Affinage

FAF1

FAS-associated factor 1 · UniProt Q9UNN5

Length
650 aa
Mass
74.0 kDa
Annotated
2026-04-28
59 papers in source corpus 29 papers cited in narrative 29 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FAF1 is a multidomain scaffold protein that couples ubiquitin-dependent protein quality control to diverse signaling outputs including apoptosis, NF-κB suppression, innate antiviral immunity, and ferroptosis resistance. Through its C-terminal UBX domain and an adjacent helix, FAF1 docks onto the p97/VCP-Ufd1-Npl4 complex, stabilizing the Ufd1 UT3 domain to accelerate ubiquitin-dependent substrate unfolding; its UBA domain simultaneously engages polyubiquitinated clients, enabling ERAD, chromatin extraction of SUMOylated/ubiquitinated replication factors, and targeted degradation of substrates such as TβRII and KCC2 (PMID:23293021, PMID:34644576, PMID:41790892, PMID:28443643). FAF1 also functions as a Fas death-inducing signaling complex (DISC) component that binds Fas, FADD, and caspase-8 to potentiate extrinsic apoptosis upstream of caspase-8, an interaction competitively inhibited by HSP70 (PMID:12702723, PMID:25935138). Its UAS domain sequesters free polyunsaturated fatty acids into a hydrophobic core to prevent lipid peroxidation and ferroptosis, while its SUMO-interacting motifs target sumoylated substrates such as mineralocorticoid receptor and SAP130 for ubiquitin-dependent degradation; FAF1 activity is regulated by CK2 phosphorylation (Ser289/291), AKT phosphorylation (Ser582), IKKε phosphorylation (Ser556), parkin-mediated ubiquitination, and XIAP-mediated ubiquitination (PMID:35467977, PMID:30935967, PMID:11378439, PMID:28443643, PMID:30472208, PMID:23307929).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1995 High

    The discovery that FAF1 physically associates with the Fas cytoplasmic domain and potentiates Fas-induced apoptosis established FAF1 as a pro-apoptotic factor in Fas signaling, opening the question of its precise position in the pathway.

    Evidence Yeast two-hybrid screen, co-immunoprecipitation in mammalian cells, overexpression apoptosis assay in L cells

    PMID:8524870

    Open questions at the time
    • Mechanism of apoptosis potentiation undefined
    • Endogenous stoichiometry at Fas not determined
    • No domain mapping of FAF1 interaction regions
  2. 2001 High

    Identification of CK2 as the major kinase phosphorylating FAF1 at Ser289/291, and mapping of the UB2 domain as the apoptosis-executing region independent of Fas binding, separated FAF1's pro-apoptotic activity from its Fas-interaction function and identified a first regulatory post-translational modification.

    Evidence In vitro kinase assays with MALDI-MS phosphosite mapping; deletion mutant overexpression with caspase/apoptosis readouts; in vivo phosphorylation and nuclear import assays

    PMID:11378439 PMID:11527403 PMID:12832043

    Open questions at the time
    • Functional consequence of CK2 phosphorylation on apoptosis not demonstrated
    • Endogenous UB2 domain sufficiency not tested
    • Kinase-substrate relationship not validated in loss-of-function setting
  3. 2003 High

    Demonstrating that FAF1 is a bona fide DISC component that interacts with FADD and caspase-8, and that its pro-apoptotic activity is epistatic to caspase-8, placed FAF1 mechanistically upstream in the extrinsic death pathway.

    Evidence Endogenous co-immunoprecipitation of FAF1 with Fas-DISC in Jurkat cells, dominant-negative rescue, epistasis in FADD/caspase-8-deficient cells

    PMID:12702723

    Open questions at the time
    • Structural basis of FAF1–FADD–caspase-8 interaction unknown
    • Relative contribution of FAF1 versus other DISC components not quantified
  4. 2007 High

    The finding that FAF1 suppresses NF-κB by binding IKKβ via its leucine-zipper domain and disrupting IKK complex assembly revealed a second major signaling role, connecting FAF1 to inflammatory pathway regulation.

    Evidence Reciprocal co-immunoprecipitation, IKK kinase assay, FAF1 overexpression and siRNA knockdown with TNF-α/IL-1β/LPS stimulation

    PMID:17684021

    Open questions at the time
    • In vivo relevance not shown with knockout
    • Whether NF-κB suppression is linked to FAF1 pro-apoptotic role unclear
  5. 2011 High

    Crystal structure of the FAF1 UBX domain revealed the FcisP touch-turn motif responsible for p97/VCP binding, providing the first structural framework for understanding FAF1's role as a VCP cofactor.

