Affinage

XAF1

XIAP-associated factor 1 · UniProt Q6GPH4

Length
301 aa
Mass
34.6 kDa
Annotated
2026-06-11
100 papers in source corpus 35 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

XAF1 is a stress-inducible, zinc-finger tumor suppressor that integrates apoptotic, cell-cycle, ER-stress, autophagy, and innate-immune programs by acting as a multivalent scaffold and regulator of protein ubiquitination (PMID:11175744, PMID:25313037, PMID:35902580). It was first defined as a direct XIAP-binding antagonist that neutralizes XIAP's caspase-inhibitory and anti-apoptotic activity and drives XIAP redistribution from cytosol to nucleus (PMID:11175744, PMID:11087668), with the interaction mapped to a C-terminal XIAP-RING-binding domain (PMID:22811387); beyond inhibition, XAF1 converts the XIAP-XAF1 complex into an active E3 ligase that ubiquitinates and degrades Survivin and, via a CUL4A/DDB1 complex, Chk1 (PMID:17613533, PMID:25535897). Its discrete zinc-finger domains confer distinct interactions that reprogram ubiquitin-dependent stability of key regulators: XAF1 binds p53 (ZF6) to block MDM2-mediated ubiquitination and engages Siah2 and ZNF313 (ZF5/ZF7) to stabilize p53 and activate p21 turnover (PMID:25313037), stabilizes IRF-1 by blocking CHIP-mediated degradation while serving as its transcriptional coactivator (PMID:30042418), and uses ZF6/ZF7 to drive ZNF313-mediated K48 degradation of TRIM28, thereby relieving TRIM28-dependent p53 ubiquitination (PMID:39532800). XAF1 also assembles a BRCA1 destruction complex to degrade ERα via ZF4 and ZF5/6 (PMID:35430604), destabilizes GRP78 and CHIP during ER stress (PMID:35902580), blocks K63-linked ubiquitination and activation of AKT1 (PMID:37384528), and acts as a VCP adaptor stabilizing RNF114 to degrade JUP and promote colorectal metastasis (PMID:38095639). In innate immunity, MAVS- and TBK1-dependent phosphorylation at Ser252 drives nuclear XAF1, where it de-SUMOylates TRIM28 via its PHD domain to open antiviral chromatin and stabilizes IRF1, while the XAF1-XIAP axis restrains the CUL3-KLHL22-IRF7 module to prevent type-I IFN hyperproduction (PMID:37595039, PMID:35972291, PMID:36394357). XAF1 transcription is tightly controlled, induced by STAT1/ISRE and IRF-1/IRF-E and repressed by HSF1 and p53 (PMID:18035482, PMID:16530516, PMID:16303760, PMID:21678496). XAF1 is itself a degradation target of TRIM28 and TRIM47 (PMID:39532800, PMID:39834862). Functional consequences established in vivo include regulation of apoptosis and metabolic insulin signaling, osteoclastogenesis, and antiviral defense (PMID:37384528, PMID:38957269, PMID:36394357).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2001 High

    Established XAF1's founding molecular identity: a direct XIAP-interacting protein that antagonizes XIAP's anti-caspase and anti-apoptotic function, answering what XAF1 does at the protein level.

    Evidence Yeast two-hybrid, co-IP, in vitro caspase/apoptosis assays, subcellular fractionation in cells

    PMID:11087668 PMID:11175744

    Open questions at the time
    • Did not map the interaction interface
    • Mechanism of XIAP nuclear redistribution unresolved
  2. 2007 High

    Showed XAF1 not only inhibits but reprograms XIAP into an active E3 ligase that degrades Survivin, expanding XAF1 from antagonist to a switch that redirects IAP catalytic activity.

    Evidence Co-IP, MG132 rescue, XIAP RING mutant, siRNA and XAF1-/- clones, endogenous ternary complex IP

    PMID:17613533

    Open questions at the time
    • IAP binding selectivity rules not defined
    • How XAF1 selects Survivin as substrate unclear
  3. 2009 Medium

    Linked XAF1 to cell-cycle control by showing it activates Chk1 to enforce G2/M arrest, broadening its role beyond apoptosis.

    Evidence Co-IP, kinase assay, cell-cycle synchronization, Chk1 siRNA epistasis, flow cytometry

    PMID:19628579

    Open questions at the time
    • Single lab
    • Reconciliation with later XAF1-XIAP-mediated Chk1 degradation not addressed
  4. 2012 High

    Defined XAF1's domain architecture and mapped a C-terminal XIAP RING-binding domain, providing the structural basis for XIAP engagement and reciprocal XAF1 ubiquitination.

    Evidence Limited proteolysis, NMR interaction mapping, in vitro ubiquitination assay

    PMID:22811387

    Open questions at the time
    • Full-length structure not solved
    • Functions of individual zinc fingers not yet assigned
  5. 2014 High

    Resolved how individual zinc fingers confer substrate-specific control of p53 stability and activity, establishing XAF1 as a domain-encoded ubiquitination regulator.

    Evidence Co-IP, domain-deletion mutants, in vitro ubiquitination, reporters, xenografts (p53/Siah2/ZNF313); CUL4A/DDB1 siRNA epistasis for Chk1 degradation

    PMID:25313037 PMID:25535897

    Open questions at the time
    • Stoichiometry of multi-partner complexes unknown
    • Context determining Chk1 stabilization vs degradation undefined
  6. 2018 High

    Established a XAF1-IRF-1 positive feedback loop in which XAF1 blocks CHIP-mediated IRF-1 degradation and coactivates IRF-1 transcription, repressed by oncogenic Ras/ERK.

