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. 2020 Aug;12(8):a036426. doi: 10.1101/cshperspect.a036426

Regulation of Cell Death and Immunity by XIAP

Philipp J Jost 1,2,3, Domagoj Vucic 4
PMCID: PMC7397824  PMID: 31843992

Abstract

X-chromosome-linked inhibitor of apoptosis protein (XIAP) controls cell survival in several regulated cell death pathways and coordinates a range of inflammatory signaling events. Initially identified as a caspase-binding protein, it was considered to be primarily involved in blocking apoptosis from both intrinsic as well as extrinsic triggers. However, XIAP also prevents TNF-mediated, receptor-interacting protein 3 (RIPK3)-dependent cell death, by controlling RIPK1 ubiquitylation and preventing inflammatory cell death. The identification of patients with germline mutations in XIAP (termed XLP-2 syndrome) pointed toward its role in inflammatory signaling. Indeed, XIAP also mediates nucleotide-binding oligomerization domain-containing 2 (NOD2) proinflammatory signaling by promoting RIPK2 ubiquitination within the NOD2 signaling complex leading to NF-κB and MAPK activation and production of inflammatory cytokines and chemokines. Overall, XIAP is a critical regulator of multiple cell death and inflammatory pathways making it an attractive drug target in tumors and inflammatory diseases.

XIAP AND THE INHIBITOR OF APOPTOSIS PROTEIN FAMILY

The evolutionarily conserved family of inhibitor of apoptosis proteins (IAPs) contains structurally related regulators of diverse cellular processes (Varfolomeev and Vucic 2011). IAPs were originally identified in baculoviruses because of their ability to inhibit virus-induced apoptosis and allow viral amplification (Crook et al. 1993; Birnbaum et al. 1994). Subsequently, through functional screens and bioinformatics efforts, IAP genes and proteins were identified in all metazoan organisms including eight human IAP proteins (Liston et al. 1996; Salvesen and Duckett 2002). Among the human IAP proteins, X-chromosome-linked IAP (XIAP) and cellular IAP1 and 2 (c-IAP1 and c-IAP2) are the most studied, although other IAP proteins (NAIP, ML-IAP, survivin, ILP2, and Apollon) also play important roles in cell survival, cell cycle, inflammation, and overall homeostasis (Fulda and Vucic 2012).

XIAP protein contains three signature baculovirus IAP repeat (BIR) domains, which are conserved 70–80 amino acid zinc–coordinating regions that regulate protein–protein interactions and are instrumental for XIAP function (Sun et al. 2000; Ndubaku et al. 2009). Many of the BIR-mediated protein–protein interactions use a pocket on the BIR domain that binds to amino-terminal tetrapeptides called IAP-binding motifs (IBMs). The specific BIR sequence of each IAP protein is very important because small variations in the sequence dictate the binding of different interaction partners. The BIR1 domain of XIAP interacts with TAB1 and thus potentially regulates signaling by the TAB-TAK1 complex (Lu et al. 2007). BIR2 and the linker region between BIR1 and BIR2 bind to and inhibit active caspases 3 and 7 (Chai et al. 2001; Huang et al. 2001; Riedl et al. 2001). BIR2 also binds to the kinase receptor-interacting protein 2 (RIPK2), which allows XIAP to ubiquitinate RIPK2 in the nucleotide-binding oligomerization domain-containing 2 (NOD2) signaling pathway (Krieg et al. 2009; Damgaard et al. 2012; Goncharov et al. 2018; Stafford et al. 2018). The BIR3 domain of XIAP binds to and inhibits activation of caspase-9 by blocking its dimerization, which is needed for autocleavage. The BIR3 domain of XIAP also associates with Smac (second mitochondrial activator of caspases)/DIABLO (direct IAP-binding protein with low pI) and other IBM-containing proteins such as serine protease HtrA2, resulting in the antagonism of XIAP antiapoptotic activity (Liu et al. 2000; Sun et al. 2000; Wu et al. 2000).