    Evidence X-ray crystallography at 2.9 Å resolution

    PMID:21414298

    Open questions at the time
    • Full-length FAF1 structure not resolved
    • Structural basis of FAF1–VCP functional coupling not determined
  6. 2013 High

    Biochemical reconstitution showing FAF1 bridges VCP-Npl4-Ufd1 (via UBX) and polyubiquitinated substrates (via UBA) to promote ERAD, plus the discovery that the UAS domain polymerizes upon binding unsaturated fatty acids, expanded FAF1 from a death receptor adaptor to a multifunctional protein quality control and lipid-sensing factor.

    Evidence Co-immunoprecipitation, ERAD functional assays, in vitro polymerization assays with fatty acids, mutagenesis

    PMID:23293021 PMID:23720822

    Open questions at the time
    • ERAD substrate specificity unknown
    • Physiological role of UAS-fatty acid interaction not tested in vivo
  7. 2013 High

    Demonstration that parkin directly ubiquitinates FAF1 for degradation, and that FAF1 accumulation in parkin-deficient contexts drives dopaminergic neurodegeneration, linked FAF1 to Parkinson's disease pathogenesis.

    Evidence In vitro E3 ubiquitination reconstitution, gene-trap mice, MPTP model with Faf1gt/gt mice showing neuroprotection

    PMID:23307929

    Open questions at the time
    • Whether FAF1 accumulation is a major driver versus a contributing factor in PD unclear
    • Human genetic evidence for FAF1 in familial PD absent
  8. 2014 High

    Cryo-EM visualization of the p97-FAF1 complex (3–6 FAF1 per hexamer ring) and identification of the FFAT-VAPB interaction tethering FAF1/p97 to the ER membrane established the structural and spatial organization of FAF1 in ER-associated quality control.

    Evidence Cryo-EM at 17 Å, stoichiometry analysis; yeast two-hybrid and co-immunoprecipitation for VAPB interaction

    PMID:24619421 PMID:24885147

    Open questions at the time
    • High-resolution structure of the full p97-FAF1-substrate complex lacking
    • VAPB-FAF1 interaction not validated in vivo
  9. 2016 High

    Discovery that FAF1 translocates to the nucleus under oxidative stress and directly activates PARP1, triggering parthanatos, and that FAF1/p97 promotes extraction of ubiquitinated/SUMOylated replication factors from stalled forks, broadened FAF1's roles to nuclear stress responses and genome maintenance.

    Evidence Subcellular fractionation with PARP1 activity assay, AAV in vivo overexpression; chromatin fractionation and replication fork dynamics in C. elegans and human cells

    PMID:26842564 PMID:27662363

    Open questions at the time
    • Whether PARP1 activation and replication fork functions involve the same FAF1 pools unknown
    • PARP1 binding interface on FAF1 not mapped
  10. 2017 High

    The finding that FAF1 destabilizes TβRII by recruiting VCP/E3 ligase, and that AKT phosphorylation at Ser582 disrupts this function to enhance TGF-β signaling and metastasis, revealed a growth-factor-regulated switch controlling FAF1-VCP substrate targeting.

    Evidence Co-immunoprecipitation, in vitro AKT kinase assay, FAF1 KO mice, MMTV-PyMT breast cancer model, plasma membrane fractionation

    PMID:28443643

    Open questions at the time
    • Whether Ser582 phosphorylation globally impairs FAF1-VCP function or is substrate-selective unknown
    • Structural mechanism of phosphorylation-induced VCP dissociation not resolved
  11. 2018 High

    Demonstration that FAF1 aggregates compete with TRIM31 for MAVS binding to suppress antiviral signaling, and that IKKε phosphorylation at Ser556 triggers FAF1 de-aggregation and lysosomal clearance, established FAF1 as a signal-regulated checkpoint in innate immunity.

    Evidence Co-immunoprecipitation, in vitro IKKε kinase assay, FAF1 KO mice with viral challenge, aggregate/de-aggregation analysis

    PMID:30472208

    Open questions at the time
    • Structural basis of FAF1 aggregation and how phosphorylation triggers de-aggregation unclear
    • Whether FAF1-MAVS suppression operates in all cell types not tested
  12. 2021 High

    Synthetic lethality between FAF1 and USP7 in both C. elegans and mammalian cells demonstrated that FAF1-mediated extraction and USP7-mediated deubiquitination cooperatively maintain SUMO/ubiquitin balance at replication forks, revealing a druggable vulnerability.

