Affinage

XIAP

E3 ubiquitin-protein ligase XIAP · UniProt P98170

Length
497 aa
Mass
56.7 kDa
Annotated
2026-06-11
100 papers in source corpus 37 papers cited in narrative 37 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

XIAP is a bifunctional anti-apoptotic protein that combines direct caspase inhibition with RING-domain E3 ubiquitin ligase activity to control cell death, innate immune signaling, and cell-fate decisions (PMID:10548111, PMID:18708583). Its tandem BIR domains engage the apoptotic machinery: the BIR1-BIR2 linker binds the caspase-3 active site while the BIR domain contacts an adjacent enzyme surface (PMID:10548111), and full-length XIAP, but not caspase-9-inhibiting truncations, blocks death-receptor signaling upstream of mitochondrial cytochrome c and Smac release (PMID:15282301). XIAP is the molecular discriminator between type I and type II FAS apoptosis, imposing a brake on effector caspases that renders type II cells dependent on mitochondrial amplification (PMID:19626005). Its C-terminal RING domain functions as an E3 ligase that ubiquitinates a broad substrate set—including PTEN, COMMD1, Cdc42, Bcl-2, Mdm2, Siva1, HIF1α, and IFT88—linking XIAP to PTEN/Akt survival signaling, copper homeostasis, cytoskeletal regulation, autophagy, and ciliary biology (PMID:19473982, PMID:18795889, PMID:28661476, PMID:29020630, PMID:23749209, PMID:28666324, PMID:38351372). RING-dependent auto-ubiquitination also sets XIAP's own abundance, and the RING domain is required for full caspase inhibition in vivo (PMID:18708583). Beyond apoptosis, XIAP nucleates NF-κB signaling: its BIR1 domain dimerizes and binds TAB1 to activate TAK1/NF-κB (PMID:17560374), while its BIR2 domain binds and ubiquitinates RIP2 to drive NOD1/2 innate immune responses (PMID:19667203, PMID:29452636). XIAP further restrains necroptotic and inflammatory death by regulating RIP1/RIP3- and RIPK2-dependent pathways, with its loss causing TNF/RIP3-dependent excessive cell death and caspase-8-driven inflammasome activation (PMID:24882010, PMID:36647737). XIAP stability is tuned by Akt phosphorylation at Ser87 (PMID:14645242), RING S-nitrosylation (PMID:20670888), ARTS/Siah-1-mediated degradation (PMID:21185211), and deubiquitylation by USP9X and USP7 (PMID:27317434, PMID:36243803), while its translation is controlled through IRES-dependent mechanisms involving MDM2 and HuR (PMID:19411066, PMID:21102524).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1999 High

    Established the structural and residue-level basis for how XIAP inhibits caspase-3, defining the BIR2 domain fold and the linker region that engages the protease active site.

    Evidence NMR structure of the BIR2 domain with site-directed mutagenesis

    PMID:10548111

    Open questions at the time
    • Did not resolve the BIR3-caspase-9 interaction
    • Mechanism of RING-domain E3 activity not addressed
  2. 2001 High

    Tested whether XIAP is essential for apoptosis suppression in vivo, revealing functional redundancy through compensatory upregulation of c-IAP1/2.

    Evidence XIAP knockout mouse with histopathology and Western blot

    PMID:11313486

    Open questions at the time
    • Redundancy obscures cell-type-specific XIAP roles
    • Non-apoptotic functions not examined
  3. 2004 High

    Distinguished caspase-9- versus effector-caspase-directed XIAP activity, showing full-length XIAP blocks death-receptor signaling upstream of mitochondrial amplification.

    Evidence Domain-dissection overexpression with cytochrome c release and mitochondrial potential assays

    PMID:15282301

    Open questions at the time
    • Did not establish which caspase step is rate-limiting in physiological context
    • Single-lab overexpression system
  4. 2007 High

    Defined the structural basis by which XIAP activates NF-κB, showing BIR1 dimerization and TAB1 binding drive TAK1/NF-κB signaling independent of caspase inhibition.

    Evidence Crystal structure of BIR1-TAB1 complex with mutagenesis and NF-κB reporters

    PMID:17560374

    Open questions at the time
    • Physiological stimuli triggering this axis not fully mapped
    • Relationship to RIP2 signaling not addressed here
  5. 2008 High

    Demonstrated that the RING domain governs XIAP protein stability and is required for full caspase inhibition in vivo, revealing a paradoxical pro-apoptotic effect of BIR-only protein.

    Evidence RING-deletion knock-in mice with caspase-3 activity and lymphoma models

    PMID:18708583

    Open questions at the time
    • Substrate(s) accounting for in vivo phenotype not identified here
    • Mechanism linking stability to caspase inhibition incomplete
  6. 2009 High

    Identified XIAP as the discriminator between type I and type II FAS apoptosis, defining its role as an effector-caspase brake requiring mitochondrial amplification in type II cells.

    Evidence XIAP and BID knockout mice with genetic epistasis and SMAC mimetic

    PMID:19626005

    Open questions at the time
    • Molecular determinant of type I vs II identity beyond XIAP threshold unclear
  7. 2009 High

    Connected XIAP to innate immunity by showing BIR2-RIP2 binding is required for NOD1/2-dependent NF-κB activation.