    Evidence Co-IP, domain mutagenesis, ubiquitination assays, ChIP, reporters, IRF-1 knockdown epistasis, xenografts

    PMID:30042418

    Open questions at the time
    • Direct coactivator mechanism on chromatin not detailed
  7. 2022 High

    Demonstrated XAF1's reach across ER stress, estrogen signaling, and antiviral type-I IFN control, showing it tunes diverse substrate degradation programs and prevents IFN hyperproduction.

    Evidence Co-IP, chain-specific ubiquitination assays, domain mutants, genetic KO/transgenic mice, viral infection and xenograft models (GRP78/CHIP, ERα/BRCA1, IRF1, CUL3-KLHL22-IRF7)

    PMID:35430604 PMID:35902580 PMID:35972291 PMID:36394357

    Open questions at the time
    • How a single protein coordinates these distinct complexes in different compartments is unresolved
  8. 2023 High

    Revealed signal-induced nuclear and metabolic functions: TBK1 phosphorylation drives nuclear XAF1 to de-SUMOylate TRIM28 and open antiviral chromatin, XAF1 blocks K63-ubiquitination of AKT1, and acts as a VCP adaptor controlling metastasis.

    Evidence Phospho-site mapping, de-SUMOylation and ATAC-type assays, K63/K48 ubiquitination assays, VCP adaptor co-IP, multiple KO mouse and xenograft models (TRIM28/IRF1, AKT1/FOXO1, RNF114/JUP)

    PMID:37384528 PMID:37595039 PMID:38095639

    Open questions at the time
    • Catalytic basis of XAF1 de-SUMOylation activity not characterized
    • How cytosolic vs nuclear pools are partitioned unclear
  9. 2024 High

    Extended XAF1 to non-cell-autonomous and tissue-specific roles, including secretion that activates Lck-ERK in T cells, ZNF313-driven TRIM28 degradation, and control of osteoclast apoptosis.

    Evidence ZF-domain mutants, secretion/endocytosis assays, Lck phosphorylation, K48 ubiquitination, global/chimeric Xaf1 KO mice (secreted XAF1, TRIM28, osteoclast XIAP-caspase)

    PMID:38957269 PMID:39532800 PMID:39615106

    Open questions at the time
    • Mechanism of unconventional secretion incompletely defined
    • Physiological scope of secreted XAF1 signaling unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How XAF1's seven zinc fingers are dynamically partitioned among its many partners and compartments to specify which program (apoptosis, IFN, ER stress, metabolism) is engaged in a given stress context remains unresolved.
  • No integrated structural model of multi-partner selection
  • Quantitative rules governing compartment-specific function lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0098772 molecular function regulator activity 4 GO:0060090 molecular adaptor activity 2 GO:0140110 transcription regulator activity 2
Localization
GO:0005634 nucleus 2 GO:0005739 mitochondrion 2 GO:0005829 cytosol 1
Pathway
R-HSA-168256 Immune System 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-162582 Signal Transduction 2 R-HSA-1640170 Cell Cycle 2 R-HSA-8953897 Cellular responses to stimuli 2 R-HSA-9612973 Autophagy 2
Partners
AKT1ESR1IRF1TP53TRIM28VCPXIAPZNF313
Complex memberships
BRCA1 destruction complexXIAP-XAF1 complexZNF313-mediated destruction complex

