Alternative titles; symbols
HGNC Approved Gene Symbol: XIAP
SNOMEDCT: 1162830004;
Cytogenetic location: Xq25 Genomic coordinates (GRCh38) : X:123,859,708-123,913,972 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xq25 | Lymphoproliferative syndrome, X-linked, 2 | 300635 | X-linked recessive | 3 |
The XIAP gene belongs to the 'inhibitor of apoptosis protein' (IAP) gene family, which also includes HIAP1 (601721), and HIAP2 (601712). XIAP has a capacity to block apoptosis by directly inhibiting certain caspases. In addition to its antiapoptotic function, XIAP is involved in a variety of signaling pathways and/or cellular responses through ubiquitylation or as a signal transducer for the Nod-like receptors NOD1 (605980) and NOD2 (605956), which play a role in innate immunity (review by Latour and Aguilar, 2015).
Duckett et al. (1996) cloned the XIAP gene, which they referred to as hILP, for 'human IAP-like protein.' They reported that the gene encodes a 497-amino acid polypeptide with a predicted mass of 57 kD. They further noted that the sequence contains BIRs (baculovirus IAP repeats) and RING finger domains. Duckett et al. (1996) considered data gleaned from EST database analysis to be evidence that hILP is one of several human genes related to IAP. Duckett et al. (1996) expressed hILP in mammalian cell lines and found that it was able to block virally induced apoptosis.
Uren et al. (1996) reported that XIAP, which they called MIHA, shares 43% protein sequence identity with HIAP1 and HIAP2. Uren et al. (1996) determined that expression of XIAP in mammalian cells significantly reduced ICE (147678)-mediated apoptosis.
Liston et al. (1996) found that XIAP inhibited serum deprivation-induced apoptosis and apoptosis triggered by treatment with menadione, a potent inducer of free radicals. Northern blot analysis revealed XIAP expression as a 9-kb mRNA in all fetal and adult tissues tested except peripheral blood leukocytes.
Farahani et al. (1997) isolated cDNAs encoding miap3, the mouse XIAP homolog. The predicted 496-amino acid mouse protein is 94% identical to human XIAP.
Deveraux et al. (1997) showed that human X-linked IAP directly inhibits at least 2 members of the caspase family of cell-death proteases, caspase-3 (CASP3; 600636) and caspase-7 (CASP7; 601761). As the caspases are highly conserved throughout the animal kingdom and are the principal effectors of apoptosis, these findings suggested how IAPs might inhibit cell death, providing evidence for a mechanism of action for these mammalian cell-death suppressors.
To determine why proteasome inhibitors prevent thymocyte death, Yang et al. (2000) examined whether proteasomes degrade antiapoptotic molecules in cells induced to undergo apoptosis. The HIAP2 and XIAP inhibitors of apoptosis were selectively lost in glucocorticoid- or etoposide-treated thymocytes in a proteasome-dependent manner before death. IAPs catalyzed their own ubiquitination in vitro, an activity requiring the RING domain. Overexpressed wildtype HIAP2, but not a RING domain mutant, was spontaneously ubiquitinated and degraded, and stably expressed XIAP lacking the RING domain was relatively resistant to apoptosis-induced degradation and, correspondingly, more effective at preventing apoptosis than wildtype XIAP. Yang et al. (2000) concluded that autoubiquitination and degradation of IAPs may be a key event in the apoptotic program.
XIAP interacts with caspase-9 (CASP9; 602234) and inhibits its activity, whereas SMAC (605219) relieves this inhibition through interaction with XIAP. Srinivasula et al. (2001) demonstrated that XIAP associates with the active caspase-9-APAF1 (602233) holoenzyme complex through binding to the amino terminus of the linker peptide on the small subunit of caspase-9, which becomes exposed after proteolytic processing of procaspase-9 at asp315. Supporting this observation, point mutations that abrogate the proteolytic processing but not the catalytic activity of caspase-9, or deletion of the linker peptide, prevented caspase-9 association with XIAP and its concomitant inhibition. Srinivasula et al. (2001) noted that the N-terminal 4 residues of caspase-9 linker peptide share significant homology with the N-terminal tetrapeptide in mature SMAC and in the Drosophila proteins Hid/Grim/Reaper, defining a conserved class of IAP-binding motifs. Consistent with this finding, binding of the caspase-9 linker peptide and SMAC to the BIR3 domain of XIAP is mutually exclusive, suggesting that SMAC potentiates caspase-9 activity by disrupting the interaction of the linker peptide of caspase-9 with BIR3. Srinivasula et al. (2001) concluded that their studies reveal a mechanism in which binding to the BIR3 domain of XIAP by 2 conserved peptides, one from SMAC and the other from caspase-9, has opposing effects on caspase activity and apoptosis.