    Evidence Genetic knockdown/knockout, chromatin fractionation, synthetic lethality assays in C. elegans and mammalian cells

    PMID:34644576

    Open questions at the time
    • Clinical relevance of USP7-FAF1 synthetic lethality not validated in cancer models
    • Specific fork substrates jointly regulated not identified
  13. 2022 High

    The discovery that the FAF1 UAS domain assembles a globular structure to sequester free PUFAs and prevent iron-catalyzed lipid peroxidation, with FAF1 deficiency causing ferroptosis sensitivity in cells and hepatic injury in mice, established an unanticipated cytoprotective lipid-buffering function.

    Evidence FAF1 KO cells and mice on PUFA-enriched diet, ferroptosis and lipid peroxidation assays, structural/biochemical analysis

    PMID:35467977

    Open questions at the time
    • Structural details of PUFA sequestration pocket not resolved at atomic level
    • Tissue-specific importance of ferroptosis protection unknown
  14. 2025 High

    Cryo-EM and reconstituted unfolding assays revealed that FAF1's helix-UBX segment tethers Ufd1's UT3 domain to the p97 N-domain, accelerating initiator-ubiquitin unfolding and substrate engagement by the ATPase motor — providing the first mechanistic explanation for how FAF1 stimulates p97-dependent proteolysis.

    Evidence Cryo-EM structure determination, in vitro reconstituted FRET-based unfolding assay, mutagenesis of helix-Ufd1 interface

    PMID:41278724 PMID:41790892

    Open questions at the time
    • Whether helix-Ufd1 tethering is universally required for all FAF1-dependent substrates untested
    • How UAS and UBA domains coordinate with UBX during active unfolding not structurally resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • A full structural model integrating all FAF1 domains (FID, UAS, UBA, UBX, SIMs, FFAT) in the context of the p97 hexamer and membrane-associated substrates is needed to explain how a single adaptor coordinates ERAD, replication fork processing, receptor turnover, and lipid buffering.
  • No full-length FAF1 structure available
  • Substrate selectivity determinants across different FAF1-p97 functions unresolved
  • How multiple post-translational modifications (CK2, AKT, IKKε, parkin, XIAP) are integrated to regulate FAF1 in a context-dependent manner is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 7 GO:0008289 lipid binding 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005829 cytosol 3 GO:0005634 nucleus 2 GO:0005694 chromosome 2 GO:0005783 endoplasmic reticulum 2 GO:0005886 plasma membrane 1
Pathway
R-HSA-392499 Metabolism of proteins 5 R-HSA-5357801 Programmed Cell Death 5 R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 3 R-HSA-69306 DNA Replication 2 R-HSA-73894 DNA Repair 2
Partners
CASP8FADDFASIKBKBMAVSPARP1VAPBVCP
Complex memberships
Fas-DISCp97/VCP-Ufd1-Npl4

