanisms, and quantitative findings for human FAF2/UBXD8/ETEA/UBXN3B. It is useful as a concise evidence map linking FAF2 to ERAD, lipid droplet biology, ER–mitochondria contacts, peroxisome quality control, and p97/VCP-dependent substrate extraction.

8) References (URLs and publication dates)

Ganji R. et al. Nature Communications (Feb 2023). “The p97-UBXD8 complex regulates ER-Mitochondria contact sites by altering membrane lipid saturation and composition.” https://doi.org/10.1038/s41467-023-36298-2 (ganji2023thep97ubxd8complex pages 1-2)
Koyano F. et al. Nature Communications (Oct 2024). “AAA+ ATPase chaperone p97/VCPFAF2 governs basal pexophagy.” https://doi.org/10.1038/s41467-024-53558-x (koyano2024aaa+atpasechaperone pages 1-2)
Olzmann J.A. et al. PNAS (Jan 2013). “Spatial regulation of UBXD8 and p97/VCP controls ATGL-mediated lipid droplet turnover.” https://doi.org/10.1073/pnas.1213738110 (olzmann2013spatialregulationof pages 3-4)
Fujisawa R. et al. eLife (Aug 2022). “Multiple UBX proteins reduce the ubiquitin threshold of the mammalian p97-UFD1-NPL4 unfoldase.” https://doi.org/10.7554/eLife.76763 (fujisawa2022multipleubxproteins pages 1-2)
Raman M. et al. Nature Cell Biology (Sep 2015). “Systematic proteomics of the VCP–UBXD adaptor network…” https://doi.org/10.1038/ncb3238 (raman2015systematicproteomicsof pages 4-6)
Huo X.-Y. et al. Nature Communications (Nov 2025). “A UBH-UBX module amplifies p97/VCP’s unfolding power…” https://doi.org/10.1038/s41467-025-65166-4 (huo2025aubhubxmodule pages 1-2)

