XIAP Gene

The XIAP gene (XIAP stands for "X-Linked Inhibitor Of Apoptosis") is a protein-coding gene located on chromosome Xq25. Alternative splicing results in multiple transcript variants. Pseudogenes of this gene are found on chromosomes 2 and 11.

The XIAP gene encodes a protein belonging to a family of apoptotic suppressor proteins. The apoptosis inhibitor family (IAP) proteins are important regulators of apoptosis through interaction with components of the apoptotic signaling cascades. They were discovered in baculovirus and their human homologs can be referred to as BIRC (Baculovirus IAP Repeat Containing) proteins.

The encoded protein acts by binding to tumor necrosis factor receptor-associated factors TRAF1 and TRAF2 and inhibits menadione-induced-menadione is a potent inducer of free radicals-(Gerasimenko JV et al 2002), interleukin-1-beta converting enzyme-induced apoptosis. XIAP- protein also directly inhibits caspase-3 and caspase-7 by binding to specific molecular structures of the active site of CASP3 and CASP7 and impeding substrate entry. It inactivates CASP9 by maintaining it in a monomeric, inactive state.

Mutations in this gene are the cause of:

X-linked lymphoproliferative syndrome (Lymphoproliferative Syndrome, X-Linked, 2, also called XLP2).

XIAP protein is a multifunctional protein that not only regulates caspases and apoptosis, but also modulates inflammatory signaling and immunity, copper homeostasis, mitogenic kinase signaling, cell proliferation, and cell invasion and metastasis. It acts as an E3 ubiquitin-protein ligase that regulates NF-kappa-B signaling. Target proteins for its E3 ubiquitin protein ligase activity include: RIPK1, CASP3, CASP7, CASP8, CASP9, MAP3K2/MEKK2, DIABLO/SMAC, AIFM1, CCS and BIRC5/Survivin. XIAP protein acts as an important regulator of innate immune signaling via regulating Nodlike receptors (NLRs). Suppresses ripoptosome formation through ubiquitination of RIPK1 and CASP8. XIAP protein acts as a positive regulator of Wnt signaling and ubiquitinates TLE1, TLE2, TLE3, TLE4, and AES.

1. Dziadzio M et al. (2015) Symptomatic male and female carriers in a large Caucasian kindred with XIAP deficiency. J Clin Immun 35: 439-444.
2. Gerasimenko JV et al (2002) Menadione-induced apoptosis: roles of cytosolic Ca(2+) elevations and the mitochondrial permeability transition pore. J Cell Sci. 2002 Feb 1;115(Pt 3):485-97.
3. Latour S et al (2015) XIAP deficiency syndrome in humans. Semin. Cell Dev Biol 39: 115-123.
4. Nishida N et al (2015) Dysgammaglobulinemia associated with glu349del, a hypomorphic XIAP mutation. J Invest Allergol Clin Immun 25: 205-213.
5. Pachlopnik Schmid J et al (2011) Clinical similarities and differences of patients with X-linked lymphoproliferative syndrome type 1 (XLP-1/SAP deficiency) versus type 2 (XLP-2/XIAP deficiency). Blood 117: 1522-1529.
6. Rigaud S et al. (2006) XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome. Nature 444: 110-114.
7. Worthey EA et al (2011) Making a definitive diagnosis: successful clinical application of whole exome sequencing in a child with intractable inflammatory bowel disease. Genet Med 13: 255-262.
8. Yang X et al. (2015) A female patient with incomplete hemophagocytic lymphohistiocytosis caused by a heterozygous XIAP mutation associated with non-random X-chromosome inactivation skewed toward the wild-type XIAP allele. J Clin Immun 35: 244-248.
9. Zhao M et al (2010) A novel XIAP mutation in a Japanese boy with recurrent pancytopenia and splenomegaly. Haematologica 95: 688-689.