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 FAF1 was identified as a protein that specifically interacts with the cytoplasmic domain of wild-type Fas (but not the lprcg-mutated Fas) via yeast two-hybrid screen, and this interaction was confirmed in mammalian cells; transient expression of FAF1 in L cells potentiated Fas-induced apoptosis. Yeast two-hybrid screen, co-immunoprecipitation in mammalian cells, transient overexpression apoptosis assay Proceedings of the National Academy of Sciences of the United States of America High 8524870
1999 Human FAF1 (hFAF1) N-terminal region (aa 1–201), containing an upstream ubiquitin homology domain, binds to the death domain of Fas but not the lprcg mutant; GST-hFAF1 fusion protein pulled down in vitro translated Fas. GST pulldown, in vitro translation, cDNA cloning and characterization Biochemical and biophysical research communications Medium 10462485
2001 Overexpression of hFAF1 in BOSC23 cells induces apoptosis (membrane blebbing, nuclear condensation, phosphatidylserine exposure, caspase-3 activation); the apoptotic potential requires the downstream ubiquitin homologous domain (UB2) and adjacent nuclear localization signal, but not the Fas-binding domain. Transient overexpression, flow cytometry, caspase activity assays, deletion mutant analysis Biochemical and biophysical research communications Medium 11527403
2001 CK2 phosphorylates FAF1 at Ser289 and Ser291 in vitro and is the major cellular kinase responsible for FAF1 phosphorylation; CK2 holoenzyme and isolated catalytic alpha subunit both phosphorylate FAF1. In vitro kinase assay with recombinant CK2, MALDI-MS phosphosite identification, tissue extract kinase assays The international journal of biochemistry & cell biology High 11378439
2003 FAF1 is a component of the Fas-DISC: it interacts with FADD and caspase-8 in vivo and in vitro; the death effector domains (DEDs) of caspase-8 and FADD interact with the aa 181–381 region of FAF1. Endogenous FAF1 co-immunoprecipitates with Fas-DISC components in Jurkat cells. A dominant-negative FAF1 deletion mutant lacking the N-terminus protected cells from Fas-induced apoptosis. FAF1-mediated cell death was suppressed in FADD- and caspase-8-deficient cells, placing FAF1 upstream of caspase-8. Co-immunoprecipitation, in vitro binding, confocal microscopy, overexpression/dominant-negative analysis, genetic epistasis with FADD/caspase-8-deficient cells The Journal of biological chemistry High 12702723
2003 CK2 phosphorylates FAF1 at Ser289/291 in vivo (at least one site confirmed); phosphorylation-deficient FAF1 mutant shows delayed nuclear import compared to wild-type, but FAF1 phosphorylation status does not affect its ability to potentiate Fas-induced apoptosis. In vivo phosphorylation analysis, nuclear import assay with phosphorylation-deficient mutant FEBS letters Medium 12832043
2004 FAF1 selectively coactivates mineralocorticoid receptor (MR)-mediated transcription but does not transactivate glucocorticoid receptor (GR) in a mouse hippocampal cell line, suggesting a role as a receptor-specific transcriptional coregulator. Yeast two-hybrid screening, co-expression in hippocampal cell line, transient transactivation reporter assays (MMTV-Luc) Molecular pharmacology Medium 14978255
2007 FAF1 inhibits NF-κB activation by interacting with IKKβ (via its leucine-zipper domain) in response to TNF-α, IL-1β, and LPS stimuli, disrupting IKK heterocomplex (IKKα/β) and homocomplex formation and attenuating IKKγ recruitment to IKKβ. FAF1 overexpression reduced IKKβ activity; FAF1 depletion increased it. Co-immunoprecipitation, kinase activity assays, FAF1 overexpression and siRNA knockdown The Journal of biological chemistry High 17684021
2011 Crystal structure of human FAF1 UBX domain determined at 2.9 Å resolution; reveals a conserved FcisP touch-turn motif in the p97/VCP-binding region, providing structural basis for FAF1-p97/VCP interaction. X-ray crystallography Biochemical and biophysical research communications High 21414298
2013 FAF1 promotes ERAD by forming a complex with VCP-Npl4-Ufd1 via its UBX domain and binding polyubiquitinated proteins via its UBA domain; VCP associates only when complexed with Npl4-Ufd1. VCP association to UBX domain regulates ubiquitin binding to UBA domain without direct UBA-UBX interaction. Co-immunoprecipitation, structural and biochemical analysis, ERAD functional assays The Journal of biological chemistry High 23293021