At the very carboxy terminal of XIAP is a really interesting new gene (RING) domain, which imparts ubiquitin ligase activity (Vaux and Silke 2005), whereas its centrally located ubiquitin-associated (UBA) domain confers binding to monoubiquitin and polyubiquitin chains (Gyrd-Hansen et al. 2008; Blankenship et al. 2009). Ubiquitination involves covalent modification of target proteins with the 76-amino-acid protein ubiquitin, and requires the enzymatic activity of a ubiquitin-activating enzyme (E1), a ubiquitin-conjugating enzyme (E2), and a ubiquitin ligase (E3) (Hershko and Ciechanover 1998). Monoubiquitination occurs when a single ubiquitin molecule is attached to a lysine residue of the substrate protein (Hershko and Ciechanover 1998). However, ubiquitin contains seven lysine residues and a free amino terminus, thus allowing the synthesis of polyubiquitin chains through eight different isopeptide linkages (Pickart and Fushman 2004). XIAP can assemble various polyubiquitin chains on itself and its substrates in collaboration with E2 enzymes of the UbcH5 family (Dynek et al. 2010; Vucic et al. 2011). The most prominent substrates of the E3 activity of XIAP include apoptotic caspases, Smac, and RIPK2 (Morizane et al. 2005; Qin et al. 2016). In many cases, XIAP-mediated ubiquitination leads to substrate degradation (SMAC) (MacFarlane et al. 2002; Galbán and Duckett 2010). However, K63-linked RIPK2 ubiquitination does not affect RIPK2 stability but rather promotes NF-κB and MAPK signaling (Damgaard et al. 2012; Goncharov et al. 2018).

XIAP IN APOPTOSIS

XIAP's ability to bind to and inhibit the caspases that mediate apoptotic cell death was the primary focus of scientists after its initial discovery. Proapoptotic caspases are proteases that dismantle the cell, and therefore must be tightly regulated to prevent uncontrolled cell death or, alternatively, the unwanted survival of damaged or malignant cells. In apoptotic signaling, XIAP binds to caspases 3 and 7 by virtue of a linker region located between BIR domains 1 and 2 (Deveraux et al. 1997; Wilkinson et al. 2004). Indeed, this relatively small linker region is the only part of XIAP that physically interacts with the executioner caspases (Huang et al. 2001). In contrast, XIAP binds to initiator caspase-9 with its BIR3 domain (Deveraux and Reed 1999). XIAP binds to the executioner and initiator caspases with different affinities, but binding serves the same purpose, which is inhibition of apoptosis. Binding of XIAP to caspase-8 is detectable, but unlikely to be relevant biologically because the binding affinity is several magnitudes below that observed for caspases 3 and 7 (Eckelman et al. 2006). XIAP therefore serves as a repressor and regulator of the final steps of apoptotic signaling, acting mostly at the level of activation of executioner caspases.

The family of IAP proteins has several members (Deveraux and Reed 1999; Salvesen and Duckett 2002). Despite their sequence similarities and the presence of BIR domains in other IAP proteins, the ability to directly bind to and inhibit caspases appears restricted to XIAP. It has therefore been referred to as outsider of the family of IAP proteins (Eckelman et al. 2006). XIAP-deficient mice lack overt phenotypes (Harlin et al. 2001; Olayioye et al. 2005), so the field tended to think of XIAP as a protein with relatively low importance in apoptosis signaling. However, it required the right stimulus and a specific condition to understand the relevance of XIAP in apoptosis (Fig. 1). One example is the activation of FAS (CD95) by FAS ligand (FAS-L), which triggers cell death in most cell types but uses additional signaling pathways depending on the cellular origin. In type I cells, such as lymphocytes, FAS (CD95) stimulation directly activates caspase-8 to trigger executioner caspase processing and cell death. In contrast, in type II cells, such as hepatocytes, caspase-8 also cleaves the proapoptotic BH3 protein BID to amplify the apoptotic signal via the mitochondrial route (Yin et al. 1999; Kaufmann et al. 2007; McKenzie et al. 2008). This mitochondrial amplification step of the apoptotic signal results in the BID-dependent activation of the proapoptotic BCL-2 proteins BAX/BAK eventually resulting in the loss of mitochondrial outer membrane potential (MOMP). The loss of MOMP results in the release of cytochrome c from the intermembrane space promoting formation and activation of a protein complex termed the apoptosome. This protein complex is comprised of procaspase-9, APAF-1, and cytochrome c and on assembly cleaves and activates caspase-9 to induce executioner caspase activation such as caspase-3 and -7. It becomes evident that the fine balance between apoptosis-inducing factors, such as cytochrome c or SMAC/DIABLO, and apoptosis-inhibiting factors such as XIAP defines to a large degree the process of apoptotic cell death execution.

Figure 1.

Figure 1.