References

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(koyano2024aaa+atpasechaperone pages 2-2): Fumika Koyano, Koji Yamano, Tomoyuki Hoshina, Hidetaka Kosako, Yukio Fujiki, Keiji Tanaka, and Noriyuki Matsuda. Aaa+ atpase chaperone p97/vcpfaf2 governs basal pexophagy. Nature Communications, Oct 2024. URL: https://doi.org/10.1038/s41467-024-53558-x, doi:10.1038/s41467-024-53558-x. This article has 17 citations and is from a highest quality peer-reviewed journal.
(olzmann2013spatialregulationof pages 1-2): James A. Olzmann, Caleb M. Richter, and Ron R. Kopito. Spatial regulation of ubxd8 and p97/vcp controls atgl-mediated lipid droplet turnover. Proceedings of the National Academy of Sciences, 110:1345-1350, Jan 2013. URL: https://doi.org/10.1073/pnas.1213738110, doi:10.1073/pnas.1213738110. This article has 288 citations and is from a highest quality peer-reviewed journal.
(olzmann2013spatialregulationof pages 2-3): James A. Olzmann, Caleb M. Richter, and Ron R. Kopito. Spatial regulation of ubxd8 and p97/vcp controls atgl-mediated lipid droplet turnover. Proceedings of the National Academy of Sciences, 110:1345-1350, Jan 2013. URL: https://doi.org/10.1073/pnas.1213738110, doi:10.1073/pnas.1213738110. This article has 288 citations and is from a highest quality peer-reviewed journal.
(ganji2023thep97ubxd8complex pages 3-4): Rakesh Ganji, Joao A. Paulo, Yuecheng Xi, Ian Kline, Jiang Zhu, Christoph S. Clemen, Conrad C. Weihl, John G. Purdy, Steve P. Gygi, and Malavika Raman. The p97-ubxd8 complex regulates er-mitochondria contact sites by altering membrane lipid saturation and composition. Nature Communications, Feb 2023. URL: https://doi.org/10.1038/s41467-023-36298-2, doi:10.1038/s41467-023-36298-2. This article has 51 citations and is from a highest quality peer-reviewed journal.
(olzmann2013spatialregulationof pages 3-4): James A. Olzmann, Caleb M. Richter, and Ron R. Kopito. Spatial regulation of ubxd8 and p97/vcp controls atgl-mediated lipid droplet turnover. Proceedings of the National Academy of Sciences, 110:1345-1350, Jan 2013. URL: https://doi.org/10.1073/pnas.1213738110, doi:10.1073/pnas.1213738110. This article has 288 citations and is from a highest quality peer-reviewed journal.
(olzmann2013spatialregulationof pages 5-6): James A. Olzmann, Caleb M. Richter, and Ron R. Kopito. Spatial regulation of ubxd8 and p97/vcp controls atgl-mediated lipid droplet turnover. Proceedings of the National Academy of Sciences, 110:1345-1350, Jan 2013. URL: https://doi.org/10.1073/pnas.1213738110, doi:10.1073/pnas.1213738110. This article has 288 citations and is from a highest quality peer-reviewed journal.
(olzmann2013spatialregulationof pages 4-5): James A. Olzmann, Caleb M. Richter, and Ron R. Kopito. Spatial regulation of ubxd8 and p97/vcp controls atgl-mediated lipid droplet turnover. Proceedings of the National Academy of Sciences, 110:1345-1350, Jan 2013. URL: https://doi.org/10.1073/pnas.1213738110, doi:10.1073/pnas.1213738110. This article has 288 citations and is from a highest quality peer-reviewed journal.
(ganji2023thep97ubxd8complex pages 2-3): Rakesh Ganji, Joao A. Paulo, Yuecheng Xi, Ian Kline, Jiang Zhu, Christoph S. Clemen, Conrad C. Weihl, John G. Purdy, Steve P. Gygi, and Malavika Raman. The p97-ubxd8 complex regulates er-mitochondria contact sites by altering membrane lipid saturation and composition. Nature Communications, Feb 2023. URL: https://doi.org/10.1038/s41467-023-36298-2, doi:10.1038/s41467-023-36298-2. This article has 51 citations and is from a highest quality peer-reviewed journal.
(ganji2023thep97ubxd8complex pages 11-12): Rakesh Ganji, Joao A. Paulo, Yuecheng Xi, Ian Kline, Jiang Zhu, Christoph S. Clemen, Conrad C. Weihl, John G. Purdy, Steve P. Gygi, and Malavika Raman. The p97-ubxd8 complex regulates er-mitochondria contact sites by altering membrane lipid saturation and composition. Nature Communications, Feb 2023. URL: https://doi.org/10.1038/s41467-023-36298-2, doi:10.1038/s41467-023-36298-2. This article has 51 citations and is from a highest quality peer-reviewed journal.
(ganji2023thep97ubxd8complex pages 9-10): Rakesh Ganji, Joao A. Paulo, Yuecheng Xi, Ian Kline, Jiang Zhu, Christoph S. Clemen, Conrad C. Weihl, John G. Purdy, Steve P. Gygi, and Malavika Raman. The p97-ubxd8 complex regulates er-mitochondria contact sites by altering membrane lipid saturation and composition. Nature Communications, Feb 2023. URL: https://doi.org/10.1038/s41467-023-36298-2, doi:10.1038/s41467-023-36298-2. This article has 51 citations and is from a highest quality peer-reviewed journal.
(ganji2023thep97ubxd8complex pages 5-6): Rakesh Ganji, Joao A. Paulo, Yuecheng Xi, Ian Kline, Jiang Zhu, Christoph S. Clemen, Conrad C. Weihl, John G. Purdy, Steve P. Gygi, and Malavika Raman. The p97-ubxd8 complex regulates er-mitochondria contact sites by altering membrane lipid saturation and composition. Nature Communications, Feb 2023. URL: https://doi.org/10.1038/s41467-023-36298-2, doi:10.1038/s41467-023-36298-2. This article has 51 citations and is from a highest quality peer-reviewed journal.
(ganji2023thep97ubxd8complex pages 6-7): Rakesh Ganji, Joao A. Paulo, Yuecheng Xi, Ian Kline, Jiang Zhu, Christoph S. Clemen, Conrad C. Weihl, John G. Purdy, Steve P. Gygi, and Malavika Raman. The p97-ubxd8 complex regulates er-mitochondria contact sites by altering membrane lipid saturation and composition. Nature Communications, Feb 2023. URL: https://doi.org/10.1038/s41467-023-36298-2, doi:10.1038/s41467-023-36298-2. This article has 51 citations and is from a highest quality peer-reviewed journal.
(ganji2023thep97ubxd8complex media 5198145b): Rakesh Ganji, Joao A. Paulo, Yuecheng Xi, Ian Kline, Jiang Zhu, Christoph S. Clemen, Conrad C. Weihl, John G. Purdy, Steve P. Gygi, and Malavika Raman. The p97-ubxd8 complex regulates er-mitochondria contact sites by altering membrane lipid saturation and composition. Nature Communications, Feb 2023. URL: https://doi.org/10.1038/s41467-023-36298-2, doi:10.1038/s41467-023-36298-2. This article has 51 citations and is from a highest quality peer-reviewed journal.
(koyano2024aaa+atpasechaperone pages 10-11): Fumika Koyano, Koji Yamano, Tomoyuki Hoshina, Hidetaka Kosako, Yukio Fujiki, Keiji Tanaka, and Noriyuki Matsuda. Aaa+ atpase chaperone p97/vcpfaf2 governs basal pexophagy. Nature Communications, Oct 2024. URL: https://doi.org/10.1038/s41467-024-53558-x, doi:10.1038/s41467-024-53558-x. This article has 17 citations and is from a highest quality peer-reviewed journal.
(huo2025aubhubxmodule pages 10-11): Xin-Yu Huo, Di Liu, Rong Zou, Zhao-Peng Li, Yunxia Li, Lifeng Pan, Yaoyang Zhang, and Zai-Rong Zhang. A ubh-ubx module amplifies p97/vcp’s unfolding power to facilitate protein extraction and degradation. Nature Communications, Nov 2025. URL: https://doi.org/10.1038/s41467-025-65166-4, doi:10.1038/s41467-025-65166-4. This article has 9 citations and is from a highest quality peer-reviewed journal.
(fujisawa2022multipleubxproteins pages 9-10): Ryo Fujisawa, Cristian Polo Rivera, and Karim PM Labib. Multiple ubx proteins reduce the ubiquitin threshold of the mammalian p97-ufd1-npl4 unfoldase. Aug 2022. URL: https://doi.org/10.7554/elife.76763, doi:10.7554/elife.76763. This article has 40 citations and is from a domain leading peer-reviewed journal.
(huo2025aubhubxmodule pages 1-2): Xin-Yu Huo, Di Liu, Rong Zou, Zhao-Peng Li, Yunxia Li, Lifeng Pan, Yaoyang Zhang, and Zai-Rong Zhang. A ubh-ubx module amplifies p97/vcp’s unfolding power to facilitate protein extraction and degradation. Nature Communications, Nov 2025. URL: https://doi.org/10.1038/s41467-025-65166-4, doi:10.1038/s41467-025-65166-4. This article has 9 citations and is from a highest quality peer-reviewed journal.
(koyano2024aaa+atpasechaperone pages 15-16): Fumika Koyano, Koji Yamano, Tomoyuki Hoshina, Hidetaka Kosako, Yukio Fujiki, Keiji Tanaka, and Noriyuki Matsuda. Aaa+ atpase chaperone p97/vcpfaf2 governs basal pexophagy. Nature Communications, Oct 2024. URL: https://doi.org/10.1038/s41467-024-53558-x, doi:10.1038/s41467-024-53558-x. This article has 17 citations and is from a highest quality peer-reviewed journal.
(fujisawa2022multipleubxproteins pages 1-2): Ryo Fujisawa, Cristian Polo Rivera, and Karim PM Labib. Multiple ubx proteins reduce the ubiquitin threshold of the mammalian p97-ufd1-npl4 unfoldase. Aug 2022. URL: https://doi.org/10.7554/elife.76763, doi:10.7554/elife.76763. This article has 40 citations and is from a domain leading peer-reviewed journal.
(fujisawa2022multipleubxproteins pages 14-15): Ryo Fujisawa, Cristian Polo Rivera, and Karim PM Labib. Multiple ubx proteins reduce the ubiquitin threshold of the mammalian p97-ufd1-npl4 unfoldase. Aug 2022. URL: https://doi.org/10.7554/elife.76763, doi:10.7554/elife.76763. This article has 40 citations and is from a domain leading peer-reviewed journal.
(raman2015systematicproteomicsof pages 1-3): Malavika Raman, Mikhail Sergeev, Maija Garnaas, John R. Lydeard, Edward L. Huttlin, Wolfram Goessling, Jagesh V. Shah, and J. Wade Harper. Systematic proteomics of the vcp–ubxd adaptor network identifies a role for ubxn10 in regulating ciliogenesis. Sep 2015. URL: https://doi.org/10.1038/ncb3238, doi:10.1038/ncb3238. This article has 99 citations and is from a highest quality peer-reviewed journal.
(raman2015systematicproteomicsof pages 11-13): Malavika Raman, Mikhail Sergeev, Maija Garnaas, John R. Lydeard, Edward L. Huttlin, Wolfram Goessling, Jagesh V. Shah, and J. Wade Harper. Systematic proteomics of the vcp–ubxd adaptor network identifies a role for ubxn10 in regulating ciliogenesis. Sep 2015. URL: https://doi.org/10.1038/ncb3238, doi:10.1038/ncb3238. This article has 99 citations and is from a highest quality peer-reviewed journal.