2013 FAF1 UAS domain polymerizes upon interaction with long-chain unsaturated fatty acids, analogous to the UAS domain of Ubxd8, suggesting the UAS domain is a conserved motif for interaction with long-chain unsaturated fatty acids. In vitro polymerization/oligomerization assays with fatty acid treatment, mutagenesis Journal of lipid research Medium 23720822
2013 Parkin acts as an E3 ubiquitin ligase to directly ubiquitinate FAF1 both in vitro and in cells; PD-linked parkin mutations disrupt FAF1 ubiquitination and degradation, causing elevated FAF1 expression. FAF1 accumulation in the substantia nigra pars compacta of MPTP-treated mice contributes to dopaminergic neurodegeneration, which is attenuated in Faf1gt/gt mice. In vitro ubiquitination assay, cellular ubiquitination assay, gene trap mutant mice, MPTP PD model, locomotor/cell death assays Human molecular genetics High 23307929
2014 p97/VCP-FAF1 complex structure resolved by cryo-EM at 17 Å; FAF1 binds p97 stably in a stoichiometry of 3 to 6 with FAF1 positioned above the p97 ring. Cryo-EM structural analysis, biochemical binding stoichiometry analysis The Journal of biological chemistry High 24619421
2014 FAF1 contains a non-canonical FFAT motif that mediates direct interaction with the MSP domain of VAPB, thereby linking FAF1/p97 to VAPB at the ER membrane. FAF1 mediates VAPB interaction with ubiquitinated proteins and p97, and FAF1 knockdown reduces VAPB association with ubiquitinated proteins. Yeast two-hybrid, co-immunoprecipitation, siRNA knockdown, proteasome inhibition assays BMC biology Medium 24885147
2014 FAF1 interacts with CD40 cytoplasmic tail (via the TRAF6-binding domain) through FAF1's N-terminal FID domain; CD40 ligation induces FAF1 expression in an NF-κB-dependent manner, and FAF1 suppresses CD40-induced NF-κB activation via negative feedback. Yeast two-hybrid, in vitro and in vivo co-immunoprecipitation, knockdown and overexpression NF-κB reporter assays Cell death & disease Medium 24810049
2015 HSP70 competitively binds FAF1 via its 1–120 aa N-terminal sequence, inhibiting FAF1-FAS interaction and suppressing Fas signaling pathway activation and apoptosis in cardiomyocytes; an N-terminal deletion mutant of HSP70 (HSP70-ΔN) lost the ability to bind FAF1 and protect against apoptosis. Co-immunoprecipitation, transfection with deletion mutants, caspase-8 activity assays, apoptosis assays Cell stress & chaperones Medium 25935138
2016 FAF1 translocates from cytoplasm to nucleus upon oxidative stress and promotes catalytic activation of PARP1 via direct physical interaction; FAF1 depletion prevented PARP1-linked downstream events (energetic collapse, mitochondrial depolarization, AIF nuclear translocation) and necrosis. FAF1 overexpression in mouse ventral midbrain promoted PARP1 activation and dopaminergic neurodegeneration in MPTP model. Immunoprecipitation, subcellular fractionation, live imaging, siRNA knockdown, AAV-mediated overexpression in mouse MPTP model, PARP1 activity assay Cell death and differentiation High 27662363
2016 UBXN-3/FAF1 promotes CDC-48/p97-dependent turnover and disassembly of DNA replication factor complexes by binding the licensing factor CDT-1 and other ubiquitylated proteins on chromatin; FAF1 inactivation stabilizes CDT-1 and CDC-45/GINS on chromatin, causing replication fork defects and genome instability in C. elegans and human cells. Genetic knockdown, chromatin fractionation, epistasis analysis, replication fork dynamics assay (C. elegans and human cells) Nature communications High 26842564
2017 FAF1 destabilizes TGF-β type II receptor (TβRII) at the cell surface by recruiting the VCP/E3 ligase complex. Activated AKT directly phosphorylates FAF1 at Ser582, disrupting the FAF1-VCP complex and reducing FAF1 at the plasma membrane, resulting in TβRII accumulation and enhanced TGF-β signaling and breast cancer metastasis. Co-immunoprecipitation, in vitro kinase assay, FAF1 knockout mice, in vitro/in vivo EMT and metastasis models, MMTV-PyMT transgenic mice, plasma membrane fractionation Nature communications High 28443643
2017 FAF1 interacts with XIAP; XIAP promotes ubiquitination of FAF1 and blocks FAF1-mediated cell death by interfering with the caspase cascade. FAF1 attenuates XIAP-mediated NF-κB activation. The specific interaction domains were mapped. Co-immunoprecipitation, domain mapping, ubiquitination assay, cell death assay, NF-κB reporter assay Biochimica et biophysica acta. Molecular cell research Medium 28414080