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 XAF1 binds directly to XIAP and antagonizes XIAP's anti-caspase activity and anti-apoptotic function. XAF1 expression triggers redistribution of XIAP from the cytosol to the nucleus. Yeast two-hybrid screening, co-immunoprecipitation, in vitro apoptosis and caspase activity assays, subcellular fractionation/immunofluorescence Nature cell biology High 11175744
2000 Overexpressed XAF1 blocks both the caspase-inhibiting and anti-apoptotic activities of XIAP. XAF1 encodes a zinc finger protein of ~34 kDa. Yeast two-hybrid, overexpression in cells with caspase activity and apoptosis assays Genomics High 11087668
2007 XAF1 binds XIAP, cIAP1, cIAP2, Livin, TsIAP, and NAIP (but not Survivin directly). The XAF1-XIAP complex activates XIAP's E3 ubiquitin ligase (RING) activity to ubiquitinate and degrade Survivin via the proteasome. IFN-β induction forms an endogenous XIAP-XAF1-Survivin ternary complex facilitating Survivin degradation. Co-immunoprecipitation, proteasome inhibitor (MG132) rescue, XIAP RING mutant, siRNA knockdown of XIAP, XAF1-/- stable clones, immunoprecipitation of endogenous complex The Journal of biological chemistry High 17613533
2007 XAF1 promotes TNF-α-induced apoptosis by translocating to the mitochondria, promoting XIAP inactivation through a mitochondrial pathway. XAF1 overexpression also sensitizes trophoblast cells to Fas-mediated apoptosis. XAF1 overexpression, subcellular fractionation, apoptosis assays, siRNA knockdown; confocal microscopy for localization The Journal of biological chemistry Medium 17329253
2006 XAF1 expression is activated by STAT1 binding to an interferon-stimulated response element (ISRE) located at -55 to -66 nt upstream of the first ATG of XAF1 gene. IFN-β induces XAF1 expression through this STAT1-ISRE interaction; STAT1 knockdown or blockade of its phosphorylation abolishes induction. Luciferase reporter assay, EMSA, chromatin immunoprecipitation, siRNA knockdown of STAT1 Cancer letters High 18035482
2006 All-trans retinoic acid (ATRA) induces XAF1 expression via IRF-1 binding to an IRF-E element located at -30 to -38 nt upstream of the XAF1 ATG. Site-directed mutagenesis of IRF-E-XAF1 abolishes promoter activity and IRF-1 binding. Luciferase reporter assay, EMSA, chromatin immunoprecipitation, site-directed mutagenesis Gastroenterology High 16530516
2005 HSF1 represses XAF1 transcription by binding to a heat-shock element in the XAF1 promoter (-862/-821 nt region). Inactivation of this element by mutation or HSF1 inhibitor restores XAF1 promoter activity. Luciferase reporter assay, EMSA, chromatin immunoprecipitation, site-directed mutagenesis, HSF1 overexpression/siRNA The Journal of biological chemistry High 16303760
2009 XAF1 interacts with and activates checkpoint kinase 1 (Chk1), leading to inactivation of Cdc25C and subsequently the Cdc2-cyclin B complex, causing G2/M cell cycle arrest. XAF1 is predominantly expressed in G2/M phase. Chk1 suppression abrogates XAF1-induced G2/M arrest. Co-immunoprecipitation, kinase assay, immunoblotting, cell cycle synchronization, siRNA knockdown of Chk1, flow cytometry Carcinogenesis Medium 19628579
2006 XAF1 expression elevated p53 protein stability and its target gene expression, and the apoptosis-sensitizing function of XAF1 was markedly impeded by blockade of p53 function, placing XAF1 upstream of p53-mediated apoptotic stress response. Overexpression, immunoblotting, siRNA/dominant-negative p53 epistasis, flow cytometry for apoptosis Oncogene Medium 16909101
2012 XAF1 has a distinct domain organization with a compact N-terminal domain (NTD), middle domain (MD), a 42-residue unstructured linker, and a C-terminal domain (CTD). A XIAP RING-binding domain (XAF1 RBD) is located at the C-terminal portion (Thr251-Ser301) with a dissociation constant of ~18 μM for XIAP RING. Interaction of XAF1 RBD with XIAP RING is required for XIAP-mediated ubiquitination of XAF1. Limited proteolysis, peptide mass fingerprinting, NMR spectroscopy (interaction mapping), in vitro ubiquitination assay Protein science High 22811387
2014 XAF1 binds directly to the N-terminal proline-rich domain of p53 via zinc finger domain 6, interfering with MDM2 binding and ubiquitination of p53. XAF1 also stimulates HIPK2-mediated Ser-46 phosphorylation of p53 by blocking Siah2-mediated HIPK2 ubiquitination. XAF1 further activates ZNF313, a p21(WAF1)-targeting ubiquitin E3 ligase, via zinc finger domain 7. XAF1 interacts with p53, Siah2, and ZNF313 through zinc finger domains 5, 6, and 7, respectively. Co-immunoprecipitation, domain mutagenesis (truncated/domain-deleted XAF1 mutants), in vitro ubiquitination assays, immunoblotting, reporter assays, xenograft tumor studies Proceedings of the National Academy of Sciences of the United States of America High 25313037
2018 XAF1 forms a positive feedback loop with IRF-1: XAF1 binds to the multifunctional domain 2 (MFD2) of IRF-1 via zinc finger domain 6, blocking CHIP-mediated ubiquitination and degradation of IRF-1, thereby stabilizing and activating IRF-1. XAF1 also functions as a transcriptional coactivator of IRF-1 on proapoptotic gene promoters. Oncogenic Ras/ERK signaling represses XAF1 transcription to disrupt this loop. Co-immunoprecipitation, domain mutagenesis, ubiquitination assays, chromatin immunoprecipitation, luciferase reporter, IRF-1 knockdown epistasis, xenograft tumor studies Cell death & disease High 30042418
2017 XAF1 directly interacts with metallothionein 2A (MT2A) and facilitates its lysosomal degradation, raising free intracellular zinc levels and activating p53 and inactivating XIAP. MT2A in turn destabilizes XAF1 protein via lysosomal pathway, establishing mutual antagonism. XAF1 is a transcriptional target of MTF-1. Wild-type but not MT2A binding-deficient mutant XAF1 increases free zinc and drives p53 activation. Co-immunoprecipitation, domain mutagenesis (MT2A binding-deficient XAF1), lysosomal pathway inhibition, intracellular zinc measurement, p53 activity assays, xenograft studies Proceedings of the National Academy of Sciences of the United States of America High 28507149
