Evolution of Our Understanding of XIAP Deficiency

Abstract

X-linked inhibitor of apoptosis (XIAP) deficiency is a rare inborn error of immunity first described in 2006. XIAP deficiency is characterised by immune dysregulation and a broad spectrum of clinical manifestations, including haemophagocytic lymphohistiocytosis (HLH), inflammatory bowel disease (IBD), hypogammaglobulinemia, susceptibility to infections, splenomegaly, cytopaenias, and other less common autoinflammatory phenomena. Since the first description of the disease, many XIAP deficient patients have been identified and our understanding of the disease has grown. Over 90 disease causing mutations have been described and more inflammatory disease manifestations, such as hepatitis, arthritis, and uveitis, are now well-recognised. Recently, following the introduction of reduced intensity conditioning (RIC), outcomes of allogeneic haematopoietic stem cell transplantation (HSCT), the only curative treatment option for XIAP deficiency, have improved. The pathophysiology of XIAP deficiency is not fully understood, however it is known that XIAP plays a role in both the innate and adaptive immune response and in immune regulation, most notably through modulation of tumour necrosis factor (TNF)-receptor signalling and regulation of NLRP3 inflammasome activity. In this review we will provide an up to date overview of both the clinical aspects and pathophysiology of XIAP deficiency.

Keywords: BIRC4; NOD2; X-linked lymphoproliferative disease; XIAP deficiency; haematopoietic stem cell transplantation; haemophagocytic lymphohistiocytosis; inflammasome; inflammatory bowel disease.

Figure 1

Overview of all disease causing mutations in the XIAP/BIRC4 gene that have thus far been reported. The position of each of the reported mutations associated with XIAP deficiency is depicted along the XIAP protein and gene structure. Shown are the 6 coding exons that are present in the XIAP/BIRC4 gene and the 5 functional domains of the XIAP protein. Mutations are grouped by mutation type. Missense mutations cluster in the BIR2 and RING domain of the XIAP protein.

Figure 2

XIAP's protein domains and their individual specific protein interactions and functions. Well-known is that XIAP's BIR2 and 3 domains directly inhibit caspase-3, −7 and −9 (, –27). BIR1 has been isolated as the BCL10-binding region within XIAP. This interaction plays a role in the Dectin-1 signalling pathway (28). Furthermore, BIR1 recruits the TAB1/TAK1 complex, which is essential for activation of the NF-κB and MAPK pathways (–31). BIR2 interacts with RIPK2, which forms a necessary step in the NOD1/2 signalling pathways leading to NF-κB and MAPK activation (5, 32, 33). The UBA domain is able to directly bind polyubiquitin chains and is required for activation of NF-κB, likely via its binding to polyubiquitinated NEMO (34). The C-terminal RING finger domain of XIAP has E3 ubiquitin ligase function, enabling XIAP to target proteins for proteasomal degradation or alter protein function (35). For example, the ubiquitin ligase activity of XIAP is critical for NOD2 mediated activation of NF-κB, via the polyubiquitination of RIKP2 (36). Created with BioRender.com.

Figure 3

XIAP plays a key function in various immune pathways. (A) XIAP is required for pattern recognition receptors (PPR) mediated innate immune responses. (i) XIAP is essential for the NOD1/2 induced activation of the NF-κB and MAPK pathways and secretion of pro-inflammatory cytokines and chemokines (40). NOD1 and NOD2 are intracellular PRRs that bind DAP and MDP, respectively (41, 42). Upon ligand binding, XIAP, together with cIAP1/2, ubiquitinates RIPK2, which subsequently acts as a scaffold for the TAK/TAB1 and IKK complexes, leading to activation of the MAPK and NF-κB pathways, respectively (5, 36, 40). The TAK/TAB1 also links to the IKK complex, thereby inducing activation of the NF-κB pathway (5, 36, 43, 44). Upon NOD activation, XIAP also recruits LUBAC, which in turn conjugates linear Ub chains to RIPK2. The concurrent ubiquitination of RIPK2 by XIAP and LUBAC is necessary for efficient activation of the canonical IKK for NF-κB activation (36, 44, 45). (ii) XIAP is necessary in Dectin-1 signalling. Dectin-1 is a transmembrane PRR that detects β-glucan. Upon Dectin-1 stimulation, XIAP binds and ubiquitinates BCL-10, which is essential for the activation of the NF-κB and MAPK pathways and cytokine production. BCL-10 is also involved in Rac1-dependent phagocytosis, which again relies on ubiquitination of BCL-10 by XIAP (28). (B) XIAP regulates the activation of inflammasomes via TLR/TNFR signalling. (i) Following TNFR1 and TLR signalling, RIPK3 can recruit RIKP1 to activate caspase-8 (46, 47). In this process, XIAP has an inhibitory effect on the ripopotosome by controlling the ubiquitination of RIKP1 in a RIPK3-dependent manner (6, 48). (ii) XIAP inhibits MLKL necroptotic signalling, which is promoted by RIPK3 in the absence of caspase-8 (48). (iii) TLR-MyD88 signalling causes the proteasomal degradation of cIAP1 and its adaptor TRAF2 by inducing TNF and TNFR2 signalling. This proteasomal degradation is inhibited by TLR-TRIF induced IFN-β. Loss of XIAP promotes LPS-induced cIAP1 degradation. Subsequently, cIAP1 loss in the absence of XIAP promotes TLR-induced RIPK3 caspase-8 and IL-1β activity, eventually leading to IL-1β maturation, caspase-8 cleavage and enhanced cell death (49). (iiii) TNFR2 activation acts as a signal 1 for priming the canonical inflammasome and induces expression of pro-inflammatory cytokines. XIAP loss and TNFR1 signalling play a role as signal 2 for activation of the inflammasome. This is mediated by RIPK1 and ROS production. In the absence of XIAP, TNFR2 stimulation leads to TNF production, followed by TNFR1 mediated cell death (50). Created with BioRender.com.

Figure 4

Simplified model of the disease pathophysiology underlying the inflammatory phenomena that are observed in XIAP deficiency. In XIAP deficiency, both the adaptive immune response and the innate immune response are compromised. Additionally, intracellular pathogens are less effectively cleared through xenophagy in the absence of XIAP. Taken together, this results in the persistence of pathogens, which, in turn leads to uncontrolled activation of inflammasomes when regulation by XIAP is lacking. Overall, the result is overproduction of pro-inflammatory cytokines and cell death, leading to a chronic state of hyperinflammation, which can manifest as HLH, IBD, HLH-like disease, arthritis and other inflammatory phenomena. Created with BioRender.com.