IKKB (603258) is required for NFKB (see 164011) activation by TNFA (191160), whereas IKKA (600664) is dispensable. Using immune complex kinase assays to measure the effect of TNFA on the activities of IKK and JNK (e.g., 602897) in wildtype or RelA (164014)-, IKKA-, or IKKB-deficient mouse embryonic fibroblasts, Tang et al. (2001) found that JNK activation is transient in wildtype and Ikka -/- fibroblasts but sustained in RelA -/- and Ikkb -/- cells. In contrast, IKK activation was also transient but robust in Ikka -/- and wildtype fibroblasts but severely impaired in Ikkb -/- cells. Immunoblot analysis showed that Tnfa induced expression of XIAP in wildtype but not RelA -/- cells, indicating that XIAP is targeted by NFKB. Transient expression of XIAP in HeLa cells inhibited JNK activation by TNFA without affecting JNK expression levels. Expression of a dominant-negative JNKK2 (603014) mutant (K149M) or a constitutively active JNKK2-JNK1 (601158) fusion protein attenuated or enhanced, respectively, JNK activation and, in RelA -/- fibroblasts, cell death. Tang et al. (2001) concluded that IKK negatively modulates JNK activity, most likely through the induction of NFKB target genes encoding proteins such as XIAP, which interfere with TNFA-mediated, but not IL1 (147760)-mediated, JNK activation and apoptosis.
Sanna et al. (2002) determined that ILPIP (ALS2CR2; 607333) potentiates the antiapoptotic activity of XIAP by enhancing XIAP-mediated activation of JNK1 and other JNK family members, but not by modulating XIAP-mediated caspase inhibition. They also found that expression of a catalytically inactive TAK1 (MAP3K7; 602614) mutant blocked the XIAP/ILPIP activation of JNK1. In vivo coprecipitation experiments showed that both ILPIP and XIAP interact with TAK1 and TRAF6 (602355). Sanna et al. (2002) concluded that XIAP-mediated protection from apoptosis utilizes both a JNK1 activation pathway that involves ILPIP and a caspase inhibition pathway that is independent of ILPIP.
By targeted deletion, Cummins et al. (2004) disrupted the XIAP gene in human colon cancer cells. Deletion of the XIAP gene did not interfere with basal proliferation, but it enhanced sensitivity to exogenously added TRAIL (TNFSF10; 603598). TRAIL increased apoptosis in both XIAP knockout cells and wildtype cells, but the increase was markedly greater in knockout cells. The increased apoptosis in knockout cells correlated with higher levels of cleaved CASP3, but not of CASP7 or CASP9, compared with wildtype cells. Over a broad range of TRAIL doses, XIAP knockout cells exhibited reduced clonogenic survival and proliferation. Cummins et al. (2004) concluded that XIAP is a nonredundant modulator of TRAIL-mediated apoptosis.
Mufti et al. (2006) stated that XIAP interacts with and regulates the levels of COMMD1 (607238), a protein associated with a form of copper toxicosis in Bedlington terriers. They found that Xiap levels were greatly reduced by intracellular copper accumulation in affected Bedlington terriers, in other dogs with copper toxicosis disorders, in patients with Wilson disease (277900), and in human embryonic kidney (HEK293) cells cultured under high copper conditions. Elevated copper levels in HEK293 cells caused a profound, reversible conformational change in endogenous XIAP due to direct binding of copper to XIAP, which accelerated its degradation and significantly decreased its ability to inhibit CASP3, resulting in a lower apoptotic threshold that sensitized the cells to apoptosis. Mufti et al. (2006) hypothesized that regulation of cell death through XIAP may contribute to the pathophysiology of copper toxicosis disorders.