2014 The XIAP-XAF1 complex degrades Chk1 via K48-linked ubiquitination through a CUL4A/DDB1-based E3 ubiquitin ligase. Without XAF1, XIAP stabilizes Chk1; when XAF1 is present, XIAP facilitates Chk1 degradation. Depletion of CUL4A or DDB1 prevents XIAP-XAF1-mediated Chk1 degradation. Co-immunoprecipitation, siRNA knockdown of CUL4A/DDB1, ubiquitination assays, immunoblotting, cell viability after irradiation Cancer biology & therapy Medium 25535897
2011 XAF1 induces autophagy through upregulation of Beclin-1 expression and inhibition of the Akt/p70S6K pathway. Beclin-1 knockdown or 3-methyladenine suppressed XAF1-induced autophagy but enhanced XAF1-induced apoptosis, indicating crosstalk between autophagy and apoptosis downstream of XAF1. Adenovirus-mediated overexpression, siRNA knockdown of Beclin-1, pharmacological inhibition (3-MA, caspase inhibitor), immunoblotting, immunofluorescence, xenograft Cancer letters Medium 21788101
2011 XAF1 is a transcriptional target of wild-type p53: p53 binds a responsive element (-95 to -86 nt) in the XAF1 promoter to suppress XAF1 transcription. Reciprocally, overexpressed XAF1 activates wild-type p53 via post-translational modification (enhanced nuclear accumulation and transcriptional activity), forming a feedback loop. Chromatin immunoprecipitation (ChIP) for p53 binding, site-directed mutagenesis, luciferase reporter assay, siRNA knockdown of p53, immunoblotting Molecular carcinogenesis Medium 21678496
2014 p300-dependent acetylation of IRF-1 promotes XAF1 gene activation. IRF-1 binds to the XAF1 promoter and this binding is enhanced by p300-mediated IRF-1 acetylation; two acetylation sites on IRF-1 were identified. Chromatin immunoprecipitation, in vivo and in vitro acetylation assays, siRNA knockdown of p300/IRF-1/XAF1 in cells and in vivo (Thy-1 nephritis rat model), luciferase reporter assay Cell death & disease Medium 24743731
2022 XAF1 destabilizes GRP78 (ER stress sensor) through assembly of a ZNF313-mediated destruction complex. XAF1 also destabilizes CHIP ubiquitin E3 ligase, thereby blocking CHIP-mediated K63-linked ubiquitination and subsequent phosphorylation of IRE1α involved in adaptive ER stress response. XAF1 transcription is activated through PERK-Nrf2 signaling. XAF1-/- tumors show reduced response to ER stress inducers. Co-immunoprecipitation, ubiquitination assays (K63-specific), genetic KO/overexpression, immunoblotting, xenograft tumor assays, correlation in primary breast carcinomas Cell death & disease High 35902580
2023 XAF1 functions as an adaptor of valosin-containing protein (VCP) and facilitates VCP-mediated deubiquitination of the E3 ligase RNF114. Stabilized RNF114 promotes K48-linked ubiquitination and degradation of junction plakoglobin (JUP), driving CRC cell migration and metastasis. Co-immunoprecipitation, ubiquitination assays (K48-specific), protein stability assays, migration/invasion assays, xenograft models, clinical sample correlation The Journal of cell biology High 38095639
2023 Upon RNA virus infection, MAVS recruits XAF1 and TBK1; TBK1 phosphorylates XAF1 at serine-252 and promotes its nuclear translocation. Nuclear XAF1 interacts with TRIM28 guided by IRF1 at antiviral gene loci, and XAF1 de-SUMOylates TRIM28 via its PHD domain, increasing chromatin accessibility and inducing antiviral gene transcription. XAF1-deficient mice are susceptible to RNA virus infection. Co-immunoprecipitation, phosphorylation site mapping, nuclear translocation assays (imaging), SUMO modification assays, chromatin accessibility assays (ATAC-seq type), XAF1-deficient mouse model, domain mutagenesis (PHD domain) Science advances High 37595039
2022 XAF1 stabilizes IRF1 by antagonizing CHIP-mediated degradation of IRF1, forming a positive feedback loop to induce antiviral gene expression (DDX58, DDX60, MX1, OAS2). XAF1 knockout attenuates antiviral innate immunity in vitro and in vivo; XAF1-KO mice show more severe lung injury and higher mortality upon influenza infection. Co-immunoprecipitation, protein stability assays, XAF1 KO (cell lines and mice), overexpression, immunoblotting, antiviral gene induction assays, in vivo influenza infection model Journal of virology High 35972291
2022 XAF1 associates specifically with IRF7 and inhibits XIAP activity. The XAF1-XIAP axis controls the activity of KLHL22, an adaptor of the BTB-CUL3-RBX1 E3 ligase complex via a ubiquitin-dependent pathway. CUL3-KLHL22 directly targets IRF7 for K48-linked ubiquitination and proteasomal degradation, thus preventing hyperproduction of type I IFN. XAF1-KO and XIAP-transgenic mice display resistance to viral infection with elevated IFN-I production. Co-immunoprecipitation, K48-ubiquitination assays, XAF1-KO mice, XIAP-transgenic mice, viral infection models, immunoblotting EMBO reports High 36394357
2023 XAF1 directly interacts with the N-terminal region of AKT1, blocking K63-linked poly-ubiquitination and subsequent AKT activation. Xaf1 knockout in mice causes AKT activation in muscle and fat tissues and reduces body weight gain and insulin resistance on high-fat diet. FOXO1 transcriptionally activates XAF1, forming a negative feedback loop with AKT1. Co-immunoprecipitation/pulldown, K63-ubiquitination assays, Xaf1 KO mice, Pten heterozygous mouse model, orthotopic tumorigenesis assay, domain mutant (P277L), luciferase reporter for FOXO1-XAF1 axis Cell reports High 37384528