    Evidence Reciprocal Co-IP and NF-κB reporters in XIAP-deficient cells

    PMID:19667203

    Open questions at the time
    • Ubiquitin linkage on RIP2 not yet defined at this stage
  8. 2009 High

    Expanded XIAP's E3 ligase substrate repertoire to PTEN, linking XIAP to Akt survival signaling via PTEN degradation and nuclear exclusion.

    Evidence In vitro ubiquitination, Co-IP, and XIAP-/- MEFs

    PMID:19473982

    Open questions at the time
    • Single-lab data
    • In vivo physiological relevance of PTEN regulation not established
  9. 2009 High

    Established XIAP as the primary E3 ligase controlling COMMD1 abundance, mapping the COMM domain leucine repeats required for binding.

    Evidence GST pulldown, mutagenesis, and ubiquitination assay

    PMID:18795889

    Open questions at the time
    • Physiological copper-handling consequence not directly tested here
  10. 2010 Medium

    Defined post-translational and translational control of XIAP: S-nitrosylation inactivates the RING, and IRES-dependent translation is regulated by MDM2 and HuR.

    Evidence Biotin-switch assays, IRES reporters, RNA-protein binding, polysome fractionation

    PMID:19411066 PMID:19825980 PMID:20670888 PMID:21102524

    Open questions at the time
    • Integration of these regulatory layers in single cells not resolved
    • Some findings single-lab and Medium confidence
  11. 2010 High

    Identified the ARTS/Siah-1 axis as a dedicated route for XIAP degradation through BIR1 binding distinct from caspase sites.

    Evidence Co-IP, ubiquitination assays, ARTS-KO and Siah-KO cells

    PMID:21185211

    Open questions at the time
    • Conditions selecting this pathway over auto-ubiquitination unclear
  12. 2014 High

    Revealed XIAP, via its RING domain, restrains TNF/RIP3-dependent inflammatory cell death and aberrant RIP1 ubiquitylation in dendritic cells.

    Evidence XIAP KO and RING-deletion mice with RIP3/caspase epistasis and IL-1β ELISA

    PMID:24882010

    Open questions at the time
    • Direct enzymatic relationship between XIAP and RIP1 not fully defined
  13. 2017 High

    Broadened XIAP substrate diversity to Cdc42, HIF1α, and Bcl-2, linking it to cytoskeletal dynamics, hypoxic gene expression, and mitochondrial apoptosis via distinct ubiquitin linkages.

    Evidence In vitro ubiquitination with site-specific mutants, ternary-complex Co-IP, KO MEFs and in vivo assays

    PMID:28661476 PMID:28666324 PMID:29020630

    Open questions at the time
    • Substrate selectivity determinants among many targets unresolved
    • Some axes Medium confidence
  14. 2018 High

    Mechanistically refined NOD2 signaling, showing RIP2 kinase activity is dispensable while its conformation governs XIAP BIR2 binding and lysine-specific ubiquitination drives the pathway.

    Evidence Co-IP, MS ubiquitination-site mapping, RIP2 mutagenesis and kinase inhibitors

    PMID:29452636

    Open questions at the time
    • Downstream E2 and chain architecture not fully detailed
  15. 2023 High

    Showed that in XIAP deficiency, caspase-8 drives pyroptotic GSDMD processing and GSDMD-independent NLRP3/IL-1β activation, explaining the inflammatory phenotype of XIAP loss.

    Evidence Patient tissue plus multi-KO macrophage epistasis and IL-1β readouts

    PMID:36647737

    Open questions at the time
    • Direct XIAP substrate restraining caspase-8 not pinpointed
  16. 2024 High

    Extended XIAP E3 activity to ciliary biology, showing TGF-β-driven XIAP ubiquitination of IFT88 causes cilia loss and hepatic stellate cell activation in fibrosis.

    Evidence In vitro ubiquitination, Ift88-KO mice, and CCl4 liver fibrosis model

    PMID:38351372

    Open questions at the time
    • Generalizability to other ciliated tissues not tested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How XIAP achieves selectivity among its many E3 substrates and how its caspase-inhibitory, NF-κB-activating, and ligase functions are coordinated within a single cell remains unresolved.
  • No unifying model of substrate choice
  • Spatiotemporal partitioning of XIAP functions undefined
  • Mendelian disease link not directly established within this corpus

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016874 ligase activity 7 GO:0016740 transferase activity 3 GO:0098772 molecular function regulator activity 3 GO:0140096 catalytic activity, acting on a protein 3
Localization
GO:0005829 cytosol 2 GO:0005929 cilium 2 GO:0005739 mitochondrion 1
Pathway
R-HSA-392499 Metabolism of proteins 6 R-HSA-5357801 Programmed Cell Death 5 R-HSA-168256 Immune System 4 R-HSA-162582 Signal Transduction 3 R-HSA-9612973 Autophagy 2
Partners
BCL-2CDC42COMMD1PTENRIP2TAB1USP7USP9X
Complex memberships
ARTS-XIAP-Bcl-2 ternary complexXIAP-RIP2 (NOD signaling)XIAP-Siva1-TAK1 ternary complexXIAP-TAB1-TAK1