Dohi et al. (2007) stated that the antiapoptotic function of survivin (BIRC5; 603352) appears to rely on interactions with other molecules, including XIAP, and that mitochondrial and cytosolic survivin differ with respect to cell death inhibition. Using rat and human cells, Dohi et al. (2007) showed that protein kinase A (see 176911) phosphorylated survivin in the cytosol, but not in mitochondria. This phosphorylation event disrupted the binding interface between survivin and XIAP. Conversely, mitochondrial survivin or a nonphosphorylatable survivin mutant bound XIAP avidly, enhanced XIAP stability, synergistically inhibited apoptosis, and accelerated tumor growth in immunocompromised mice. Dohi et al. (2007) concluded that differential phosphorylation of survivin by PKA in subcellular microdomains regulates tumor cell apoptosis via its interaction with XIAP.
Kim et al. (2008) showed that ectopic expression of Xiap in bovine aortic endothelial cells blocked Tnf-induced apoptosis by a caspase-independent mechanism. Xiap-associated cell survival was the result of enhanced nitric oxide (NO) production. Xiap partially localized in caveolae, where it interacted via a motif within its BIR3 domain with caveolin-1 (CAV1; 601047), a regulator of NO production. Endothelial NO synthase (NOS3; 163729) binding to caveolin-1 was competitively inhibited by Xiap, suggesting that Xiap modulates NO production by releasing endothelial NO synthase from caveolin-1. In addition, Xiap-dependent NO controlled endothelial cell migration.
As summarized by Jost et al. (2009), distinct cell types differ in the mechanisms by which the 'death receptor' FAS (134637) triggers their apoptosis. In type I cells, such as lymphocytes, activation of effector caspases by FAS-induced activation of caspase-8 (601763) suffices for cell killing; in type II cells, including hepatocytes and pancreatic beta-cells, caspase cascade amplification through caspase-8-mediated activation of the proapoptotic BID (601197) is essential. Jost et al. (2009) demonstrated that loss of XIAP function by gene targeting or treatment with a DIABLO (605219) mimetic drug in mice rendered hepatocytes and beta-cells independent of BID for FAS-induced apoptosis. Jost et al. (2009) concluded that their results showed that XIAP is the critical discriminator between type I and type II apoptosis signaling and suggested that IAP inhibitors should be used with caution in cancer patients with underlying liver conditions.
Using RT-PCR analysis, Jeon et al. (2013) showed that XIAP was strongly expressed in normal placenta, but that its expression was decreased in second and third trimester-onset preeclamptic placenta. Further analysis revealed that decreased expression of XIAP under hypoxic conditions induced apoptosis in HTR-8 SV/neo human trophoblasts, with involvement of HIF1A (603348), a key transcription factor in hypoxia-induced gene regulation. Hypoxia induced translocation of XIAP from cytoplasm to nucleus in HTR-8/SVneo trophoblasts, which was mediated by HIF1A. In nucleus, XIAP interacted and colocalized with IMUP2 (C19ORF33; 619711) and increased IMUP2 expression, thereby inducing apoptosis in trophoblasts.
Crystal Structure
To reveal the mechanisms of effector caspase inhibition by inhibitors of apoptosis, and to provide a basis for improved drug design, Chai et al. (2001) determined the crystal structure of an active caspase-7 bound to a potent inhibitory domain of XIAP (residues 124 to 240). Similarly, Huang et al. (2001) reported the crystal structure of the complex between human caspase-7 and the BIR2 domain and the proceeding linker of XIAP. Riedl et al. (2001) reported the crystal structure of the BIR2 domain of XIAP in complex with caspase-3. They determined that the mechanism of inhibition is due to a steric blockade prohibitive of substrate binding.
Shiozaki et al. (2003) reported the crystal structure of caspase-9 in an inhibitory complex with the BIR3 domain of XIAP at 2.4-angstrom resolution. The structure revealed that the BIR3 domain forms a heterodimer with a caspase-9 monomer. The surface of caspase-9 that interacts with BIR3 also mediates its homodimerization. Monomeric caspase-9 is catalytically inactive due to the absence of a supporting sequence element that could be provided by homodimerization. The authors concluded that XIAP sequesters caspase-9 in a monomeric state, which serves to prevent catalytic activity.