2022 XAF1 destabilizes estrogen receptor α (ERα) through assembly of a BRCA1-mediated destruction complex; XAF1 interacts with ERα and BRCA1 via zinc finger domains 5/6 and 4, respectively. Mutants lacking ZF5/6 or ZF4 fail to drive ERα ubiquitination. XAF1 is activated by E2 through a GPER (G protein-coupled estrogen receptor)-mediated non-genomic pathway, and ERα represses XAF1 for E2-driven proliferation. Co-immunoprecipitation, domain mutagenesis (ZF4/5/6 deletion mutants), ubiquitination assays, XAF1+/+ and XAF1-/- xenograft tumor models, immunoblotting, promoter methylation analysis Oncogene High 35430604
2022 XAF1 is translocated into mitochondria to stimulate ROS production and ATM-AMPK signaling, directing autophagic flux toward apoptosis in response to temozolomide. A mutant XAF1 lacking zinc finger domain 6 fails to localize to mitochondria and cannot activate ROS-ATM-AMPK signaling or autophagy-mediated apoptosis. Mitochondrial fractionation, domain mutagenesis (ZF6 deletion), ROS measurement, ATM-AMPK pathway immunoblotting, flow cytometry, XAF1-restored xenograft tumors Neuro-oncology advances Medium 35274103
2024 XAF1 interacts with RING domains of TRIM28 and ZNF313 via zinc finger domains ZF6 and ZF7, respectively, facilitating ZNF313-induced K48-linked ubiquitination and proteasomal degradation of TRIM28. By destabilizing TRIM28, XAF1 blocks TRIM28-mediated ubiquitination of p53 and RLIM, prevents p53-HDAC1 interaction, and blocks TWIST1 stabilization. Conversely, TRIM28 ubiquitinates XAF1 via K48-linked polyubiquitination to protect tumor cells from apoptosis. Co-immunoprecipitation, domain mutagenesis (ZF6 and ZF7 deletion mutants), K48-ubiquitination assays, immunoblotting, invasion/EMT assays, xenograft tumor studies Molecular biomedicine High 39532800
2024 XAF1 depletion in osteoclasts decreases apoptosis by facilitating the interaction between XIAP and caspase-3/7, thereby promoting osteoclastogenesis. Activation of XAF1 with a XIAP inhibitor suppresses osteoclast formation. Global and chimeric Xaf1 KO mouse models show increased osteoclast number and enhanced bone resorption. Xaf1 global and chimeric KO mouse models (OVX and osteolysis), in vitro osteoclast differentiation, Co-IP of XIAP-caspase-3/7, caspase activity assays, bone histomorphometry Journal of orthopaedic translation High 38957269
2006 XAF1 can induce apoptosis and cooperate with TNF-α via the mitochondrial pathway (cytochrome c release, blocked by Bcl2) independently of XIAP interaction. In Saos-2 cells, no interaction between Xaf1 and XIAP was detected; Xaf1 also sensitizes XIAP-/- fibroblasts to TNF-α. Inducible overexpression, cytochrome c release assay, Bcl2 overexpression rescue, XIAP-/- fibroblasts (genetic epistasis), no Xaf1-XIAP interaction detected by co-IP Molecular and cellular biochemistry Medium 16432762
2008 JNK1 upregulates XAF1 expression through induction of IRF-1, which then binds to the IRF-E within the XAF1 promoter. Site mutation of IRF-E or IRF-1 siRNA abrogates JNK1-induced XAF1 transcription. JNK1 wild-type/dominant-negative constructs, siRNA knockdown of IRF-1, luciferase reporter with mutated IRF-E, RT-PCR and immunoblotting Carcinogenesis Medium 19056926
2015 CTCF binds the XAF1 promoter in a methylation-sensitive manner and maintains open chromatin configuration, inhibiting CpG methylation and repressive histone modifications. Loss of CTCF binding leads to XAF1 epigenetic silencing. Chromatin immunoprecipitation, transgene reporter assays, methylation-sensitive CTCF binding experiments Scientific reports Medium 26443201
2019 SARM1 deficiency leads to strong selective overexpression of XAF1 in prion-infected mice, resulting in increased pro-apoptotic caspase activity and neuronal death, exacerbating prion disease. SARM1 thus acts as a regulator suppressing XAF1-mediated neuronal apoptosis. SARM1-/- mouse model with prion infection, whole-transcriptome analysis, caspase activity assays, neuronal death quantification The Journal of experimental medicine Medium 30842236
2012 XAF1 interacts with XIAP during dengue virus (DENV2) infection as confirmed by co-immunoprecipitation and co-localization by confocal microscopy. XAF1 knockdown reduces caspase-3/8/9 and PARP expression, while XAF1 overexpression upregulates them, establishing a role for XAF1 in promoting apoptosis in DENV2-infected vascular endothelial cells. Co-immunoprecipitation with anti-XAF1 antibody, confocal microscopy co-localization, siRNA knockdown, overexpression, immunoblotting FASEB journal Medium 23207547
2024 TRIM47 interacts with XAF1 and promotes its ubiquitination and proteasomal degradation. TRIM47 overexpression causes XAF1-dependent suppression of apoptosis and autophagy in HNSCC cells; XAF1 overexpression reverses the proliferative effect of TRIM47 overexpression. Co-immunoprecipitation, ubiquitination assays, overexpression/knockdown, autophagy inhibitor rescue, xenograft tumor model iScience Medium 39834862
2024 XAF1 is secreted from stressed cancer cells via an unconventional endo-lysosomal trafficking pathway; zinc finger domain 4 (ZF4) is essential for this secretion. Secreted XAF1 is internalized into T cells via clathrin-mediated endocytosis and directly interacts with and phosphorylates Lck (lymphocyte-specific protein tyrosine kinase), activating RAF-MEK-ERK signaling and stimulating T cell proliferation, migration, and tumor infiltration. Subcellular fractionation, ZF4 domain mutant, clathrin-mediated endocytosis inhibition, Lck co-immunoprecipitation/phosphorylation assay, ERK signaling readouts, Xaf1+/+ vs Xaf1-/- xenograft with IFN-γ and recombinant XAF1 injection Neoplasia High 39615106
2025 Xaf1 orchestrates PANoptosis in cochlear hair cells through direct interaction with and transcriptional regulation of ZBP1, placing Xaf1 hierarchically upstream of ZBP1 in the PANoptosis signaling cascade. Xaf1 knockdown via AAV-based gene delivery in cochlear hair cells reduces neomycin-induced ototoxicity. Single-nucleus RNA sequencing, overexpression and knockdown assays in vitro, AAV-based in vivo Xaf1 knockdown, ZBP1 interaction and transcriptional regulation assays Cell proliferation Medium 40600354

