# XIAP
**XIAP** (X-linked inhibitor of apoptosis protein), also known as **BIRC4**, hILP, and MIHA, is a human protein that directly suppresses apoptosis, the programmed death of cells, by binding and inhibiting caspases, the proteases that execute cell disassembly[1](https://aacrjournals.org/clincancerres/article/13/20/5995/194737/The-Inhibitor-of-Apoptosis-Proteins-as-Therapeutic) • [2](https://pmc.ncbi.nlm.nih.gov/articles/PMC2957808/). It is encoded on the [X chromosome](https://www.edgepedia.org/x-chromosome) at Xq25[3](https://www.ncbi.nlm.nih.gov/clinvar/RCV001219664/). Beyond its antiapoptotic role, XIAP acts as an E3 ubiquitin ligase and participates in signaling pathways, and inherited loss of its function causes a form of X-linked lymphoproliferative disease[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC2957808/) • [4](https://search.clinicalgenome.org/kb/gene-validity/CGGV%3Aassertion_de468a50-5a60-43c8-bc73-a7f6938534a3-2026-07-22T16%3A00%3A00.000Z).
| Key fact | Detail |
|---|---|
| Names and gene | X-linked inhibitor of apoptosis protein; also hILP, MIHA, BIRC4; located at Xq25[1](https://aacrjournals.org/clincancerres/article/13/20/5995/194737/The-Inhibitor-of-Apoptosis-Proteins-as-Therapeutic) • [3](https://www.ncbi.nlm.nih.gov/clinvar/RCV001219664/) |
| Domain structure | Three baculoviral IAP repeat (BIR) domains, a ubiquitin-associated (UBA) domain, and a C-terminal RING finger domain[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC2957808/) |
| Caspase targets | The BIR1–BIR2 linker region inhibits caspase-3 and caspase-7; the BIR3 domain inhibits caspase-9[5](https://www.nature.com/articles/nrm1496) |
| Endogenous antagonist | Smac/DIABLO, released from mitochondria, uses its N-terminal tetrapeptide (Ala-Val-Pro-Ile) to compete with caspase-9 for the BIR3 binding groove[5](https://www.nature.com/articles/nrm1496) • [6](https://pmc.ncbi.nlm.nih.gov/articles/PMC7692959/) |
| Enzymatic activity | The RING domain functions as an E3 ubiquitin ligase; XIAP can catalyze its own autoubiquitination[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC2957808/) |
| Disease link | Germline XIAP deficiency causes X-linked lymphoproliferative disease due to XIAP deficiency (XLP2), first reported in 2006[4](https://search.clinicalgenome.org/kb/gene-validity/CGGV%3Aassertion_de468a50-5a60-43c8-bc73-a7f6938534a3-2026-07-22T16%3A00%3A00.000Z) |
| Drug development | Smac mimetics such as birinapant, LCL161, and AT-406/Debio 1143 have been evaluated in early clinical trials as cancer therapeutics[7](https://aacrjournals.org/clincancerres/article/21/22/5030/78997/Promises-and-Challenges-of-Smac-Mimetics-as-Cancer) |
## Structure and caspase inhibition
XIAP is a broadly expressed protein whose study has centered on its interactions with caspases, the proteases that carry out the ordered disassembly of the cell during apoptosis[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC2957808/). The protein contains three BIR (baculoviral IAP repeat) domains, a ubiquitin-binding UBA domain, and a RING finger domain[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC2957808/).
The two caspase targets are inhibited by different parts of the protein. Effector caspases: inhibition of caspase-3 and caspase-7 depends on the linker region between the BIR1 and BIR2 domains, which occupies the caspase active site; structural work showed the BIR domains themselves are dispensable for this inhibition[5](https://www.nature.com/articles/nrm1496) • [8](https://pubmed.ncbi.nlm.nih.gov/11257230/). The modes differ between the two enzymes: caspase-3 is inhibited competitively through its active site, while caspase-7 inhibition involves both the linker and the BIR2 domain in a mixed competitive and noncompetitive mechanism[9](https://pubmed.ncbi.nlm.nih.gov/11359776/). Initiator caspase: the BIR3 domain inhibits caspase-9 by sequestering it in a monomeric state, so the active site cannot be productively formed; this inhibition depends on binding between a conserved surface groove of BIR3 and the N-terminal tetrapeptide (Ala-Thr-Pro-Phe) of the small subunit of caspase-9[5](https://www.nature.com/articles/nrm1496).
## Antagonism by Smac
The endogenous counterweight to XIAP is Smac (also called DIABLO), a protein of the mitochondrial intermembrane space that is released into the cytosol in response to cell death signals[6](https://pmc.ncbi.nlm.nih.gov/articles/PMC7692959/). Smac uses its N-terminal tetrapeptide, Ala-Val-Pro-Ile, to compete with caspase-9 for the same conserved surface groove of the XIAP BIR3 domain, effectively removing XIAP-mediated inhibition of caspase-9[5](https://www.nature.com/articles/nrm1496). IBM-containing proteins such as Smac, and synthetic small-molecule mimics of that motif, can neutralize XIAP's caspase-inhibitory properties through steric occlusion of the domains XIAP uses to bind caspases[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC2957808/).