Solution Structure
To understand the structural basis of molecular recognition between SMAC and the IAPs, Liu et al. (2000) determined the solution structure of the BIR3 domain of XIAP complexed with a functionally active 9-residue peptide derived from the N terminus of SMAC. Wu et al. (2000) performed the same experiment. They found that the N-terminal 4 residues (ala-val-pro-ile) in SMAC/DIABLO recognize a surface groove on BIR3, with the first residue ala binding a hydrophobic pocket and making 5 hydrogen bonds to neighboring residues on BIR3. These observations provided a structural explanation for the roles of the SMAC N terminus as well as for the conserved N-terminal sequences in the Drosophila proteins Hid/Grim/Reaper. In conjunction with other observations, Wu et al. (2000) concluded that their results reveal how SMAC may relieve IAP inhibition of caspase-9 activity. In addition to explaining a number of biologic observations, both Liu et al. (2000) and Wu et al. (2000) suggested that their structural analyses identified potential targets for drug screening that may be used for the treatment of cancers that overexpress IAPs.
Rigaud et al. (2006) determined that the XIAP gene comprises 6 exons.
Rajcan-Separovic et al. (1996) used fluorescence in situ hybridization (FISH) to map the XIAP gene to chromosome Xq25. By FISH, Farahani et al. (1997) mapped the mouse miap3 gene to the X chromosome, region A3-A5.
In affected males from 3 families with X-linked lymphoproliferative syndrome-2 (XLP2; 300635), Rigaud et al. (2006) identified hemizygous frameshift, nonsense, and deletion mutations in the XIAP gene (300079.0001-300079.0003). Despite similarities in clinical features, patients with XIAP deficiency showed different cellular manifestations than did patients with SAP deficiency (XLP1; 308240). Rigaud et al. (2006) showed that apoptosis of lymphocytes from XIAP-deficient patients is enhanced in response to various stimuli, including the T-cell antigen receptor (TCR)-CD3 complex (see 186790), the death receptor CD95 (134637), and the TNF-associated apoptosis-inducing ligand receptor (TRAILR; see 603613). Rigaud et al. (2006) also found that XIAP-deficient patients, like SAP-deficient patients, have low numbers of natural killer T lymphocytes (NKT cells), indicating that XIAP is required for the survival and/or differentiation of NKT cells. The observation that XIAP deficiency and SAP deficiency are both associated with a defect in NKT cells strengthened the hypothesis that NKT cells have a key role in the immune response to Epstein-Barr virus (EBV). Furthermore, by identifying an XLP immunodeficiency that is caused by mutations in XIAP, Rigaud et al. (2006) showed that XIAP is a potent regulator of lymphocyte homeostasis in vivo.
Worthey et al. (2011) identified a missense mutation of a highly conserved cysteine in the XIAP gene in a child with XLP2 manifesting as intractable inflammatory bowel disease (300079.0004).
In 9 Japanese male patients from 6 unrelated Japanese families with XLP2, Yang et al. (2012) identified 6 different truncating mutations in the XIAP gene (see, e.g., 300079.0005-300079.0007). The mutations were found by direct screening of the XIAP gene after exclusion of mutations in the SH2D1A gene (300490). The mothers of patients from families 1 through 5 were heterozygous carriers of the mutations, whereas the mother of 2 sibs (family 6) did not carry the mutation in peripheral blood, suggesting germline mosaicism. Flow cytometric analysis of patient lymphocytes showed decreased expression in 7 of 8 patients; low-normal expression was found in a patient (patient 4) with an in-frame deletion mutation (E349del; 300079.0005) who had a milder phenotype with only hypogammaglobulinemia and recurrent infections. The expression pattern of XIAP in carrier mother cells was variably reduced or showed a bimodal pattern. Western blot analysis, performed on 3 patients, showed decreased XIAP levels.