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Identification of XAF1 as an antagonist of XIAP anti-Caspase activity. Nature cell biology 374 11175744
2000 Expression and genetic analysis of XIAP-associated factor 1 (XAF1) in cancer cell lines. Genomics 187 11087668
2007 Degradation of survivin by the X-linked inhibitor of apoptosis (XIAP)-XAF1 complex. The Journal of biological chemistry 136 17613533
2006 Correlation between the single-site CpG methylation and expression silencing of the XAF1 gene in human gastric and colon cancers. Gastroenterology 92 17087954
2006 Promoter CpG hypermethylation and downregulation of XAF1 expression in human urogenital malignancies: implication for attenuated p53 response to apoptotic stresses. Oncogene 77 16909101
2006 Biological markers of interferon-beta therapy: comparison among interferon-stimulated genes MxA, TRAIL and XAF-1. Multiple sclerosis (Houndmills, Basingstoke, England) 73 16459719
2004 XAF1 expression is significantly reduced in human melanoma. The Journal of investigative dermatology 64 15610524
2018 XAF1 forms a positive feedback loop with IRF-1 to drive apoptotic stress response and suppress tumorigenesis. Cell death & disease 62 30042418
2014 XAF1 directs apoptotic switch of p53 signaling through activation of HIPK2 and ZNF313. Proceedings of the National Academy of Sciences of the United States of America 61 25313037
2007 XAF1 mediates tumor necrosis factor-alpha-induced apoptosis and X-linked inhibitor of apoptosis cleavage by acting through the mitochondrial pathway. The Journal of biological chemistry 59 17329253
2007 Frequent alteration of XAF1 in human colorectal cancers: implication for tumor cell resistance to apoptotic stresses. Gastroenterology 59 17570219
2005 HSF1 down-regulates XAF1 through transcriptional regulation. The Journal of biological chemistry 52 16303760
2014 Tumor suppressor XAF1 induces apoptosis, inhibits angiogenesis and inhibits tumor growth in hepatocellular carcinoma. Oncotarget 50 24980821
2006 Xaf1 can cooperate with TNFalpha in the induction of apoptosis, independently of interaction with XIAP. Molecular and cellular biochemistry 49 16432762
2007 The role of XAF1 in cancer. Current opinion in investigational drugs (London, England : 2000) 48 17621877
2009 Identification of XAF1 as a novel cell cycle regulator through modulating G(2)/M checkpoint and interaction with checkpoint kinase 1 in gastrointestinal cancer. Carcinogenesis 41 19628579
2014 Sublytic C5b-9 triggers glomerular mesangial cell apoptosis via XAF1 gene activation mediated by p300-dependent IRF-1 acetylation. Cell death & disease 40 24743731
2007 Silencing of the XAF1 gene by promoter hypermethylation in cancer cells and reactivation to TRAIL-sensitization by IFN-beta. BMC cancer 40 17376236
2014 Synergistic suppression effect on tumor growth of hepatocellular carcinoma by combining oncolytic adenovirus carrying XAF1 with cisplatin. Journal of cancer research and clinical oncology 39 25240826
2006 All-trans retinoic acid induces XAF1 expression through an interferon regulatory factor-1 element in colon cancer. Gastroenterology 39 16530516
2011 XIAP-associated factor 1 (XAF1), a novel target of p53, enhances p53-mediated apoptosis via post-translational modification. Molecular carcinogenesis 38 21678496
2011 The XAF1 tumor suppressor induces autophagic cell death via upregulation of Beclin-1 and inhibition of Akt pathway. Cancer letters 38 21788101
2007 XAF1 mediates apoptosis through an extracellular signal-regulated kinase pathway in colon cancer. Cancer 38 17385215
2009 Restoration of XAF1 expression induces apoptosis and inhibits tumor growth in gastric cancer. International journal of cancer 36 19358264
2006 Switch to full-length of XAF1 mRNA expression in prostate cancer cells by the DNA methylation inhibitor. International journal of cancer 35 16353137
2010 Tumor suppressor XIAP-Associated factor 1 (XAF1) cooperates with tumor necrosis factor-related apoptosis-inducing ligand to suppress colon cancer growth and trigger tumor regression. Cancer 34 20082449
2017 Identification of XAF1-MT2A mutual antagonism as a molecular switch in cell-fate decisions under stressful conditions. Proceedings of the National Academy of Sciences of the United States of America 30 28507149
2019 SARM1 deficiency up-regulates XAF1, promotes neuronal apoptosis, and accelerates prion disease. The Journal of experimental medicine 29 30842236
2012 XAF1 contributes to dengue virus-induced apoptosis in vascular endothelial cells. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 27 23207547
2007 Disturbed expression of the apoptosis regulators XIAP, XAF1, and Smac/DIABLO in gastric adenocarcinomas. Diagnostic molecular pathology : the American journal of surgical pathology, part B 27 17471152
2018 Bisphenol A induced male germ cell apoptosis via IFNβ-XAF1-XIAP pathway in adult mice. Toxicology and applied pharmacology 26 30017639
2007 Regulation of XAF1 expression in human colon cancer cell by interferon beta: activation by the transcription regulator STAT1. Cancer letters 26 18035482
2014 Admixture fine-mapping in African Americans implicates XAF1 as a possible sarcoidosis risk gene. PloS one 25 24663488
2016 Berberine induces mitochondrial apoptosis of EBV-transformed B cells through p53-mediated regulation of XAF1 and GADD45α. International journal of oncology 24 27121748