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 NMR structure of XIAP BIR2 domain revealed a three-stranded antiparallel beta-sheet and four alpha-helices resembling a zinc finger; mutagenesis showed conserved residues in the BIR1-BIR2 linker region are critical for caspase-3 inhibition, suggesting they bind the active site while the BIR domain interacts with an adjacent site on the enzyme. NMR structure determination, site-directed mutagenesis Nature High 10548111
2001 XIAP-deficient mice generated by homologous gene targeting are viable with no detectable apoptosis defects, but show compensatory upregulation of c-IAP1 and c-IAP2 protein levels, suggesting a compensatory mechanism among IAP family members. Gene targeting (knockout mouse), histopathology, Western blot Molecular and cellular biology High 11313486
1998 hILP/XIAP inhibits ICE-induced apoptosis via a mechanism dependent on selective activation of JNK1 (c-Jun N-terminal kinase 1), demonstrating a caspase-independent anti-apoptotic mechanism. Cell-based apoptosis assay, kinase activation assays Proceedings of the National Academy of Sciences of the United States of America Medium 9600909
2003 Akt (AKT1 and AKT2) physically interacts with and phosphorylates XIAP at serine-87 in vitro and in vivo; this phosphorylation protects XIAP from ubiquitination and proteasomal degradation and inhibits XIAP auto-ubiquitination, resulting in enhanced cell survival. Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis (S87D and S87A mutants), siRNA knockdown, apoptosis assays The Journal of biological chemistry High 14645242
2007 Crystal structure of the XIAP BIR1 domain in complex with TAB1 revealed a butterfly-shaped dimer; BIR1 directly interacts with TAB1 (an upstream adaptor for TAK1 kinase), and this interaction is essential for XIAP-induced TAK1 and NF-κB activation. BIR1 dimerization is also required for NF-κB activation. Smac inhibits the XIAP/TAB1 interaction without binding BIR1 directly. Crystal structure determination, structure-based mutagenesis, TAB1 siRNA knockdown, NF-κB reporter assays Molecular cell High 17560374
2008 Inactivation of the XIAP RING domain by gene targeting stabilizes XIAP protein in apoptotic thymocytes, demonstrating that XIAP E3 ubiquitin ligase activity is a major determinant of XIAP protein stability. Paradoxically, increased XIAP-BIR-only protein leads to elevated caspase-3 activity and apoptosis, and DeltaRING cells are sensitized to TNF-α-induced apoptosis, showing the RING domain is required for full caspase inhibition in vivo. Gene targeting (RING domain deletion knock-in), caspase-3 activity assays, apoptosis assays, Eμ-Myc lymphoma model Genes & development High 18708583
2009 XIAP mediates NOD1/NOD2 innate immune signaling by physically interacting with the kinase RIP2 via its BIR2 domain; XIAP-deficient cells show markedly reduced NF-κB activation in response to NOD ligands. Both NOD1 and NOD2 associate with XIAP in a RIP2-dependent manner. SMAC and SMAC-mimetic compounds disrupt the XIAP-RIP2 interaction. Co-immunoprecipitation, XIAP-deficient cells, NF-κB reporter assays, NOD1/2 overexpression Proceedings of the National Academy of Sciences of the United States of America High 19667203
2009 XIAP is the critical discriminator between type I and type II FAS-induced apoptosis: loss of XIAP function (by gene targeting or SMAC mimetic) renders hepatocytes and pancreatic beta-cells (type II cells) independent of BID for FAS-induced apoptosis, showing XIAP imposes a brake on effector caspases that necessitates mitochondrial amplification in type II cells. Gene targeting (XIAP KO mice), SMAC mimetic drug treatment, FAS-induced apoptosis assays, genetic epistasis with BID KO Nature High 19626005
2009 XIAP associates with PTEN in vitro and in vivo, promotes PTEN mono- and polyubiquitination, and acts as an E3 ubiquitin ligase for PTEN directly in vitro, leading to proteasomal degradation of PTEN and nuclear exclusion. XIAP-mediated regulation of Akt phosphorylation is PTEN-dependent. Co-immunoprecipitation, in vitro ubiquitination assay, siRNA knockdown, XIAP-/- MEFs, Western blot The Journal of biological chemistry High 19473982
2009 MDM2 physically interacts with the IRES of the XIAP 5'-UTR and positively regulates XIAP IRES-dependent translation. DNA damage and irradiation trigger MDM2 dephosphorylation and cytoplasmic relocalization, increasing IRES-dependent XIAP translation. Co-immunoprecipitation (MDM2-XIAP IRES RNA interaction), IRES reporter assays, MDM2 transfection/localization studies Cancer cell Medium 19411066