Artifacts

Edison artifact artifact-00

Citations

olzmann2013spatialregulationof pages 3-4
huo2025aubhubxmodule pages 10-11
fujisawa2022multipleubxproteins pages 10-11
huo2025aubhubxmodule pages 8-9
huo2025aubhubxmodule pages 1-2
fujisawa2022multipleubxproteins pages 1-2
raman2015systematicproteomicsof pages 4-6
raman2015systematicproteomicsof pages 3-4
fujisawa2022multipleubxproteins pages 7-9
olzmann2013spatialregulationof pages 1-2
olzmann2013spatialregulationof pages 2-3
olzmann2013spatialregulationof pages 5-6
olzmann2013spatialregulationof pages 4-5
fujisawa2022multipleubxproteins pages 9-10
fujisawa2022multipleubxproteins pages 14-15
raman2015systematicproteomicsof pages 1-3
raman2015systematicproteomicsof pages 11-13
log2 KO:WT
https://doi.org/10.1073/pnas.1213738110
https://doi.org/10.1038/s41467-023-36298-2
https://doi.org/10.1038/s41467-024-53558-x
https://doi.org/10.7554/eLife.76763
https://doi.org/10.1038/s41467-025-65166-4
https://doi.org/10.1038/ncb3238
https://doi.org/10.1038/ncb3238,
https://doi.org/10.1038/s41467-024-53558-x,
https://doi.org/10.1038/s41467-023-36298-2,
https://doi.org/10.7554/elife.76763,
https://doi.org/10.1038/s41467-025-65166-4,
https://doi.org/10.1073/pnas.1213738110,