2018 FAF1 forms aggregates that negatively regulate MAVS by competing with the E3 ligase TRIM31 for MAVS binding, thereby antagonizing K63-linked poly-ubiquitination and aggregation of MAVS. Upon viral infection, IKKε directly phosphorylates FAF1 at Ser556, triggering FAF1 de-aggregation and lysosomal degradation, relieving FAF1-dependent suppression of MAVS. FAF1 knockout mice show enhanced antiviral innate signaling. Co-immunoprecipitation, in vitro kinase assay, FAF1 KO mice, ubiquitination assay, aggregate/de-aggregation analysis Cell host & microbe High 30472208
2018 FAF1 mediates necrosis via JNK1 activation upon ischemic insult; FAF1 functions upstream of JNK1, leading to mitochondrial dysfunction and necrotic cell death. Conditional FAF1 knockout attenuated JNK1 activation and protected retinal ganglion cells from IOP-induced death. Co-immunoprecipitation, Western blotting, flow cytometry, conditional retinal FAF1 KO mice, retinal ischemia model Cell communication and signaling Medium 30200976
2019 FAF1 contains two SUMO-interacting motifs (SIMs) that mediate interaction with sumoylated mineralocorticoid receptor (MR) and repress aldosterone-activated MR transactivation in a SIM-dependent manner; FAF1/SIM promotes MR polyubiquitination and degradation and inhibits MR N/C interactions. SIM mutagenesis, co-immunoprecipitation, MR transactivation reporter assays, ubiquitination assay, siRNA knockdown Biochimica et biophysica acta. Molecular cell research Medium 30935967
2021 VCP cofactor FAF1 facilitates the extraction of SUMOylated and ubiquitylated proteins that accumulate at stalled DNA replication forks; USP7 and FAF1 inactivation is synthetically lethal in C. elegans and mammalian cells, indicating functional cooperation in maintaining the SUMO/ubiquitin balance at replication forks. Genetic knockdown/knockout, chromatin fractionation, synthetic lethality screen in C. elegans and mammalian cells, drug synergy assays Cell reports High 34644576
2022 FAF1 assembles a globular structure via its UAS domain that sequesters free polyunsaturated fatty acids (PUFAs) into a hydrophobic core, preventing PUFA peroxidation by limiting iron access, thereby blocking ferroptosis. FAF1-deficient cells became sensitive to PUFA-induced ferroptosis, and FAF1-deficient mice developed hepatic injury on a PUFA-enriched diet. FAF1 KO cells and mice, ferroptosis assays, lipid peroxidation assays, structural/biochemical analysis of FAF1-PUFA interaction Proceedings of the National Academy of Sciences of the United States of America High 35467977
2024 FAF1 recruitment to VCP is required for ubiquitin-proteasomal degradation of KCC2: FAF1 knockout abolished propofol-induced VCP-KCC2 interaction and blocked KCC2 degradation in neuronal cells; VCP inhibition in the VPM in vivo prevented KCC2 degradation and enhanced anesthesia duration. Co-immunoprecipitation, siRNA/CRISPR KO, VCP inhibitor DBeQ, in vivo stereotaxic VCP inhibition/KO in mouse VPM, KCC2 expression measurement Proceedings of the National Academy of Sciences of the United States of America Medium 39793039
2024 Sumoylation of SAP130 at Lys794, Lys878, and Lys932 is required for its interaction with FAF1 (via FAF1 SIMs); FAF1 promotes polyubiquitination and degradation of SAP130 in a sumoylation-dependent manner and mitigates SAP130's transcriptional repressor activity. In vitro and in vivo sumoylation assays, Co-immunoprecipitation, mutagenesis, ubiquitination assay, transcriptional reporter assays BMC molecular and cell biology Medium 38172660
2025 FAF1 accelerates p97-mediated ubiquitin-dependent protein unfolding by promoting unfolding of an initiator ubiquitin and its engagement by the ATPase motor; FAF1's p97-bound C-terminal UBX domain anchors a long helix that braces the UT3 domain of Ufd1, stabilizing the Ufd1-Npl4 cofactor for ubiquitin unfolding. Mutations disrupting helix-Ufd1 interaction reduced this stimulation. In vitro reconstituted unfolding system with human components, FRET-based assay, mutagenesis, cryo-EM structure determination bioRxivpreprint High 41278724
2026 FAF1 (and paralogs FAF2, UBXN7) stimulates proteasomal degradation by boosting p97-Ufd1-Npl4-mediated substrate unfolding via a helix-UBX segment that tethers the UT3 ubiquitin-binding module of Ufd1 to the p97 N-domain; mutations in the helix-Ufd1 interface reduced stimulation of degradation. Reconstituted in vitro p97-mediated unfolding coupled to proteasomal degradation, mutagenesis, biochemical assays Science advances High 41790892