## Ubiquitin ligase activity
The RING (really interesting new gene) domain at the C-terminus of XIAP gives it E3 ubiquitin ligase activity, catalyzing the transfer of ubiquitin onto substrate proteins[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC2957808/) • [10](https://cshperspectives.cshlp.org/content/early/2019/12/14/cshperspect.a036426.full.pdf). In a recombinant, cell-free system, XIAP was shown to function as an E3 ligase catalyzing its own autoubiquitination, although confirming this endogenously in living cells has been a challenge[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC2957808/).
Mouse genetics have separated XIAP's two functions. A targeted XIAP ΔRING allele, which uncouples caspase binding from the ubiquitin system, showed that removing the RING stabilized XIAP in apoptotic thymocytes, demonstrating that E3 ligase activity is a major determinant of XIAP protein stability in vivo[11](https://genesdev.cshlp.org/content/22/16/2256.full.pdf). XIAP also ubiquitinates other substrates: BIR2 binds the kinase RIPK2, allowing XIAP to ubiquitinate it in the NOD2 signaling pathway, and XIAP has been reported to downregulate the IAP family member survivin through a mechanism requiring the associated factor XAF1 and an intact RING[10](https://cshperspectives.cshlp.org/content/early/2019/12/14/cshperspect.a036426.full.pdf) • [2](https://pmc.ncbi.nlm.nih.gov/articles/PMC2957808/).
## XIAP in cancer and Smac mimetics
Many cancers overexpress IAP proteins, enabling tumor cells to evade apoptosis, and XIAP in particular has become an attractive target for cancer therapy[12](https://pmc.ncbi.nlm.nih.gov/articles/PMC7140716/). XIAP overexpression in cancer cells confers resistance to apoptosis[13](https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2026.1820203/pdf), and down-regulation of XIAP by adenoviral antisense expression induced apoptosis in ovarian cancer cells with wild-type p53[14](https://aacrjournals.org/clincancerres/article/8/7/2024/289117/ApoptosisTarget-of-Cancer-Therapy).
**Smac mimetics.** The main drug class directed at XIAP and its relatives mimics the N-terminal four amino acids of Smac required for IAP binding, but uses non-peptidic elements[7](https://aacrjournals.org/clincancerres/article/21/22/5030/78997/Promises-and-Challenges-of-Smac-Mimetics-as-Cancer). Most developed Smac mimetics are pan-selective inhibitors that in principle neutralize cIAP1, cIAP2, and XIAP, though they vary in potency against each protein[7](https://aacrjournals.org/clincancerres/article/21/22/5030/78997/Promises-and-Challenges-of-Smac-Mimetics-as-Cancer) • [15](https://aacrjournals.org/clincancerres/article/20/15/3915/206094/Molecular-Pathways-Targeting-Death-Receptors-and). Their interaction with XIAP leads to caspase activation, while binding to cIAP proteins enhances the cIAPs' E3 ligase activity, promoting autoubiquitination and proteasomal degradation of the cIAPs; the resulting accumulation of NIK activates noncanonical NF-κB signaling and upregulates TNFα, which then triggers caspase-8 activation and apoptosis[7](https://aacrjournals.org/clincancerres/article/21/22/5030/78997/Promises-and-Challenges-of-Smac-Mimetics-as-Cancer).
Compounds evaluated in early clinical trials include monovalent agents with one Smac-mimicking moiety (GDC-0917/CUDC-427, LCL161, and AT-406/Debio 1143) and bivalent agents with two Smac-mimicking elements joined by a chemical linker (TL32711/birinapant and HGS1029)[7](https://aacrjournals.org/clincancerres/article/21/22/5030/78997/Promises-and-Challenges-of-Smac-Mimetics-as-Cancer). GDC-0152 from [Genentech](https://www.edgepedia.org/genentech) was the first of these agents to enter a clinical trial, showing linear pharmacokinetics over intravenous doses from 0.049 to 1.48 mg/kg; the second-generation, orally bioavailable GDC-0917 enrolled 42 patients at doses from 5 to 600 mg daily in its phase I trial[16](https://pmc.ncbi.nlm.nih.gov/articles/PMC4247261/). Birinapant displays preferential binding to cIAP1 relative to cIAP2 and XIAP[12](https://pmc.ncbi.nlm.nih.gov/articles/PMC7140716/). A limitation of the class is the lack of suitable biomarkers to select patients likely to respond[15](https://aacrjournals.org/clincancerres/article/20/15/3915/206094/Molecular-Pathways-Targeting-Death-Receptors-and).
Because Smac degrades cIAPs but not XIAP, Smac mimetics are expected to work best in tumors with high cIAP levels, whereas a separate class of compounds modeled on the IAP antagonist ARTS binds and degrades XIAP but not cIAPs and is expected to be effective for cancers with high XIAP levels[12](https://pmc.ncbi.nlm.nih.gov/articles/PMC7140716/).