📚 Additional Documentation

Notes

(FAF2-notes.md)

FAF2 (UBXD8/ETEA) review notes

UniProt: Q96CS3 (FAF2_HUMAN), 445 aa. Synonyms: ETEA, UBXD8, UBXN3B, KIAA0887.
Domain architecture: N-terminal UBA domain (12-48), UAS domain (thioredoxin-like, CDD cd02991 UAS_ETEA),
coiled-coil (275-350), C-terminal UBX domain (357-439). The UBX domain binds p97/VCP; the UBA domain binds ubiquitin.

Core biology

FAF2 is a membrane-anchored UBX-domain p97/VCP cofactor. It recruits the VCP segregase to the ER membrane
and to lipid droplets, where it functions both in ERAD substrate extraction/retrotranslocation and in
lipid-droplet / fatty-acid metabolism.

p97/VCP cofactor + UBX/UBA

PMID:18775313
- UBXD8/FAF2 is one of the 13 UBX-domain p97 cofactors; UBX binds p97, UBA binds ubiquitin conjugates.
- UniProt IntAct: VCP NbExp=16; UBAC2 NbExp=8. ComplexPortal CPX-8104 "VCP-NPL4-UFD1-FAF2 AAA ATPase complex".

ERAD

PMID:18711132
- FAF2/UBXD8 is part of the SEL1L/HRD1 ERAD dislocation complex (with SEL1L, OS9, AUP1, UBE2J1).
PMID:24215460
- Implicated in retrotranslocation/dislocation of ERAD substrates (e.g. NHK alpha-1-antitrypsin, PMID:25660456).

Lipid droplet / ATGL regulation

PMID:23297223
PMID:23297223
- FAF2 binds PNPLA2/ATGL (lipase binding), inhibits it (lipase inhibitor activity), promotes CGI-58/ABHD5 dissociation -> inhibits lipolysis, increases LD size.
- UBAC2 interaction restricts ER->LD trafficking of FAF2.
- LD localization independently confirmed by lipid-droplet proteomics PMID:14741744 (HuH7 LD fraction).

Stress granule disassembly

PMID:34739333
- On heat shock, FAF2 binds ubiquitinated G3BP1 and recruits VCP to extract G3BP1 -> stress granule disassembly. FAF2 here acts as a protein-macromolecule adaptor bridging ubiquitinated substrate to VCP.

Annotation assessment summary

Core MF: ubiquitin binding (GO:0043130, UBA), ubiquitin protein ligase binding (GO:0031625), protein-macromolecule adaptor activity (GO:0030674) — these capture the informative p97-cofactor/adaptor function.
Core CC: ER (GO:0005783), lipid droplet (GO:0005811), VCP-NPL4-UFD1 complex (GO:0034098).
Core BP: ERAD pathway (GO:0036503), retrograde protein transport ER to cytosol (GO:0030970), lipid droplet organization (GO:0034389), stress granule disassembly (GO:0035617).
lipase binding (GO:0035473) / lipase inhibitor activity (GO:0055102): specific, experimentally supported (PMID:23297223) — keep.
Reactome extracellular region / azurophil granule lumen (neutrophil degranulation, R-HSA-6798751): bulk proteomic neutrophil-granule annotations; not the core ER/LD function — KEEP_AS_NON_CORE.
The many bare "protein binding" (GO:0005515) IPI annotations: KEEP_AS_NON_CORE (uninformative term), though several map to informative interactions captured by specific terms.
ATPase complex (GO:1904949) NAS / proteasomal protein catabolic process (GO:0010498) IEA: generic parents; keep non-core.