In 6 affected males from a large Caucasian family with XLP2, Dziadzio et al. (2015) identified a truncating mutation in the XIAP gene (300079.0008). There were 7 female carriers, 6 of whom were symptomatic to varying degrees. Flow cytometric analysis of peripheral cells from 1 of the affected males showed absence of the XIAP protein and a severely abrogated response of monocytes to NOD2 (605956), with decreased TNF-alpha (191160) production. Flow cytometric analysis of lymphocyte subsets and monocytes from 3 female carriers showed revealed preferential expression of XIAP wildtype protein and normal NOD2 function. However, the most severely affected female carrier (patient IV.9) with IBD and erythema nodosum (EN) had random X-inactivation, resulting in expression of the mutated XIAP protein in her monocytes and impaired NOD2 responses in vitro. These findings indicated that the pattern of X-inactivation can influence the phenotype in female carriers. The findings also indicated that impaired NOD2 signaling is a driving pathophysiologic mechanism of the disorder. In addition, the truncated mutation also resulted in increased activation-induced cell death (AICD) of patient-derived T-cell blasts in vitro, suggesting that the mutation also affected the antiapoptotic properties of XIAP.
Harlin et al. (2001) generated mice deficient in Xiap through homologous gene targeting. The Xiap -/- mice were viable, histopathologically normal, and lacked defects in caspase-dependent or -independent apoptosis. However, the levels of Ciap1 and Ciap2 were increased, suggesting the existence of a compensatory mechanism in the absence of XIAP expression that may be provided by these molecules.
In a review, Latour and Aguilar (2015) noted that studies have shown that certain strains of Xiap-deficient mice have compromised immunity leading to decreased survival when infected with certain pathogens, including intracellular bacteria and viruses. These infections are associated with splenomegaly and compromised innate immunity with altered cytokine production.
In bone marrow-derived macrophages (BMDMs) from Xiap-deficient mice, Chiang et al. (2022) demonstrated that Il1-beta (147720) was produced in response to stimulation with Tnf-alpha (191160) or Tlr (see 601194) agonists without the requirement of a second activation signal. This second activation signal was required by wildtype BMDMs. Furthermore, in BMDMs derived from mice that were deficient in both Xiap and Nrpl3 (600928), IL1-beta production was reduced compared to BMDMs from Xiap-deficient mice. Chiang et al. (2022) concluded that the NLRP3 inflammasome complex plays a role in the hyperinflammation in X-linked lymphoproliferative syndrome. When the Xiap-deficient BMDMs were treated with MCC950 (an NLRP3 inhibitor), chloroquine (an inhibitor of lysosome acidification) or quercetin (an antioxidant), Il1-beta overproduction was abrogated. Chiang et al. (2022) showed that treated Xiap-deficient mice with quercetin had reduced cytokine production after LPS exposure compared to untreated Xiap-deficient mice.
In affected males from a family (family 1) with X-linked lymphoproliferative syndrome (XLP2; 300635), Rigaud et al. (2006) detected hemizygosity for deletion of the cytidine at nucleotide position 291 of the XIAP gene (c.291delC), resulting in a frameshift leading to a stop codon at position 387 (G99K/X129).
In affected males from a family (family 3) with X-linked lymphoproliferative syndrome (XLP2; 300635), Rigaud et al. (2006) identified a hemizygous c.352G-T transversion in the XIAP gene, resulting in a glu118-to-ter (E118X) substitution.
In affected males from a family (family 2) with X-linked lymphoproliferative syndrome (XLP2; 300635), Rigaud et al. (2006) detected a hemizygous deletion of 2,606 nucleotides encompassing exon 2 of the XIAP gene.
In a boy with X-linked lymphoproliferative syndrome (XLP2; 300635) manifesting as intractable inflammatory bowel disease, Worthey et al. (2011) undertook whole-exome sequencing and identified a hemizygous G-to-A substitution at a highly conserved position in the XIAP gene, resulting in a hemizygous cys-to-tyr amino acid substitution at codon 203 (C203Y). This mutation was not found in more than 2,000 human control sequences or in orthologous genes from other species down to Drosophila. Confirmation of the variant in the child was carried out by Sanger sequencing, and studies on the mother confirmed the mutation and showed maternal skewed X-chromosome inactivation in natural killer, B, and T helper cell types. Functional assays demonstrated an increased susceptibility to activation-induced cell death and defective responsiveness to NOD2 (605956) ligands, consistent with loss of normal XIAP function in apoptosis and NOD2 signaling.