2010 S-nitrosylation of XIAP's RING domain (forming SNO-XIAP) by nitric oxide inhibits XIAP's E3 ubiquitin ligase and anti-apoptotic activity. SNO-caspase transnitrosylates XIAP (transferring NO to XIAP), promoting cell injury. SNO-XIAP was found in brains of Alzheimer's, Parkinson's, and Huntington's disease patients. Biotin-switch assay for S-nitrosylation, E3 ligase activity assays, mass spectrometry, transnitrosylation assay, human brain tissue analysis Molecular cell High 20670888
2010 XIAP promotes ubiquitination and degradation of COMMD1 (a copper efflux regulator) via its RING E3 ligase domain, thereby regulating intracellular copper export. Copper directly binds XIAP, causing a conformational change that destabilizes XIAP, reduces steady-state XIAP levels, and abrogates caspase inhibition, linking copper levels to cell death regulation. Ubiquitination assay, protein binding/conformational analysis, copper binding assay, caspase inhibition assay Archives of biochemistry and biophysics Medium 17382285
2009 COMMD1's COMM domain is required for interaction with XIAP; two conserved leucine repeats within the COMM domain are critically required for XIAP binding. A COMMD1 mutant unable to bind XIAP shows complete loss of basal ubiquitination and greatly increased protein stability, demonstrating XIAP is the primary E3 ligase controlling COMMD1 expression. GST pulldown, mutagenesis, ubiquitination assay, Western blot The Biochemical journal High 18795889
2010 RNA-binding protein HuR directly binds to the XIAP IRES in vitro and in vivo, stimulates IRES-dependent translation of XIAP mRNA, and promotes recruitment of XIAP mRNA into polysomes. HuR-mediated cytoprotection against etoposide requires XIAP. RNA immunoprecipitation, in vitro RNA binding assay, polysome fractionation, XIAP knockdown rescue experiments Oncogene High 21102524
2010 HuR binds to both the 3'-UTR and coding sequence of XIAP mRNA, stabilizing the transcript and elevating XIAP protein levels. Decreasing cellular polyamines increases cytoplasmic HuR and HuR-XIAP mRNA complexes, promoting XIAP mRNA stability and resistance to apoptosis. RNA immunoprecipitation, mRNA stability assay, HuR overexpression/knockdown, polyamine depletion experiments Nucleic acids research Medium 19825980
2010 ARTS (a mitochondrial protein) binds XIAP at BIR1 (distinct from caspase-binding sites) and recruits E3 ligase Siah-1 as an adaptor to induce Siah-1-mediated ubiquitination and degradation of XIAP. Cells lacking either Siah or ARTS contain higher steady-state XIAP levels. Co-immunoprecipitation, ubiquitination assay, ARTS-KO and Siah-KO cell analysis Molecular cell High 21185211
2013 XIAP suppresses autophagy by acting as a previously unidentified E3 ubiquitin ligase for Mdm2, a negative regulator of p53. This XIAP-Mdm2-p53 pathway operates downstream of the PI3K/Akt pathway to control serum starvation-induced autophagy. In vitro ubiquitination assay, epistasis analysis with PI3K/Akt inhibitors, XIAP knockdown/overexpression, autophagy assays, mouse xenograft model The EMBO journal High 23749209
2014 Loss of XIAP or its RING domain leads to TNF-dependent, RIP3-dependent excessive cell death and IL-1β secretion from dendritic cells triggered by TLR stimuli. Loss of XIAP results in aberrantly elevated ubiquitylation of RIP1 outside of TNFR complex I, and RING domain deletion (not just XIAP loss) is sufficient for this phenotype. Gene-targeted mice (XIAP KO and RING domain deletion), TLR stimulation assays, IL-1β ELISA, RIP3/caspase KO epistasis, ubiquitylation analysis Cell reports High 24882010
2018 Selective XIAP antagonism blocks NOD2-mediated inflammatory signaling and cytokine production by disrupting XIAP-RIP2 binding and preventing XIAP-mediated ubiquitination of RIP2. RIP2 kinase activity is dispensable for NOD2 signaling; rather, the conformation of the RIP2 kinase domain regulates binding to XIAP BIR2. Specific lysine residues on RIP2 are required for NOD2 pathway signaling (XIAP ubiquitination sites). Co-immunoprecipitation, ubiquitination site mapping (mass spectrometry), RIP2 kinase inhibitor studies, mutagenesis of RIP2 lysine residues, NF-κB/MAPK activation assays Molecular cell High 29452636