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X-chromosome-linked inhibitor of apoptosis protein (XIAP) in FAS/CD95-mediated cell death. The pool of XIAP defines the propensity of cells to undergo apoptotic cell death in response to extrinsic cellular stress such as FAS/CD95 activation. XIAP prevents the activity of processed caspases and thereby increases the threshold for apoptosis activation. XIAP itself is kept in check by proapoptotic factors released from compromised mitochondria such as SMAC/DIABLO that bind and prevent its activity. Cell types with high levels of XIAP such as hepatocytes require amplification of an FAS/CD95-mediated cell death signal via BID-dependent mitochondrial outer membrane potential (MOMP) and subsequent release of SMAC/DIABLO to inhibit XIAP function and thereby allow for apoptosis to occur. (Cyt. c) cytochrome c.

A major difference between type I and type II cells in terms of apoptosis execution is XIAP. Intracellular levels of XIAP are higher in type II cells when compared with type I cells effectively blocking activation of the executioner caspases. BID cleavage in type II cells triggers MOMP, which releases SMAC from mitochondria. SMAC binding to XIAP probably blocks the inhibition of the executioner caspases by XIAP (Jost et al. 2009). Therefore, XIAP fine-tunes sensitivity to FAS-L in different cell types (Varfolomeev et al. 2009).

XIAP IN RIPK3 SIGNALING AND INFLAMMATORY CELL DEATH

After several years of research into the role of XIAP in conventional apoptosis and caspase inhibition, it became clear that XIAP also controls inflammatory forms of cell death. Initial work studied the response of Xiap−/− myeloid cells in inflammation because patients with a germline mutation in XIAP suffer from a hyperinflammatory syndrome termed X-linked lymphoproliferative syndrome type 2 (Rigaud et al. 2006). More detail on this rare but very informative condition is provided in the section entitled, “Genetic Mutations in XIAP Define the XLP-2 Syndrome.”

In an effort to understand how XIAP controls inflammation, murine Xiap−/− myeloid cells were treated with lipopolysaccharide (LPS) as a Toll-like receptor 4 (TLR-4) agonist (Yabal et al. 2014). They released substantial amounts of caspase-1-dependent bioactive IL-1β, whereas similarly treated wild-type cells did not. Moreover, Xiap−/− cells activated a form of programmed and highly inflammatory cell death requiring the kinase RIPK3 (Yabal et al. 2014). Additional genetic experiments revealed that this LPS-induced cell death is mediated by TNF and eventually results in the release of IL-1β (Yabal et al. 2014; Lawlor et al. 2015; Wicki et al. 2016). Indeed, earlier examination of the contribution of individual IAP family members to TNF-mediated cell death found a substantial contribution of XIAP to the suppression of TNF- and RIPK1/RIPK3-mediated cell death in myeloid cells (Wong et al. 2014).

The identification of a role for XIAP in TNF signaling and RIPK3-dependent cell death initially caused some skepticism because, unlike c-IAP1 and c-IAP2, XIAP is not found within the TNF receptor 1 (TNFR1) signaling complex (Bertrand et al. 2008; Varfolomeev et al. 2008; Haas et al. 2009; Vince et al. 2012). Rather, XIAP may be part of a cytosolic protein complex containing RIPK1 and RIPK3 (Yabal et al. 2014). Indeed, the TNF-induced ubiquitylation pattern on cytosolic RIPK1 is controlled by XIAP (Mehrotra et al. 2010). In macrophages or dendritic cells, the genetic ablation of XIAP results in an elevated ubiquitylation of RIPK1 (Yabal et al. 2014). This suggested that XIAP is not the primary ligase in the complex that ubiquitylates RIPK1 but possibly controls the presence or the activation status of an alternative ligase responsible for RIPK1 ubiquitylation that has not been identified to date.

Subsequent work in myeloid cells showed that XIAP represses TLR/MyD88-induced and TNF/TNFR2-dependent proteasomal degradation of TRAF2 and c-IAP1 (Lawlor et al. 2017). Thus, in the absence of XIAP, loss of TRAF2 and c-IAP1 sensitizes the cells to proinflammatory cell death. The mechanistic details of how XIAP prevents the degradation of TRAF2 and cIAP1 still have to be worked out. It is also unclear whether additional functions of XIAP impact on TNF or necroptotic signaling, but it is clear that XIAP functions in a distinct manner from c-IAP1 or c-IAP2.

The molecular functions of XIAP that have been identified using Xiap−/− mice largely require the RING domain of XIAP (Schile et al. 2008). Thus, knockin mice expressing carboxy-terminally truncated XIAP deficient for the RING domain that can still bind to activated caspases phenocopy Xiap−/− mice in their exacerbated response to LPS (Yabal et al. 2014). Therefore, XIAP can regulate inflammation independent of it binding to caspases.