Source papers

Stage 0 corpus · 59 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 miR-24 regulates apoptosis by targeting the open reading frame (ORF) region of FAF1 in cancer cells. PloS one 197 20195546
1995 A Fas-associated protein factor, FAF1, potentiates Fas-mediated apoptosis. Proceedings of the National Academy of Sciences of the United States of America 167 8524870
2003 Fas-associated factor 1, FAF1, is a member of Fas death-inducing signaling complex. The Journal of biological chemistry 89 12702723
2009 FAS-associated factor 1 (FAF1): diverse functions and implications for oncogenesis. Cell cycle (Georgetown, Tex.) 80 19597341
2019 Ammonia regulates chicken tracheal cell necroptosis via the LncRNA-107053293/MiR-148a-3p/FAF1 axis. Journal of hazardous materials 77 31791863
2004 DAXX, FLASH, and FAF-1 modulate mineralocorticoid and glucocorticoid receptor-mediated transcription in hippocampal cells--toward a basis for the opposite actions elicited by two nuclear receptors? Molecular pharmacology 72 14978255
2021 6-Gingerol protects against cerebral ischemia/reperfusion injury by inhibiting NLRP3 inflammasome and apoptosis via TRPV1 / FAF1 complex dissociation-mediated autophagy. International immunopharmacology 58 34537481
2013 Complex of Fas-associated factor 1 (FAF1) with valosin-containing protein (VCP)-Npl4-Ufd1 and polyubiquitinated proteins promotes endoplasmic reticulum-associated degradation (ERAD). The Journal of biological chemistry 53 23293021
2011 FAF1, a gene that is disrupted in cleft palate and has conserved function in zebrafish. American journal of human genetics 51 21295280
2007 FAF1 suppresses IkappaB kinase (IKK) activation by disrupting the IKK complex assembly. The Journal of biological chemistry 51 17684021
2018 FAF1 Regulates Antiviral Immunity by Inhibiting MAVS but Is Antagonized by Phosphorylation upon Viral Infection. Cell host & microbe 47 30472208
1999 Identification and characterization of human Fas associated factor 1, hFAF1. Biochemical and biophysical research communications 46 10462485
2017 FAF1 phosphorylation by AKT accumulates TGF-β type II receptor and drives breast cancer metastasis. Nature communications 43 28443643
2001 Apoptosis induced by human Fas-associated factor 1, hFAF1, requires its ubiquitin homologous domain, but not the Fas-binding domain. Biochemical and biophysical research communications 42 11527403
2013 Accumulation of the parkin substrate, FAF1, plays a key role in the dopaminergic neurodegeneration. Human molecular genetics 39 23307929
2013 UAS domain of Ubxd8 and FAF1 polymerizes upon interaction with long-chain unsaturated fatty acids. Journal of lipid research 38 23720822
2016 Chromatin-associated degradation is defined by UBXN-3/FAF1 to safeguard DNA replication fork progression. Nature communications 37 26842564
2022 FAF1 blocks ferroptosis by inhibiting peroxidation of polyunsaturated fatty acids. Proceedings of the National Academy of Sciences of the United States of America 33 35467977
2016 FAF1 mediates regulated necrosis through PARP1 activation upon oxidative stress leading to dopaminergic neurodegeneration. Cell death and differentiation 33 27662363
2014 VAPB/ALS8 interacts with FFAT-like proteins including the p97 cofactor FAF1 and the ASNA1 ATPase. BMC biology 30 24885147
2015 HSP70 inhibits stress-induced cardiomyocyte apoptosis by competitively binding to FAF1. Cell stress & chaperones 27 25935138
2001 Phosphorylation of the Fas associated factor FAF1 by protein kinase CK2 and identification of serines 289 and 291 as the in vitro phosphorylation sites. The international journal of biochemistry & cell biology 27 11378439
2022 Circ_0004354 might compete with circ_0040039 to induce NPCs death and inflammatory response by targeting miR-345-3p-FAF1/TP73 axis in intervertebral disc degeneration. Oxidative medicine and cellular longevity 26 35039758
2014 The p97-FAF1 protein complex reveals a common mode of p97 adaptor binding. The Journal of biological chemistry 25 24619421
2020 MiR-26a-5p Serves as an Oncogenic MicroRNA in Non-Small Cell Lung Cancer by Targeting FAF1. Cancer management and research 24 32848467
2017 Long non‑coding RNA FAF1 promotes intervertebral disc degeneration by targeting the Erk signaling pathway. Molecular medicine reports 24 29257270
2008 Fas-associated factor (FAF1) is required for the early cleavage-stages of mouse embryo. Molecular human reproduction 24 18303090
2020 Germline Mutations in FAF1 Are Associated With Hereditary Colorectal Cancer. Gastroenterology 22 32179092
2014 Interaction between ribosome assembly factors Krr1 and Faf1 is essential for formation of small ribosomal subunit in yeast. The Journal of biological chemistry 21 24990943
2012 KRT8, FAF1 and PTH1R gene polymorphisms are associated with leg weakness traits in pigs. Molecular biology reports 18 23196707