2008 Following TNFα stimulation, XIAP interacts with and ubiquitinates MEKK2, a kinase associated with bi-phasic NF-κB activation, to regulate a second wave of NF-κB activation in an ubiquitin ligase-dependent manner. Co-immunoprecipitation, ubiquitination assay, NF-κB reporter assays, XIAP overexpression Cellular signalling Medium 18761086
2009 XIAP is cleaved by caspase-3 and caspase-7 during apoptosis in T lymphocytes, generating a p29 fragment. The p29 fragment retains the ability to bind caspase-3 and -7. Cleavage is inhibited by pan-caspase inhibitor Z-VAD.FMK. In vitro cleavage assay with recombinant caspases, co-immunoprecipitation, cell-based apoptosis assays Cancer research Medium 10766165
2004 Full-length XIAP (but not a truncation mutant retaining only caspase-9 inhibition) blocks CD95-mediated mitochondrial cytochrome c and Smac/DIABLO release, loss of mitochondrial membrane potential, and caspase-3 processing, demonstrating that full-length XIAP inhibits caspase activation upstream of mitochondrial amplification of death receptor signals. Stable overexpression of full-length vs. truncation mutant XIAP, cytochrome c release assay, mitochondrial membrane potential assay, RNA interference knockdown Molecular and cellular biology High 15282301
2017 XIAP (via its RING domain E3 ligase activity) directly binds Cdc42 and conjugates poly-ubiquitin chains to lysine-166 of Cdc42, targeting it for proteasomal degradation. XIAP depletion increases Cdc42 protein stability and activity, enhancing filopodia formation in a Cdc42-dependent manner and promoting tumor cell lung colonization. Co-immunoprecipitation, in vitro ubiquitination assay, mutagenesis (K166 Cdc42), XIAP knockdown, filopodia quantification, in vivo lung colonization assay Cell death & disease High 28661476
2017 ARTS (Sept4_i2) brings XIAP and Bcl-2 into a ternary complex at the outer mitochondrial membrane upon apoptotic induction, allowing XIAP to function as an E3 ligase that ubiquitylates Bcl-2 at lysine-17 for degradation. ARTS binding to Bcl-2 involves the BH3 domain of Bcl-2. Bcl-2 K17A mutant is more stable and more protective against apoptosis. Bcl-2 ubiquitylation is reduced in both XIAP- and Sept4/ARTS-deficient MEFs. Co-immunoprecipitation (ternary complex), in vitro ubiquitination assay, mutagenesis (Bcl-2 K17A, BH3 domain), KO MEFs, cell death assays Cell reports High 29020630
2016 USP9X is the mitotic deubiquitinase of XIAP; USP9X deubiquitylates and stabilizes XIAP, leading to increased resistance toward mitotic spindle poisons. Knockdown of USP9X or XIAP sensitizes lymphoma cells to spindle poisons and delays lymphoma development in a murine model. Co-immunoprecipitation, deubiquitylation assay, siRNA knockdown, cell viability assays, Eμ-Myc murine lymphoma model EMBO molecular medicine High 27317434
2022 USP7 deubiquitinates XIAP to inhibit its proteasomal degradation; USP7 inhibition reduces XIAP protein levels and induces caspase-dependent apoptosis. Combinatorial inhibition of USP7 and XIAP enhances apoptosis in vitro and in vivo. Proteomics/GSEA analysis, co-immunoprecipitation, ubiquitination/deubiquitination assay, USP7 modulation (overexpression and inhibition), in vivo tumor xenograft Oncogene Medium 36243803
2010 HAX-1 physically interacts with the BIR2 and BIR3 domains of XIAP (confirmed by GST pulldown and surface plasmon resonance); XIAP binds the C-terminal domain of HAX-1. HAX-1 suppresses polyubiquitination of XIAP, enhancing XIAP stability, and the HAX-1-XIAP complex inhibits apoptosis. GST pulldown, surface plasmon resonance, co-immunoprecipitation, polyubiquitination assay, cell viability assay Biochemical and biophysical research communications Medium 20171186
2009 Siva1 interacts with XIAP via the RING domain of XIAP and N-terminal domains of Siva1; XIAP, Siva1, and TAK1 form a ternary complex. Siva1 inhibits XIAP/TAK1-TAB1-mediated NF-κB activation while enhancing JNK activation, shifting the balance toward apoptosis. XIAP ubiquitin ligase activity mediates Lys-48-linked polyubiquitylation of Siva1. Co-immunoprecipitation (ternary complex), reporter gene assays, Siva1 knockdown, ubiquitination assay (K48 linkage determination) Journal of cell science Medium 19584092
2017 XIAP promotes Lys63-linked polyubiquitination of HIF1α in a Ubc13 (E2)-dependent manner, promoting HIF1α nuclear retention and increased expression of HIF1-responsive genes. Inhibition of this pathway reduces nuclear HIF1α, promoter occupancy, and cell viability. Co-immunoprecipitation, Lys63-specific ubiquitin chain assay, Ubc13 depletion, HIF1α nuclear fractionation, HIF target gene expression assay Nucleic acids research Medium 28666324