Falcon deep-research findings (incorporated 2026-06)

Systematic VCP-UBXD adaptor interactome (Raman 2015) classifies FAF2/UBXD8 as a membrane-tethered p97 adaptor in ERAD/lipid-droplet homeostasis, recovering interactors AMFR, DERLIN2, AUP1, BAG6, UBAC2 plus the shared UFD1L/NPLOC4 module PMID:26389662. Added as a MEDIUM-relevance reference (PMID:26389662; DOI:10.1038/ncb3238) and id-only to the ERAD-pathway supported_by.
All other major 2022-2025 Falcon papers were ALREADY incorporated in the completed review: Fujisawa 2022 eLife ubiquitin-threshold (PMID:35920641), Ganji 2023 ER-mito contact/lipid-saturation (PMID:36746962), Koyano 2024 basal pexophagy (PMID:39472561), Huo 2025 UBH-UBX module (PMID:41258083), and Olzmann 2013 ATGL/lipid-droplet (PMID:23297223). No new additions needed for these.
Falcon reiterates FAF2's UBH (ubiquitin-binding helix) adjacent to UBX amplifies p97-UFD1L-NPLOC4 unfolding ~2-fold and is sufficient (with UFD1/NPLOC4) to extract membrane proteins from ER and mitochondria; FAF2-KO stabilized CD4 ~10-fold (already captured via PMID:41258083) [DOI:10.1038/s41467-025-65166-4].
Falcon confirms FAF2/p97 suppresses basal pexophagy by extracting ubiquitylated PMP70/PEX16, preventing OPTN recruitment (already captured via PMID:39472561) [DOI:10.1038/s41467-024-53558-x].
No new disease/substrate/localization finding for FAF2 beyond what the completed review already documents; the review was already comprehensive for the recent literature.

Pn Notes

(FAF2-pn-notes.md)

FAF2 PN Consistency Notes

Generated: 2026-06-18
Project: PROTEOSTASIS
Scope: PN consistency rereview against local AIGR review and available deep-research artifacts
UniProt: Q96CS3
AIGR review status: COMPLETE
Review batch: proteostasis-batch-2026-06-11
Batch change status: added

Source Files Checked

AIGR review YAML: present - genes/human/FAF2/FAF2-ai-review.yaml
AIGR review HTML: missing - genes/human/FAF2/FAF2-ai-review.html
Gene notes: present - genes/human/FAF2/FAF2-notes.md
GOA TSV: present - genes/human/FAF2/FAF2-goa.tsv
UniProt record: present - genes/human/FAF2/FAF2-uniprot.txt
PN dossier: projects/PROTEOSTASIS/reports/phase1_dossiers/FAF2.md
PN consistency section: projects/PROTEOSTASIS/reports/phase1_dossiers/_sections/FAF2.md
PN projection report: projects/PROTEOSTASIS/reports/pn_projection/pn_projected_gene_go_summary.tsv
PN mapping audit: projects/PROTEOSTASIS/reports/pn_mapping_audit/current_mapping_scrutiny.tsv

Deep Research Files

genes/human/FAF2/FAF2-deep-research-falcon.md

AIGR Review Snapshot

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/core annotation action counts: ACCEPT: 21; KEEP_AS_NON_CORE: 16; MARK_AS_OVER_ANNOTATED: 2

PN Consistency Summary

Consistency: Excellent. Deep research, review and PN concur on the core: membrane-tethered UBX p97/VCP substrate-recruiting cofactor (UBA binds ubiquitin, UBX docks p97) in SEL1L/HRD1 ERAD dislocation, plus lipid-droplet/ATGL inhibition, stress-granule disassembly, Insig-1/SREBP, and newer pexophagy (PMID:39472561) and ER-mitochondria contact-site (PMID:36746962) roles. The review correctly avoids protein binding as core, using GO:0030674 adaptor, GO:0043130 ubiquitin binding, GO:0034098 VCP-NPL4-UFD1 complex. No contradictions.
PN story / NEW pressure: PN's only NEW projection is GO:0035694 mitochondrial protein catabolic process (verified real; NOT in GOA) from the mitoTAD-pathway row. FAF2/UBXD8 does participate in mitochondrial outer-membrane-associated degradation (mitoTAD) and p97-dependent extraction at mitochondria (PMID:41258083 "extract membrane proteins from the ER and mitochondria"), so this is a DEFENSIBLE (if non-core) ADD — but the review captures FAF2's degradation roles only as ERAD/retrotranslocation, not a mitochondrial-catabolism BP. Conclude: ERAD captured; GO:0035694 a defensible NEW (non-core), mildly broader than the review's ER-centric framing.
Evidence alignment: Good. PN UBX rows cite "18438607 / rev" and "18775313" — PMID:18775313 IS in the review (UBX/p97 cofactor family, HIGH). PMID:18438607 is NOT in the review (likely a UBX-domain review). The review's ERAD/LD/SG evidence (PMID:18711132, 23297223, 25660456, 34739333, + Falcon-added 26389662/35920641/36746962/39472561/41258083) is far richer than the PN rows.
Verdict: Fully consistent; ERAD already captured, GO:0035694 mitochondrial protein catabolic process a defensible (non-core) NEW from the mitoTAD role. PN correctly declines to over-propagate the VCP-adaptor architecture rows. No YAML change strictly required.