## XIAP deficiency and X-linked lymphoproliferative disease
Germline loss-of-function variants in XIAP cause [X-linked lymphoproliferative disease due to XIAP deficiency](https://www.edgepedia.org/x-linked-lymphoproliferative-disease-due-to-xiap-deficiency), also called XLP2. The relationship was first reported in 2006 by Rigaud and colleagues and has been repeatedly demonstrated in research and clinical diagnostic settings; the ClinGen Primary Immune Regulatory Disorders expert panel classifies the gene-disease validity as definitive[4](https://search.clinicalgenome.org/kb/gene-validity/CGGV%3Aassertion_de468a50-5a60-43c8-bc73-a7f6938534a3-2026-07-22T16%3A00%3A00.000Z). The disorder is a variable immune dysregulation condition that often presents with hemophagocytic lymphohistiocytosis, splenomegaly, hypogammaglobulinemia, inflammatory bowel disease, cytopenia, and recurrent or complicated infections[4](https://search.clinicalgenome.org/kb/gene-validity/CGGV%3Aassertion_de468a50-5a60-43c8-bc73-a7f6938534a3-2026-07-22T16%3A00%3A00.000Z). Allogeneic hematopoietic stem cell transplant is currently the only curative option for affected patients[4](https://search.clinicalgenome.org/kb/gene-validity/CGGV%3Aassertion_de468a50-5a60-43c8-bc73-a7f6938534a3-2026-07-22T16%3A00%3A00.000Z).
## References
1. [The Inhibitor of Apoptosis Proteins as Therapeutic Targets in Cancer, Clinical Cancer Research](https://aacrjournals.org/clincancerres/article/13/20/5995/194737/The-Inhibitor-of-Apoptosis-Proteins-as-Therapeutic)
2. [XIAP as a Ubiquitin Ligase in Cellular Signaling, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC2957808/)
3. [NM_001167.4(XIAP):c.272G>A (p.Arg91Lys) and X-linked lymphoproliferative disease due to XIAP deficiency, ClinVar](https://www.ncbi.nlm.nih.gov/clinvar/RCV001219664/)
4. [ClinGen Gene-Disease Validity curation: XIAP and X-linked lymphoproliferative disease due to XIAP deficiency](https://search.clinicalgenome.org/kb/gene-validity/CGGV%3Aassertion_de468a50-5a60-43c8-bc73-a7f6938534a3-2026-07-22T16%3A00%3A00.000Z)
5. [Riedl SJ, Shi Y (2004). Molecular mechanisms of caspase regulation during apoptosis. Nature Reviews Molecular Cell Biology 5, 897–907](https://www.nature.com/articles/nrm1496)
6. [XIAP's Profile in Human Cancer, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC7692959/)
7. [Promises and Challenges of Smac Mimetics as Cancer Therapeutics, Clinical Cancer Research](https://aacrjournals.org/clincancerres/article/21/22/5030/78997/Promises-and-Challenges-of-Smac-Mimetics-as-Cancer)
8. [Structural basis of caspase-7 inhibition by XIAP, PubMed](https://pubmed.ncbi.nlm.nih.gov/11257230/)
9. [X-linked inhibitor of apoptosis protein (XIAP) inhibits caspase-3 and -7 in distinct modes, PubMed](https://pubmed.ncbi.nlm.nih.gov/11359776/)
10. [Regulation of Cell Death and Immunity by XIAP, Cold Spring Harbor Perspectives in Biology](https://cshperspectives.cshlp.org/content/early/2019/12/14/cshperspect.a036426.full.pdf)
11. [Roles of XIAP ubiquitin-ligase activity, Genes & Development](https://genesdev.cshlp.org/content/22/16/2256.full.pdf)
12. [Targeting XIAP for Promoting Cancer Cell Death—The Story of ARTS and SMAC, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC7140716/)
13. [Review, Frontiers in Genetics](https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2026.1820203/pdf)
14. [Apoptosis: Target of Cancer Therapy, Clinical Cancer Research](https://aacrjournals.org/clincancerres/article/8/7/2024/289117/ApoptosisTarget-of-Cancer-Therapy)
15. [Molecular Pathways: Targeting Death Receptors and Smac Mimetics, Clinical Cancer Research](https://aacrjournals.org/clincancerres/article/20/15/3915/206094/Molecular-Pathways-Targeting-Death-Receptors-and)
16. [Small-Molecule SMAC Mimetics as New Cancer Therapeutics, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC4247261/)
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*Topic: Encyclopedia › Life and health › Biological foundations › Biochemistry and metabolism › Enzyme classes and activities › Proteolytic and peptidase enzymes › Proteases by catalytic mechanism › Cysteine proteases › Caspases and apoptotic proteolysis › Caspase regulation and inhibitors*
*Initially written Sep 17, 2026 · Reviewed: Sep 30, 2026; Oct 21, 2026 · Edited: Sep 30, 2026; Oct 21, 2026 · Last review: Oct 21, 2026*
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License: Edgepedia Community License 1.0, https://www.edgepedia.org/edgepedia/license