2015 XIAP and cIAP1 induce Beclin 1-dependent autophagy by activating NF-κB signaling through their E3 ubiquitin ligase activity, which leads to direct p65 binding to the Beclin 1 promoter and transcriptional activation. Pharmacological XIAP inhibition in overexpressing B-cell lymphoma lines reduces autophagosome biogenesis. Chromatin immunoprecipitation (p65/Beclin 1 promoter), NF-κB reporter assays, XIAP/cIAP1 overexpression, XIAP inhibitor treatment, autophagy quantification Human molecular genetics Medium 25669656
2014 XIAP co-associates with the C-terminus of Patched1 (Ptch1) in primary cilia to inhibit Ptch1-mediated cell death. Inhibition of XIAP suppresses cell proliferation and causes cell death resembling a Hedgehog loss-of-function phenotype, demonstrating that co-ordinated brain and craniofacial development depends on XIAP mediation of Hh/Ptch1-regulated cell survival. Co-immunoprecipitation (XIAP-Ptch1-C), XIAP inhibitor treatment, primary cilia localization studies, cell death assays Human molecular genetics Medium 25292199
2019 XIAP controls RIPK2 complex formation: XIAP-mediated ubiquitylation of RIPK2 prevents its deposition into detergent-insoluble higher-order speck-like structures; mutation of XIAP ubiquitylation sites on RIPK2 enhances complex formation. RIPK2 autophosphorylation at Y474 and phosphorylation status at S176 influence these structures. Detergent fractionation, RIPK2 mutagenesis (ubiquitylation sites, Y474, S176), bacterial infection model, confocal microscopy Life science alliance Medium 31350258
2023 In XIAP-deficient macrophages, extrinsic apoptotic caspase-8 promotes pyroptotic GSDMD processing; combined deletion of apoptotic (caspase-3/-7) and pyroptotic (GSDMD) machinery is required to fully abrogate cell death and bioactive IL-1β release. Caspase-8-driven NLRP3 inflammasome assembly and IL-1β maturation is independent of GSDMD and pannexin-1 channel, distinguishing this from mitochondrial apoptosis-triggered NLRP3 activation. XIAP-deficient patient tissue analysis, macrophage KO (caspase-1/-3/-7/-11, BID, GSDMD/E, pannexin-1) epistasis, caspase activity assays, IL-1β ELISA, cell death quantification The EMBO journal High 36647737
2024 XIAP functions as an E3 ubiquitin ligase for IFT88 (intraflagellar transport protein 88); TGF-β enhances XIAP-mediated ubiquitination and proteasomal degradation of IFT88 in hepatic stellate cells (HSCs), leading to primary cilia loss and HSC activation. Blocking XIAP-mediated IFT88 degradation prevents TGF-β-induced HSC activation and liver fibrosis. Co-immunoprecipitation, in vitro ubiquitination assay, Ift88-KO mice, XIAP inhibition (genetic and pharmacological), TGF-β stimulation, liver fibrosis model (CCl4) EMBO reports High 38351372
2022 XIAP mediates RIPK2 ubiquitylation and involves a TAB1/RIPK2 complex to induce transcriptional up-regulation and secretion of IL-8 and other chemokines responsible for intra-tumour neutrophil accumulation in melanoma. Alteration of the XIAP-RIPK2-TAB1 axis or neutrophil depletion reduces melanoma growth. In vitro XIAP-RIPK2 ubiquitylation analysis, TAB1/RIPK2 complex analysis, XIAP manipulation in melanoma models, neutrophil depletion, cytokine measurement, mouse melanoma models EMBO reports Medium 35437868
2006 BIRC4/XIAP protein is present in postsynaptic dendritic spines in unstimulated zebra finch auditory forebrain, where it binds and sequesters active caspase-3. Following song stimuli, caspase-3 activity at postsynaptic sites increases briefly, and caspase-3 activity is required to consolidate a persistent physiological memory trace, suggesting XIAP regulates a non-apoptotic function of caspase-3 in synaptic plasticity. Confocal and immunoelectron microscopy (localization to dendritic spines), pharmacological interference of caspase-3, zenk gene habituation assay Neuron Medium 17178408
2009 GDF5 and BMP2 stimulate the physical interaction between BMPR2 and XIAP, reducing XIAP ubiquitination and increasing XIAP protein stability, thereby allowing XIAP to bind and inactivate activated caspases and prevent apoptosis in mouse embryonic fibroblasts. Co-immunoprecipitation (BMPR2-XIAP), ubiquitination assay, BMPR2 loss-of-function, apoptosis assays Biochimica et biophysica acta Medium 19782107