Full Consistency Review

UniProt: Q96CS3 (UBXD8/ETEA) · batch: proteostasis-batch-2026-06-11 · review status: COMPLETE (very thorough; UBA-UAS-UBX p97/VCP cofactor — ERAD + lipid-droplet/ATGL + stress-granule + pexophagy + ERMCS)
PN placement: 5 rows — ER proteostasis|...|ERAD|Retrotranslocation channel complex; Mitochondrial proteostasis|Organelle-specific protein degradation|mitoTAD pathway; three UPS rows (UBX domain|VCP adaptors, VCP and associated proteins|adaptors|UBX, Ubiquitin and UBL binding|VCP-associated adaptor). PN-node mapping: ERAD group→GO:0036503 exact (in_goa); Mito-degradation class→GO:0035694 mitochondrial protein catabolic process (new_to_goa); the three UPS adaptor rows all no_mapping/context_only (GO:0019787, GO:0034098, GO:0043335, GO:0140036 as too_broad context only). Projected: GO:0036503 (in GOA), GO:0035694 (new).
Consistency: Excellent. Deep research, review and PN concur on the core: membrane-tethered UBX p97/VCP substrate-recruiting cofactor (UBA binds ubiquitin, UBX docks p97) in SEL1L/HRD1 ERAD dislocation, plus lipid-droplet/ATGL inhibition, stress-granule disassembly, Insig-1/SREBP, and newer pexophagy (PMID:39472561) and ER-mitochondria contact-site (PMID:36746962) roles. The review correctly avoids protein binding as core, using GO:0030674 adaptor, GO:0043130 ubiquitin binding, GO:0034098 VCP-NPL4-UFD1 complex. No contradictions.
PN story / NEW pressure: PN's only NEW projection is GO:0035694 mitochondrial protein catabolic process (verified real; NOT in GOA) from the mitoTAD-pathway row. FAF2/UBXD8 does participate in mitochondrial outer-membrane-associated degradation (mitoTAD) and p97-dependent extraction at mitochondria (PMID:41258083 "extract membrane proteins from the ER and mitochondria"), so this is a DEFENSIBLE (if non-core) ADD — but the review captures FAF2's degradation roles only as ERAD/retrotranslocation, not a mitochondrial-catabolism BP. Conclude: ERAD captured; GO:0035694 a defensible NEW (non-core), mildly broader than the review's ER-centric framing.
Mapping strategy: Correct. All UBX/VCP-adaptor UPS rows are conservatively no_mapping/context_only (avoids the TOMM20/HSPA8-style over-broad propagation of GO:0043335 protein unfolding / GO:0034098 to a mere adaptor). ERAD group→GO:0036503 exact is right. Mito-class→GO:0035694 is the conservative shared target. No node-status change warranted.
Evidence alignment: Good. PN UBX rows cite "18438607 / rev" and "18775313" — PMID:18775313 IS in the review (UBX/p97 cofactor family, HIGH). PMID:18438607 is NOT in the review (likely a UBX-domain review). The review's ERAD/LD/SG evidence (PMID:18711132, 23297223, 25660456, 34739333, + Falcon-added 26389662/35920641/36746962/39472561/41258083) is far richer than the PN rows.
Verdict: Fully consistent; ERAD already captured, GO:0035694 mitochondrial protein catabolic process a defensible (non-core) NEW from the mitoTAD role. PN correctly declines to over-propagate the VCP-adaptor architecture rows. No YAML change strictly required.
Recommended edits: [YAML] (optional) add GO:0035694 mitochondrial protein catabolic process (involved_in; mitoTAD/mito membrane-protein extraction, PMID:41258083) as a non-core BP to mirror the PN projection. [REF] PN-cited PMID:18438607 (UBX row) absent from review — verify whether gene-specific or a UBX-family review.

PN Dossier Context

review_batch: proteostasis-batch-2026-06-11
review_yaml: genes/human/FAF2/FAF2-ai-review.yaml
PN workbook rows: 5

PN row 1: ER proteostasis | Organelle-specific protein degradation | ER associated degradation | Retrotranslocation channel complex

UniProt: Q96CS3
In branches: ER, MI, UPS
PN-node mapping records (path + ancestors):
- [type] ER proteostasis|Organelle-specific protein degradation|ER associated degradation|Retrotranslocation channel complex
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a narrower taxonomy bucket already covered by a curated parent mapping or by gene-level annotations. No additional direct GO mapping is appropriate from this node.
- [group] ER proteostasis|Organelle-specific protein degradation|ER associated degradation
  status=mapped scope=exact GO=[GO:0036503 ERAD pathway]
  rationale: The PN group "ER associated degradation" is a direct lexical and biological match to the GO ERAD pathway term. The additional branch and class context disambiguates the source string from any broader degradation language.
- [class] ER proteostasis|Organelle-specific protein degradation
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a broad PN category rather than a single GO class. The member genes span multiple activities, complexes, or contexts, so direct propagation from this node would overstate the shared biology.
- [branch] ER proteostasis
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a top-level PN branch. This is a systems/taxonomy umbrella, not a direct GO assertion; narrower child curations carry any propagating GO mappings.