2021 USP7 and VCPFAF1 define the SUMO/Ubiquitin landscape at the DNA replication fork. Cell reports 16 34644576
2019 Identification of two independent SUMO-interacting motifs in Fas-associated factor 1 (FAF1): Implications for mineralocorticoid receptor (MR)-mediated transcriptional regulation. Biochimica et biophysica acta. Molecular cell research 16 30935967
2003 Protein kinase CK2 phosphorylates the Fas-associated factor FAF1 in vivo and influences its transport into the nucleus. FEBS letters 16 12832043
2011 Crystal structure of human FAF1 UBX domain reveals a novel FcisP touch-turn motif in p97/VCP-binding region. Biochemical and biophysical research communications 14 21414298
2008 Faf1 is expressed during neurodevelopment and is involved in Apaf1-dependent caspase-3 activation in proneural cells. Cellular and molecular life sciences : CMLS 13 18480964
2017 NLRP2 and FAF1 deficiency blocks early embryogenesis in the mouse. Reproduction (Cambridge, England) 12 28630100
2015 Identification of pathways related to FAF1/H. pylori-associated gastric carcinogenesis through an integrated approach based on iTRAQ quantification and literature review. Journal of proteomics 12 26597625
2020 A novel function of FAF1, which induces dopaminergic neuronal death through cell-to-cell transmission. Cell communication and signaling : CCS 11 32831099
2014 Fas-associated factor (Faf1) is a novel CD40 interactor that regulates CD40-induced NF-κB activation via a negative feedback loop. Cell death & disease 11 24810049
2012 Reduced FAF1 Expression and Helicobacter Infection: Correlations with Clinicopathological Features in Gastric Cancer. Gastroenterology research and practice 9 23304123
2021 FAF1 downregulation by Toxoplasma gondii enables host IRF3 mobilization and promotes parasite growth. Journal of cellular and molecular medicine 7 34464509
2018 FAF1 mediates necrosis through JNK1-mediated mitochondrial dysfunction leading to retinal degeneration in the ganglion cell layer upon ischemic insult. Cell communication and signaling : CCS 7 30200976
2017 XIAP Interacts with and Regulates the Activity of FAF1. Biochimica et biophysica acta. Molecular cell research 6 28414080
2015 Molecular Analysis of a Recurrent Sarcoma Identifies a Mutation in FAF1. Sarcoma 6 25861239
2009 Crystallization and preliminary X-ray crystallographic analysis of the N domain of p97/VCP in complex with the UBX domain of FAF1. Acta crystallographica. Section F, Structural biology and crystallization communications 6 20057067
2024 Inhibition of circ_0073932 attenuates myocardial ischemia‒reperfusion injury via miR-493-3p/FAF1/JNK. In vitro cellular & developmental biology. Animal 5 38578382
2022 Pharmacological Intervention Targeting FAF1 Restores Autophagic Flux for α-Synuclein Degradation in the Brain of a Parkinson's Disease Mouse Model. ACS chemical neuroscience 5 35230076
2000 Human Fas associated factor 1, hFAF1, gene maps to chromosome band 1p32. Molecules and cells 4 11101154
2021 Association analysis of SNPs in GRHL3, FAF1, and KCNJ2 with NSCPO sub-phenotypes in Han Chinese. Oral diseases 3 34255421
2016 Design and synthesis of fluorescent and biotin tagged probes for the study of molecular actions of FAF1 inhibitor. Bioorganic & medicinal chemistry letters 3 26810261
2025 Extracellular GMFB activates the non-canonical FAS-FAF1 pathway to induce lysosomal dysfunction in early diabetic retinopathy. International journal of biological macromolecules 2 40490177
2024 VCP controls KCC2 degradation through FAF1 recruitment and accelerates emergence from anesthesia. Proceedings of the National Academy of Sciences of the United States of America 2 39793039
2010 Crystallization and preliminary X-ray crystallographic analysis of human FAF1 UBX domain. Acta crystallographica. Section F, Structural biology and crystallization communications 2 20124726
2025 Evaluation of the role of circular RNA (circ-FAF1) as a diagnostic biomarker for breast cancer in a cohort of Egyptian breast cancer patients. Molecular biology reports 1 39881045
2024 Sumoylation of SAP130 regulates its interaction with FAF1 as well as its protein stability and transcriptional repressor function. BMC molecular and cell biology 1 38172660
2011 Crystallization and preliminary X-ray crystallographic analysis of the hexameric human p97/VCP ND1 fragment in complex with the UBX domain of human FAF1. Acta crystallographica. Section F, Structural biology and crystallization communications 1 22102026
2026 The accessory adapters FAF1, FAF2, and UBXN7 accelerate proteasomal degradation by increasing prior p97-mediated substrate unfolding. Science advances 0 41790892
2025 Faf1 accelerates p97-mediated protein unfolding by promoting ubiquitin engagement. bioRxiv : the preprint server for biology 0 41278724
2023 FAF1 Gene Involvement in Pituitary Corticotroph Tumors. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 0 38065537