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 XIAP discriminates between type I and type II FAS-induced apoptosis. Nature 371 19626005
2001 Characterization of XIAP-deficient mice. Molecular and cellular biology 356 11313486
2003 Akt phosphorylation and stabilization of X-linked inhibitor of apoptosis protein (XIAP). The Journal of biological chemistry 355 14645242
2001 XIAP: apoptotic brake and promising therapeutic target. Apoptosis : an international journal on programmed cell death 338 11445667
2011 Fas death receptor signalling: roles of Bid and XIAP. Cell death and differentiation 292 21959933
1999 NMR structure and mutagenesis of the inhibitor-of-apoptosis protein XIAP. Nature 283 10548111
2006 Targeting XIAP for the treatment of malignancy. Cell death and differentiation 254 16322751
2009 XIAP mediates NOD signaling via interaction with RIP2. Proceedings of the National Academy of Sciences of the United States of America 253 19667203
2007 XIAP induces NF-kappaB activation via the BIR1/TAB1 interaction and BIR1 dimerization. Molecular cell 233 17560374
2001 XIAP, the guardian angel. Nature reviews. Molecular cell biology 228 11433370
2014 XIAP restricts TNF- and RIP3-dependent cell death and inflammasome activation. Cell reports 217 24882010
2010 XIAP as a ubiquitin ligase in cellular signaling. Cell death and differentiation 193 19590513
2000 Expression and genetic analysis of XIAP-associated factor 1 (XAF1) in cancer cell lines. Genomics 187 11087668
2008 Regulation of apoptosis by XIAP ubiquitin-ligase activity. Genes & development 160 18708583
2010 Transnitrosylation of XIAP regulates caspase-dependent neuronal cell death. Molecular cell 155 20670888
2014 cIAPs and XIAP regulate myelopoiesis through cytokine production in an RIPK1- and RIPK3-dependent manner. Blood 150 24497535
2009 Regulation of XIAP translation and induction by MDM2 following irradiation. Cancer cell 145 19411066
2009 X-linked inhibitor of apoptosis protein (XIAP) regulates PTEN ubiquitination, content, and compartmentalization. The Journal of biological chemistry 135 19473982
2014 XIAP variants in male Crohn's disease. Gut 127 24572142
2013 XIAP inhibits autophagy via XIAP-Mdm2-p53 signalling. The EMBO journal 124 23749209
2015 FOXM1 targets XIAP and Survivin to modulate breast cancer survival and chemoresistance. Cellular signalling 104 26404623
1998 Selective activation of JNK1 is necessary for the anti-apoptotic activity of hILP. Proceedings of the National Academy of Sciences of the United States of America 104 9600909
1999 Expression and biological activity of X-linked inhibitor of apoptosis (XIAP) in human malignant glioma. Cell death and differentiation 103 10381630
2003 Regulation and targeting of antiapoptotic XIAP in acute myeloid leukemia. Leukemia 101 12970762
2006 Dynamic role of postsynaptic caspase-3 and BIRC4 in zebra finch song-response habituation. Neuron 99 17178408
2018 Disruption of XIAP-RIP2 Association Blocks NOD2-Mediated Inflammatory Signaling. Molecular cell 98 29452636
2013 MicroRNA-7 downregulates XIAP expression to suppress cell growth and promote apoptosis in cervical cancer cells. FEBS letters 98 23742934
2004 Upstream regulatory role for XIAP in receptor-mediated apoptosis. Molecular and cellular biology 91 15282301
2020 Anti-apoptotic proteins in the autophagic world: an update on functions of XIAP, Survivin, and BRUCE. Journal of biomedical science 86 32019552
2011 Erythropoietin and Wnt1 govern pathways of mTOR, Apaf-1, and XIAP in inflammatory microglia. Current neurovascular research 85 22023617
2005 Downregulation of XIAP expression induces apoptosis and enhances chemotherapeutic sensitivity in human gastric cancer cells. Cancer gene therapy 85 15706355
2020 Regulation of Cell Death and Immunity by XIAP. Cold Spring Harbor perspectives in biology 80 31843992
2020 Targeting XIAP for Promoting Cancer Cell Death-The Story of ARTS and SMAC. Cells 79 32182843
2016 Loss of XIAP facilitates switch to TNFα-induced necroptosis in mouse neutrophils. Cell death & disease 77 27735938
2010 RNA-binding protein HuR mediates cytoprotection through stimulation of XIAP translation. Oncogene 77 21102524
2019 Cannabidiol promotes apoptosis via regulation of XIAP/Smac in gastric cancer. Cell death & disease 75 31699976
2017 Degradation of Bcl-2 by XIAP and ARTS Promotes Apoptosis. Cell reports 74 29020630
2021 Evolution of Our Understanding of XIAP Deficiency. Frontiers in pediatrics 73 34222142
2007 XIAP: cell death regulation meets copper homeostasis. Archives of biochemistry and biophysics 73 17382285
2020 XIAP's Profile in Human Cancer. Biomolecules 72 33138314
2009 Stabilization of XIAP mRNA through the RNA binding protein HuR regulated by cellular polyamines. Nucleic acids research 70 19825980
2016 Discovery of Dual Inhibitors of MDM2 and XIAP for Cancer Treatment. Cancer cell 69 27666947
2000 Inhibitor of apoptosis protein hILP undergoes caspase-mediated cleavage during T lymphocyte apoptosis. Cancer research 64 10766165
2005 Application of XIAP antisense to cancer and other proliferative disorders: development of AEG35156/ GEM640. Annals of the New York Academy of Sciences 62 16394139
2022 XIAP as a multifaceted molecule in Cellular Signaling. Apoptosis : an international journal on programmed cell death 59 35661061
2016 USP9X stabilizes XIAP to regulate mitotic cell death and chemoresistance in aggressive B-cell lymphoma. EMBO molecular medicine 59 27317434
2023 Caspase-8-driven apoptotic and pyroptotic crosstalk causes cell death and IL-1β release in X-linked inhibitor of apoptosis (XIAP) deficiency. The EMBO journal 58 36647737
2021 Exosomal Circ-XIAP Promotes Docetaxel Resistance in Prostate Cancer by Regulating miR-1182/TPD52 Axis. Drug design, development and therapy 55 33976535
2016 Hematopoietic Stem Cell Transplantation for XIAP Deficiency in Japan. Journal of clinical immunology 55 27815752
2006 XIAP targeting sensitizes Hodgkin lymphoma cells for cytolytic T-cell attack. Blood 55 16868249
2010 ARTS and Siah collaborate in a pathway for XIAP degradation. Molecular cell 51 21185211
2015 XIAP and cIAP1 amplifications induce Beclin 1-dependent autophagy through NFκB activation. Human molecular genetics 48 25669656
2017 Expression and function of ABCG2 and XIAP in glioblastomas. Journal of neuro-oncology 46 28432589