PN row 2: Mitochondrial proteostasis | Organelle-specific protein degradation | mitoTAD pathway

UniProt: Q96CS3
In branches: ER, MI, UPS
PN-node mapping records (path + ancestors):
- [group] Mitochondrial proteostasis|Organelle-specific protein degradation|mitoTAD pathway
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a narrower taxonomy bucket that is already covered by a curated parent mapping or by gene-level annotations. No additional direct GO mapping is appropriate from this node.
- [class] Mitochondrial proteostasis|Organelle-specific protein degradation
  status=mapped scope=ok_for_propagation_to_go GO=[GO:0035694 mitochondrial protein catabolic process]
  rationale: This PN class groups mitochondrial protein-degradation pathways. GO mitochondrial protein catabolic process is the conservative shared target.
- [branch] Mitochondrial proteostasis
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a top-level PN branch. This is a systems/taxonomy umbrella, not a direct GO assertion; narrower child curations carry any propagating GO mappings.

PN row 3: Ubiquitin Proteasome System | Ubiquitin and UBL proteins | UBX domain | VCP adaptors | thioredoxin-like, UBA

UniProt: Q96CS3
In branches: ER, MI, UPS
Signature domains: IPR001012
Auxiliary domains: IPR054109, IPR036249
PN references (titles):
- 18438607 / rev
PN-node mapping records (path + ancestors):
- [subtype] Ubiquitin Proteasome System|Ubiquitin and UBL proteins|UBX domain|VCP adaptors|thioredoxin-like, UBA
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a UBX-domain/VCP-adaptor architecture subdivision. The domain label does not by itself establish a direct GO annotation beyond gene-level VCP-adaptor evidence.
- [type] Ubiquitin Proteasome System|Ubiquitin and UBL proteins|UBX domain|VCP adaptors
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a UPS taxonomy container. Its descendants mix catalytic roles, complex membership, binding domains, regulators, adaptors, and substrate-context labels, so a single propagating GO assertion would overstate the shared biology.
- [group] Ubiquitin Proteasome System|Ubiquitin and UBL proteins|UBX domain
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a UBX-domain protein bucket. UBX domain architecture is useful PN taxonomy but not itself a GO propagation target.
- [class] Ubiquitin Proteasome System|Ubiquitin and UBL proteins
  status=context_only scope=too_broad_to_propagate GO=[GO:0019787 ubiquitin-like protein transferase activity]
  rationale: This class groups ubiquitin, UBL modifiers, UBX/UBL-domain proteins, and UBL-containing enzymes. The branch is UPS-relevant but too mixed to propagate as a single GO annotation.
- [branch] Ubiquitin Proteasome System
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.

PN row 4: Ubiquitin Proteasome System | VCP and associated proteins | adaptors | UBX | thioredoxin-like, UBA

UniProt: Q96CS3
In branches: ER, MI, UPS
Signature domains: IPR001012
Auxiliary domains: IPR036249, IPR009060
PN references (titles):
- 18775313
PN-node mapping records (path + ancestors):
- [subtype] Ubiquitin Proteasome System|VCP and associated proteins|adaptors|UBX|thioredoxin-like, UBA
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a VCP-adaptor motif or architecture subdivision. The label is useful taxonomy but too indirect for direct GO propagation without gene-level evidence.
- [type] Ubiquitin Proteasome System|VCP and associated proteins|adaptors|UBX
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a VCP-adaptor motif or architecture subdivision. The label is useful taxonomy but too indirect for direct GO propagation without gene-level evidence.
- [group] Ubiquitin Proteasome System|VCP and associated proteins|adaptors
  status=context_only scope=too_broad_to_propagate GO=[GO:0034098 VCP-NPL4-UFD1 AAA ATPase complex]
  rationale: This PN group records VCP adaptor context, but it mixes UBX, SHP, VIM, VBM, membrane, and other adaptor classes. Direct propagation should come only from narrower complex-specific nodes or gene-level review.
- [class] Ubiquitin Proteasome System|VCP and associated proteins
  status=context_only scope=too_broad_to_propagate GO=[GO:0043335 protein unfolding]
  rationale: This class records the VCP segregase branch context, but descendants include VCP, substrate adaptors, DUBs, E3 ligases, channels, and unrelated associated enzymes. Direct propagation is restricted to narrower nodes.
- [branch] Ubiquitin Proteasome System
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.