XIAP IN INFLAMMATION, NOD SIGNALING

Xiap−/− mice fail to mount an immune response to infection with Listeria or to treatment with bacterial peptidoglycans such muramyldipeptide (MDP) (Pedersen et al. 2014). Yet, mutations in XIAP are associated with inflammatory diseases such as XLP-2 and very early-onset inflammatory bowel disease (VEO-IBD) (Damgaard et al. 2013; Pedersen et al. 2014). Recognition of invading pathogens and rapid initiation of host defense mechanisms are critical for the maintenance of homeostasis (Chen et al. 2008). Innate immune cells use pathogen-recognition receptors to detect invading pathogens and these include the nucleotide-binding oligomerization domain-containing (NOD)-like receptors (NLRs) (Chen et al. 2008). NOD1 and NOD2 are NLRs that are instrumental for innate immune responses to some bacterial infections (Franchi et al. 2009; Caruso et al. 2014). Mutations in NOD2 are also associated with inflammatory diseases, including Crohn's disease, early-onset sarcoidosis, and Blau syndrome (Hugot et al. 2001; Ogura et al. 2001; Caso et al. 2015).

Binding of MDP to NOD2 induces recruitment of RIPK2 and XIAP, the latter promoting K63-linked ubiquitination of RIPK2, which then recruits the linear ubiquitin chain assembly complex (LUBAC) (Damgaard et al. 2012). Linear ubiquitination of RIPK2 is required for full activation of the NF-κB and MAPK signaling pathways that drive the expression of many inflammatory cytokines and chemokines (Fig. 2; Damgaard et al. 2012). Several other E3 ligases reportedly bind to and promote ubiquitination of RIPK2 (Witt and Vucic 2017). Nevertheless, XIAP is essential for efficient NOD2-RIPK2 signaling (Damgaard et al. 2012; Goncharov et al. 2018; Stafford et al. 2018). The related E3 ligases c-IAP1/2 contribute to NOD2-dependent autocrine TNF signaling and amplify cytokine production in vivo (Stafford et al. 2018), but XIAP is more directly involved in signaling by NOD2 (Damgaard et al. 2012). Thus, XIAP-selective antagonists strongly inhibit NOD2-mediated activation of NF-κB and MAPK signaling and subsequent cytokine/chemokine production (Goncharov et al. 2018). XIAP uses its BIR2 domain to engage the kinase domain of RIPK2, and this association allows XIAP to ubiquitinate RIPK2. Mutation of the XIAP-dependent ubiquitination sites in RIPK2 diminishes NOD2 signaling, whereas inactivating the kinase activity of RIPK2 does not (Goncharov et al. 2018). These and other data strongly suggest that ubiquitination of RIPK2 is more important than the catalytic activity of RIPK2 for NOD2 signaling (Goncharov et al. 2018; Hrdinka et al. 2018).

Figure 2.

Figure 2.

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X-chromosome-linked inhibitor of apoptosis protein (XIAP) in inflammation plus XIAP-targeting agents. Muramyldipeptide (MDP)-binding oligomerizes nucleotide-binding oligomerization domain-containing 2 (NOD2) and recruits receptor-interacting protein 2 (RIPK2) and XIAP to promote K63-linked polyubiquitination of RIPK2 (red symbols) and subsequent linear ubiquitin chain assembly complex (LUBAC)-mediated linear polyubiquitination (purple symbols) to activate NF-κB and MAPK signaling and production of inflammatory cytokines. By disrupting RIPK2–XIAP interaction, XIAP-selective antagonists prevent RIPK2 ubiquitination and release of inflammatory cytokines.

XIAP was also reported to activate NF-κB signaling through its BIR1 domain and interaction with TAB1 (Lu et al. 2007). XIAP BIR1 adopts a dimeric structure in complex with TAB1, and disruption of BIR1 dimerization blocks XIAP BIR1-mediated NF-κB activation (Lu et al. 2007; Cossu et al. 2015). However, the physiological relevance of this BIR1-mediated interaction has not been defined yet.