2009 COMMD1 expression is controlled by critical residues that determine XIAP binding. The Biochemical journal 45 18795889
2010 Genetic analysis of BIRC4/XIAP as a putative modifier gene of Wilson disease. Journal of inherited metabolic disease 44 20517649
2020 RIPK2 NODs to XIAP and IBD. Seminars in cell & developmental biology 43 32631784
2010 Distinct 5' UTRs regulate XIAP expression under normal growth conditions and during cellular stress. Nucleic acids research 43 20385593
2009 Patients with X-linked lymphoproliferative disease due to BIRC4 mutation have normal invariant natural killer T-cell populations. Clinical immunology (Orlando, Fla.) 43 19398375
2004 XIAP as target for therapeutic apoptosis in prostate cancer. Drug news & perspectives 42 15098067
2000 Apoptosis and chemoresistance in human ovarian cancer: is Xiap a determinant? Biological signals and receptors 41 10810207
2012 Pulling the plug on a cancer cell by eliminating XIAP with AEG35156. Cancer letters 40 22776562
2005 XIAP overexpression in islet beta-cells enhances engraftment and minimizes hypoxia-reperfusion injury. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons 40 15888033
2020 Cadmium induces mitochondrial ROS inactivation of XIAP pathway leading to apoptosis in neuronal cells. The international journal of biochemistry & cell biology 38 32035180
2019 NQO1 potentiates apoptosis evasion and upregulates XIAP via inhibiting proteasome-mediated degradation SIRT6 in hepatocellular carcinoma. Cell communication and signaling : CCS 38 31842909
2010 Molecular interaction between HAX-1 and XIAP inhibits apoptosis. Biochemical and biophysical research communications 38 20171186
2008 Spongistatin 1: a new chemosensitizing marine compound that degrades XIAP. Leukemia 36 18548102
2009 XIAP-mediated protection of H460 lung cancer cells against cisplatin. European journal of pharmacology 35 19903469
2007 Che-1 activates XIAP expression in response to DNA damage. Cell death and differentiation 35 18049476
2009 GDF5 and BMP2 inhibit apoptosis via activation of BMPR2 and subsequent stabilization of XIAP. Biochimica et biophysica acta 34 19782107
2008 XIAP regulates bi-phasic NF-kappaB induction involving physical interaction and ubiquitination of MEKK2. Cellular signalling 33 18761086
2006 XIAP-mediated neuroprotection in retinal ischemia. Gene therapy 33 16307001
2012 SAP and XIAP deficiency in hemophagocytic lymphohistiocytosis. Pediatrics international : official journal of the Japan Pediatric Society 31 22672194
2009 Siva1 is a XIAP-interacting protein that balances NFkappaB and JNK signalling to promote apoptosis. Journal of cell science 31 19584092
2018 The feline calicivirus leader of the capsid protein causes survivin and XIAP downregulation and apoptosis. Virology 30 30529563
2022 Quercetin ameliorates XIAP deficiency-associated hyperinflammation. Blood 29 35687753
2022 Neutrophil extracellular traps promote keratinocyte inflammation via AIM2 inflammasome and AIM2-XIAP in psoriasis. Experimental dermatology 29 36401800
2017 Ubiquitin-dependent regulation of Cdc42 by XIAP. Cell death & disease 29 28661476
2010 Effectiveness of High Intensity Light Pulses (HILP) treatments for the control of Escherichia coli and Listeria innocua in apple juice, orange juice and milk. Food microbiology 29 21056770
2022 USP7 targets XIAP for cancer progression: Establishment of a p53-independent therapeutic avenue for glioma. Oncogene 28 36243803
2012 Combination therapy of antiandrogen and XIAP inhibitor for treating advanced prostate cancer. Pharmaceutical research 28 22451249
2017 XIAP underlies apoptosis resistance of renal cell carcinoma cells. Molecular medicine reports 27 29115633
2015 Symptomatic males and female carriers in a large Caucasian kindred with XIAP deficiency. Journal of clinical immunology 27 25943627
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
2004 Translational regulation of XIAP expression and cell survival during hypoxia in human cholangiocarcinoma. Gastroenterology 27 15578516
2020 LncRNA CYTOR attenuates sepsis-induced myocardial injury via regulating miR-24/XIAP. Cell biochemistry and function 26 32181504
2019 XIAP controls RIPK2 signaling by preventing its deposition in speck-like structures. Life science alliance 26 31350258
2014 Clinical flow cytometric screening of SAP and XIAP expression accurately identifies patients with SH2D1A and XIAP/BIRC4 mutations. Cytometry. Part B, Clinical cytometry 26 24616127
2001 Regulation of caspases and XIAP in the brain after asphyxial cardiac arrest in rats. Neuroreport 26 11726787
2017 XIAP upregulates expression of HIF target genes by targeting HIF1α for Lys63-linked polyubiquitination. Nucleic acids research 25 28666324
2022 XIAP promotes melanoma growth by inducing tumour neutrophil infiltration. EMBO reports 24 35437868
2017 High expression of XIAP and Bcl-2 may inhibit programmed cell death in glioblastomas. Arquivos de neuro-psiquiatria 24 29236891
2010 XIAP reduces muscle proteolysis induced by CKD. Journal of the American Society of Nephrology : JASN 24 20431038
2016 XIAP-associating factor 1, a transcriptional target of BRD7, contributes to endothelial cell senescence. Oncotarget 23 26802028
2014 Co-ordinated brain and craniofacial development depend upon Patched1/XIAP regulation of cell survival. Human molecular genetics 23 25292199
2008 Inhibiting XIAP expression by RNAi to inhibit proliferation and enhance radiosensitivity in laryngeal cancer cell line. Auris, nasus, larynx 23 19013033
2016 Urocortin-1 Mediated Cardioprotection Involves XIAP and CD40-Ligand Recovery: Role of EPAC2 and ERK1/2. PloS one 22 26840743
2014 XIAP protein is induced by placenta growth factor (PLGF) and decreased during preeclampsia in trophoblast cells. Systems biology in reproductive medicine 22 25003840
2014 Clinical Flow Cytometric Screening of SAP and XIAP Expression Accurately Identifies Patients with SH2D1A and XIAP/BIRC4 Mutations. Cytometry. Part B, Clinical cytometry 22 26305518
2012 XIAP: a potential determinant of ovarian follicular fate. Reproduction (Cambridge, England) 22 22653317
2024 XIAP-mediated degradation of IFT88 disrupts HSC cilia to stimulate HSC activation and liver fibrosis. EMBO reports 21 38351372

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