PN row 5: Ubiquitin Proteasome System | Ubiquitin and UBL binding | VCP-associated adaptor | with UBX & TRX-like | UBA-like

UniProt: Q96CS3
In branches: ER, MI, UPS
Signature domains: IPR054109
Auxiliary domains: IPR001012, IPR036249
PN-node mapping records (path + ancestors):
- [subtype] Ubiquitin Proteasome System|Ubiquitin and UBL binding|VCP-associated adaptor|with UBX & TRX-like|UBA-like
  status=no_mapping scope= GO=[]
  rationale: Reviewed manually as a UPS source node. No single GO term is appropriate for direct propagation from this PN label without narrower context or gene-level evidence.
- [type] Ubiquitin Proteasome System|Ubiquitin and UBL binding|VCP-associated adaptor|with UBX & TRX-like
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a UPS taxonomy container. Its descendants mix catalytic roles, complex membership, binding domains, regulators, adaptors, and substrate-context labels, so a single propagating GO assertion would overstate the shared biology.
- [group] Ubiquitin Proteasome System|Ubiquitin and UBL binding|VCP-associated adaptor
  status=no_mapping scope= GO=[]
  rationale: Reviewed as a UPS taxonomy container. Its descendants mix catalytic roles, complex membership, binding domains, regulators, adaptors, and substrate-context labels, so a single propagating GO assertion would overstate the shared biology.
- [class] Ubiquitin Proteasome System|Ubiquitin and UBL binding
  status=context_only scope=too_broad_to_propagate GO=[GO:0140036 ubiquitin-modified protein reader activity]
  rationale: This class records ubiquitin/UBL-reader context, but the subtree mixes ubiquitin, SUMO, UBL-domain, domain-architecture, catalytic, signaling, trafficking, and nucleic-acid process buckets. It is useful context, not a safe direct propagation.
- [branch] Ubiquitin Proteasome System
  status=no_mapping scope= GO=[]
  rationale: Reviewed as the top-level UPS branch. It is a project taxonomy umbrella rather than a direct GO assertion; UPS propagation must come from manually curated child nodes.

Projected GO annotations (2)

GO:0036503 ERAD pathway | scope=exact | goa_status=already_in_goa_exact | from=ER proteostasis|Organelle-specific protein degradation|ER associated degradation
GO:0035694 mitochondrial protein catabolic process | scope=ok_for_propagation_to_go | goa_status=new_to_goa | from=Mitochondrial proteostasis|Organelle-specific protein degradation

Note

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

📄 View Raw YAML

id: 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.

FAF2

Gene Description

Existing Annotations Review

Core Functions

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.

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.

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.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Research report: Human FAF2 (UniProt: Q96CS3; aliases UBXD8, ETEA, UBXN3B)—functional annotation

0) Target verification (critical disambiguation)

1) Key concepts and current understanding

1.1 What FAF2 is (core definition)

1.2 Relationship to p97/VCP “segregase/unfoldase” function

1.3 Domains and functional modules (operational view)

2) Subcellular localization and interaction partners

2.1 Localization

2.2 Interaction partners (supported by experimental evidence)

3) Primary biological functions and pathways (evidence-based)

3.1 Lipid droplet biology: regulation of ATGL-mediated lipolysis (real-world metabolic relevance)

3.2 ER–mitochondria contact site regulation via membrane lipid saturation (major 2023 advance)

3.3 Peroxisome quality control: FAF2–p97 suppresses basal pexophagy (major 2024 advance)

4) Mechanistic/biochemical framework: how FAF2 tunes p97 substrate processing

4.1 Lowering the ubiquitin threshold of the mammalian p97-UFD1-NPL4 unfoldase (2022)

4.2 UBH-UBX module and amplified “power output” (2025 mechanistic detail; included for completeness)

5) Current applications and real-world implementations

5.1 Metabolic and lipid storage phenotypes (LD turnover)

5.2 Organelle contact sites as therapeutic-relevant biology (ERMCS and lipid saturation)

5.3 Peroxisome homeostasis and selective autophagy modulation

6) Expert/authoritative analysis (what leading sources emphasize)

7) Evidence map (summary table)

8) References (URLs and publication dates)

Artifacts

Citations

📚 Additional Documentation

Notes

FAF2 (UBXD8/ETEA) review notes

Core biology

p97/VCP cofactor + UBX/UBA

ERAD

Lipid droplet / ATGL regulation

Stress granule disassembly

Annotation assessment summary

Falcon deep-research findings (incorporated 2026-06)

Pn Notes

FAF2 PN Consistency Notes

Source Files Checked

Deep Research Files

AIGR Review Snapshot

PN Consistency Summary

Full Consistency Review

PN Dossier Context

PN row 1: ER proteostasis | Organelle-specific protein degradation | ER associated degradation | Retrotranslocation channel complex

PN row 2: Mitochondrial proteostasis | Organelle-specific protein degradation | mitoTAD pathway

PN row 3: Ubiquitin Proteasome System | Ubiquitin and UBL proteins | UBX domain | VCP adaptors | thioredoxin-like, UBA

PN row 4: Ubiquitin Proteasome System | VCP and associated proteins | adaptors | UBX | thioredoxin-like, UBA

PN row 5: Ubiquitin Proteasome System | Ubiquitin and UBL binding | VCP-associated adaptor | with UBX & TRX-like | UBA-like

Projected GO annotations (2)

Note

📄 View Raw YAML