2015 XIAP associated factor 1 (XAF1) represses expression of X-linked inhibitor of apoptosis protein (XIAP) and regulates invasion, cell cycle, apoptosis, and cisplatin sensitivity of ovarian carcinoma cells. Asian Pacific journal of cancer prevention : APJCP 24 25824780
2022 XAF1 drives apoptotic switch of endoplasmic reticulum stress response through destabilization of GRP78 and CHIP. Cell death & disease 23 35902580
2008 Predictive value of expression and promoter hypermethylation of XAF1 in hepatitis B virus-associated hepatocellular carcinoma treated with transplantation. Annals of surgical oncology 23 18830757
2006 Potent antitumor efficacy of XAF1 delivered by conditionally replicative adenovirus vector via caspase-independent apoptosis. Cancer gene therapy 23 17008933
2005 Induction and redistribution of XAF1, a new antagonist of XIAP in the rat brain after transient focal ischemia. Neurobiology of disease 23 15905097
2023 XAF1 promotes anti-RNA virus immune responses by regulating chromatin accessibility. Science advances 22 37595039
2013 ROS and ERK1/2-mediated caspase-9 activation increases XAF1 expression in dexamethasone-induced apoptosis of EBV-transformed B cells. International journal of oncology 22 23685456
2008 c-Jun N-terminal kinase (JNK1) upregulates XIAP-associated factor 1 (XAF1) through interferon regulatory factor 1 (IRF-1) in gastrointestinal cancer. Carcinogenesis 22 19056926
2014 Enhancement of cellular radiation sensitivity through degradation of Chk1 by the XIAP-XAF1 complex. Cancer biology & therapy 21 25535897
2012 XAF1 is frequently methylated in human esophageal cancer. World journal of gastroenterology 21 22719195
2022 XAF1 Protects Host against Emerging RNA Viruses by Stabilizing IRF1-Dependent Antiviral Immunity. Journal of virology 19 35972291
2009 Down-regulation of the pro-apoptotic XIAP associated factor-1 (XAF1) during progression of clear-cell renal cancer. BMC cancer 19 19664236
2017 Ampelopsin-induced reactive oxygen species enhance the apoptosis of colon cancer cells by activating endoplasmic reticulum stress-mediated AMPK/MAPK/XAF1 signaling. Oncology letters 18 29250183
2021 Silencing of PGK1 Promotes Sensitivity to Paclitaxel Treatment by Upregulating XAF1-Mediated Apoptosis in Triple-Negative Breast Cancer. Frontiers in oncology 17 33747900
2023 XAF1 promotes colorectal cancer metastasis via VCP-RNF114-JUP axis. The Journal of cell biology 16 38095639
2019 TGF-β1 protects colon tumor cells from apoptosis through XAF1 suppression. International journal of oncology 16 31081052
2018 Sensitization of colorectal cancer cells to irinotecan by the Survivin inhibitor LLP3 depends on XAF1 proficiency in the context of mutated p53. Archives of toxicology 16 29947891
2012 Domain organization of XAF1 and the identification and characterization of XIAP(RING) -binding domain of XAF1. Protein science : a publication of the Protein Society 16 22811387
2016 Silencing HS6ST3 inhibits growth and progression of breast cancer cells through suppressing IGF1R and inducing XAF1. Experimental cell research 15 28017727
2015 Epigenetic silencing of the XAF1 gene is mediated by the loss of CTCF binding. Scientific reports 14 26443201
2013 Melphalan-induced apoptosis of EBV-transformed B cells through upregulation of TAp73 and XAF1 and nuclear import of XPA. Journal of immunology (Baltimore, Md. : 1950) 14 24249729
2010 Identification of a functional p53 responsive element within the promoter of XAF1 gene in gastrointestinal cancer cells. International journal of oncology 14 20198350
2022 XAF1 prevents hyperproduction of type I interferon upon viral infection by targeting IRF7. EMBO reports 13 36394357
2018 A commercial Roundup® formulation induced male germ cell apoptosis by promoting the expression of XAF1 in adult mice. Toxicology letters 13 29908847
2021 MX2 mediates establishment of interferon response profile, regulates XAF1, and can sensitize melanoma cells to targeted therapy. Cancer medicine 12 33734579
2017 Epigenetic silencing of XAF1 in high-grade gliomas is associated with IDH1 status and improved clinical outcome. Oncotarget 12 28122345
2024 XAF1 promotes osteoclast apoptosis by antagonizing the XIAP-caspase axis. Journal of orthopaedic translation 11 38957269
2019 Paradoxical epigenetic regulation of XAF1 mediates plasticity towards adaptive resistance evolution in MGMT-methylated glioblastoma. Scientific reports 11 31575897
2016 XAF1 promotes neuroblastoma tumor suppression and is required for KIF1Bβ-mediated apoptosis. Oncotarget 11 27097110
2014 A novel splice variant of XIAP-associated factor 1 (XAF1) is expressed in peripheral blood containing gastric cancer-derived circulating tumor cells. Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 10 25216542
2008 XIAP-associated factor 1 (XAF1) suppresses angiogenesis in mouse endothelial cells. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 10 18544999
2010 XAF1 expression and regulatory effects of somatostatin on XAF1 in prostate cancer cells. Journal of experimental & clinical cancer research : CR 9 21143993
2023 Anti-microRNA-1976 as a Novel Approach to Enhance Chemosensitivity in XAF1+ Pancreatic and Liver Cancer. Biomedicines 8 37189754
2019 Combined effects of XAF1 and TRAIL on the apoptosis of lung adenocarcinoma cells. Experimental and therapeutic medicine 8 31086598