In a 15-year-old Japanese boy (patient 4) with X-linked lymphoproliferative syndrome (XLP2; 300635) manifesting only as hypogammaglobulinemia with recurrent infections, Yang et al. (2012) identified a hemizygous in-frame 3-bp deletion (c.1045_1047delGAG) in exon 3 of the XIAP gene, resulting in a deletion of residue glu349 (E349del). Flow cytometric analysis of patient lymphocytes detected normal levels of XIAP.
Nishida et al. (2015) identified 3 additional Japanese boys (patients 4, 9, and 10) with XLP2 due to a hemizygous E349del variant. The disorder manifested as hypogammaglobulinemia only, although 1 of the patients developed aplastic anemia requiring hematopoietic stem cell transplantation. The patients had normal XIAP protein expression, but decreased numbers of CD19+ switched memory B cells. Patient cells did not showed increased activation-induced cell death (AICD) of T lymphocytes compared to controls. Microarray analysis indicated that the gene expression patterns were different in patients with the E349del mutation compared to patients with other mutations in the XIAP gene. Patients with E349del had 10-fold lower expression of a number of genes, including those involved in B cell development and Ig levels. Nishida et al. (2015) stated that the variant occurred in exon 4 of the XIAP gene and that it was a polymorphism in the Japanese population. Among 170 healthy Japanese individuals, 2 were heterozygous and 4 homozygous for the variant. Nishida et al. (2015) concluded that although the E349del variant is a SNP, it could be associated with hypo/dysgammaglobulinemia.
In 2 Japanese brothers (patient 6.1 and 6.2) with X-linked lymphoproliferative syndrome (XLP2; 300635), Yang et al. (2012) identified a hemizygous 2-bp deletion (c.1021_1022delAA) in exon 3, resulting in a frameshift and premature termination (Asn341TyrfsTer7). The mutation was not detected in the mother's lymphocytes, suggesting germline mosaicism. Flow cytometric and Western blot analysis of patient lymphocytes showed decreased levels of XIAP, consistent with a loss of function.
In 2 Japanese brothers (patients 3.1 and 3.2) with X-linked lymphoproliferative syndrome (XLP2; 300635), Yang et al. (2012) identified a hemizygous 1-bp deletion (c.650delG) in exon 1 of the XIAP gene, resulting in a frameshift and premature termination (Trp217CysfsTer27). Interestingly, 1 patient had a severe disorder with onset at age 2 months and recurrent EBV-associated HLH, whereas the other was asymptomatic at age 17 years. Flow cytometric and Western blot analysis of patient lymphocytes showed decreased levels of XIAP.
In 6 affected males from a large Caucasian family with X-linked lymphoproliferative syndrome (XLP2; 300635), Dziadzio et al. (2015) identified a 1-bp duplication (c.672dupT) in exon 2 of the XIAP gene, resulting in a frameshift and premature termination (Pro225SerfsTer2) in the BIR2 domain. Four of 5 affected males had severe inflammatory bowel disease (IBD), and 6 of 7 carrier females had chronic erythema nodosum (EN) and variable bowel symptoms. One female carrier was asymptomatic. Flow cytometric analysis of peripheral blood cells from 1 of the affected males showed absence of the XIAP protein and a severely abrogated response of monocytes to NOD2. Flow cytometric analysis of lymphocyte subsets and monocytes from 3 female carriers showed preferential expression of XIAP wildtype protein and normal NOD2 function. However, the most severely affected female carrier (patient IV.9) with IBD and EN had expression of mutated XIAP protein in her monocytes, leading to impaired NOD2 responses in vitro. These observations indicated that impaired NOD2 signaling is a driving pathophysiologic mechanism of the disorder. In addition, the truncated mutation also resulted in increased activation-induced cell death (AICD) of patient-derived T-cell blasts in vitro, suggesting that the mutation also affects the antiapoptotic properties of XIAP.
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