2016 RIP kinase-mediated ROS production triggers XAF1 expression through activation of TAp73 in casticin-treated bladder cancer cells. Oncology reports 8 27349281
2014 Experimental study on inhibition effects of the XAF1 gene against lung cancer cell proliferation. Asian Pacific journal of cancer prevention : APJCP 8 25292071
2017 Metabolic Endotoxemia-Activated Macrophages Promote Pancreatic β Cell Death via IFNβ-Xaf1 Pathway. Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme 7 29132171
2013 Missense polymorphisms in XIAP-associated factor-1 (XAF1) and risk of papillary thyroid cancer: correlation with clinicopathological features. Anticancer research 7 23645777
2022 XAF1 destabilizes estrogen receptor α through the assembly of a BRCA1-mediated destruction complex and promotes estrogen-induced apoptosis. Oncogene 6 35430604
2005 [Frequent epigenetic inactivation of XAF1 by promotor hypermethylation in human colon cancers]. The Korean journal of gastroenterology = Taehan Sohwagi Hakhoe chi 6 15843754
2023 Identification of XAF1 as an endogenous AKT inhibitor. Cell reports 5 37384528
2022 XAF1 overexpression exacerbates diabetes by promoting pancreatic β-cell apoptosis. Acta diabetologica 5 35829914
2024 XAF1 antagonizes TRIM28 activity through the assembly of a ZNF313-mediated destruction complex to suppress tumor malignancy. Molecular biomedicine 4 39532800
2022 XAF1 directs glioma response to temozolomide through apoptotic transition of autophagy by activation of ATM-AMPK signaling. Neuro-oncology advances 4 35274103
2022 IRF9 and XAF1 as Diagnostic Markers of Primary Sjogren Syndrome. Computational and mathematical methods in medicine 4 36132546
2014 [XAF1 inhibits cell proliferation and induces apoptosis in human lung adenocarcinoma cell line A549 in vitro]. Zhongguo fei ai za zhi = Chinese journal of lung cancer 4 25539606
2010 Methylation of cyclin-dependent kinase inhibitors, XAF1, JUNB, CDH13 and soluble Wnt inhibitors in essential thrombocythaemia. Journal of clinical pathology 4 20364027
2024 TRIM47 promotes head and neck squamous cell carcinoma malignant progression by degrading XAF1 through ubiquitination. iScience 3 39834862
2022 WZY-321 triggers glioma cell apoptosis via XAF1 up-regulation caused by MTM-mediated miR-873 down-regulation. Journal of Cancer 3 35517406
2022 Li-Fraumeni-associated pancreatic neuroendocrine tumour and XAF1 p.Glu134Ter risk modifier variant. Ecancermedicalscience 3 36819813
2012 [Relationship between methylation status of promoter and expression of XAF1 gene in papillary thyroid carcinoma]. Zhonghua yi xue za zhi 3 22944270
2012 Assessment of XAF1 as A Biomarker to Differentiate Hepatocellular Carcinoma from Nonneoplastic Liver Tissues. Chinese journal of cancer research = Chung-kuo yen cheng yen chiu 3 23358741
2025 Single-Nucleus Transcriptomics Uncovers Xaf1-Driven PANoptosis as a Therapeutic Target in Aminoglycoside-Induced Hearing Loss. Cell proliferation 2 40600354
2024 XAF1 overexpression inhibits the malignant progression and cisplatin resistance of NSCLC by activating endoplasmic reticulum stress. Molecular biology reports 2 38520543
2024 XAF1 is secreted from stressed tumor cells to activate T cell-mediated tumor surveillance via Lck-ERK signaling. Neoplasia (New York, N.Y.) 2 39615106
2021 [Effect of stable overexpression of XAF1 gene on biological characteristics of ovarian cancer A2780 cells]. Nan fang yi ke da xue xue bao = Journal of Southern Medical University 1 34134965
2016 Adenovirus encoding XAF-1 and TNF‑α in the same open reading frame efficiently inhibits hepatocellular cancer cells. Molecular medicine reports 1 27121136
2007 [Expression of HSF1 and XAF1 in gastro-intestinal cancer]. Nan fang yi ke da xue xue bao = Journal of Southern Medical University 1 17884799
2026 Gamabufotalin impedes NSCLC progression by inhibiting the mitochondrial factor CHCHD2 and modulating XAF1 expression. Biochemical pharmacology 0 41692347
2026 Hyperoside Attenuates Lupus Nephritis-Associated Mesangial Cell Apoptosis via the P53/XAF1 Pathway: Integrative Bioinformatics and In Vitro Validation. Journal of inflammation research 0 41847430
2026 XAF1 nonsense mutation rs117407731 enhances lung adenocarcinoma susceptibility via apoptosis suppression. Molecular genetics and genomics : MGG 0 42029946
2026 Identification of a Germline XAF1 Mutation in Patients With Gastrointestinal Cancers. Human mutation 0 42094237
2025 Germline TP53 p.R337H and XAF1 p.E134* Variants: Prevalence in Paraguay and Comparison with Rates in Brazilian State of Paraná and Previous Findings at the Paraguayan-Brazilian Border. Current oncology (Toronto, Ont.) 0 40558276
2023 Molecular identification and functional analysis of X-linked inhibitor of apoptosis -associated factor-1 (XAF1) in grass carp, Ctenopharyngodon idella. Fish & shellfish immunology 0 36822382
2009 [5-azacytidine treatment induces tumor suppressor gene XAF1 expression and inhibits proliferation in myeloma cells]. Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi 0 19731821
2006 [Expression and subcellular localization of XIAP and XAF1 in human normal oral keratinocytes and Tca8113 cells]. Zhonghua kou qiang yi xue za zhi = Zhonghua kouqiang yixue zazhi = Chinese journal of stomatology 0 17331366

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