GENETIC MUTATIONS IN XIAP DEFINE THE XLP-2 SYNDROME

Germline mutations in XIAP in patients define a genetic susceptibility condition termed X-linked lymphoproliferative syndrome type II (XLP-2) (Rigaud et al. 2006; Latour and Aguilar 2015). The mutations in XIAP are scattered throughout the protein and represent either nonsense mutations, frameshift mutations, or deletions, resulting in substantial irregularities of the protein (Filipovich et al. 2010; Marsh et al. 2010; Pachlopnik Schmid et al. 2011; Yang et al. 2012). The carboxy-terminal RING domain is affected by mutations either caused by nonsense or frameshift mutations within the body of the encoded gene or, alternatively, by direct localization of the mutations within the RING domain indicating that most mutations interfere with its E3 activity (Damgaard et al. 2013).

XLP-2 boys mostly present at infanthood to early adulthood with symptoms as diverse as cytopenia, fever, hepatosplenomegaly, and elevated levels of acute phase proteins such as ferritin (Latour and Aguilar 2015). The condition clinically may present as hemophagocytic lymphohistiocytosis (HLH) syndrome. XLP-2 onset has often been associated with Epstein–Barr virus (EBV) infections or alternative triggers (Aguilar and Latour 2015). It has therefore been suggested to rename the condition to X-linked HLH disease to encompass the clinical features and the absence of monoclonal lymphoproliferation as suggested in the term XLP-2 (Marsh et al. 2010).

Bone marrow transplantation represents a curative treatment option in severe cases of XLP-2 (Marsh et al. 2013). However, the conditioning regimen and the posttransplant mortality in XLP-2 patients is high, possibly a result of the exaggerated inflammatory signaling events present during the conditioning treatment phase before allogeneic stem cell transplantation. Indeed, it was recently identified that Xiap deficiency in hematopoietic recipient cells drives donor T-cell activation and graft versus host disease (GvHD) in a major mismatch bone marrow transplantation mouse model, thus mimicking allogeneic bone marrow transplantation of XLP-2 patients (Müller et al. 2019). In this setting, the aggravated mortality of allogeneic transplanted mice deficient for XIAP was followed by increased levels of proinflammatory cytokines and donor-derived T lymphocytes (Müller et al. 2019), supporting a critical role of XIAP in preventing aberrant immune activation during allogeneic transplantation. Using XIAP-deficient donor or, alternatively, XIAP-deficient recipient mice indicated that loss of XIAP specifically in the recipient hematopoietic compartment was responsible for aggravation of GvHD after allogeneic stem cell transplantation.

Given the role of EBV infections in triggering XLP-2 and the clinical symptoms associated with this systemic inflammatory syndrome, XLP-2 patients were considered to be affected primarily by hyperinflammation within the hematopoietic system. Therefore, it was a surprise when the group of Sebastian Zeissig identified loss-of-function mutations in XIAP as a common occurrence in male patients with early-onset Crohn's disease. This form of inflammatory bowel disease was observed with Mendelian frequency in families carrying mutations in XIAP and the penetrance of disease onset was relatively high in affected individuals (Speckmann and Ehl 2014; Zeissig et al. 2015). As the frequency of XIAP mutations in children and young adults with IBD-like symptoms or with symptoms associated with HLH was largely unknown, and even today only a fraction of early-onset IBD or HLH patients get screened for XIAP mutations, it is important for clinicians to be able to rapidly test for XIAP alterations. Rapid detection has become more available by a flow cytometry-based detection assay for the intracellular production of TNF in primary blood-derived monocytic cells from patients suspected to present with XLP-2 syndrome. Simulation of monocytes by a modified form of MDP, termed L18-MDP, the cognate ligand for NOD2, results in TNF production that is detectable within the cells by flow cytometry and aids in the identification of patients incapable of secreting NOD2-dependent TNF (Ammann et al. 2014).

TARGETING XIAP FOR THERAPEUTIC INTERVENTION

Expression of XIAP in several human cancers is associated with poor prognosis (Fulda and Vucic 2012). Besides promoting tumor progression, XIAP has also been implicated in tumor cell mobility, invasion, and metastasis. For example, XIAP, as well as cellular IAPs, and ML-IAP can destabilize kinase C-RAF and consequently modulate MAPK signaling and cell motility (Dogan et al. 2008; Oberoi-Khanuja et al. 2012). In addition, XIAP and survivin cooperate to promote metastasis via the activation of cell motility kinases Src and FAK (Mehrotra et al. 2010). Conversely, antagonism of IAP proteins can block tumor cell migration and invasion (Mehrotra et al. 2010). XIAP and c-IAP1 can also ubiquitinate the Rho GTPase Rac1 and target it for proteasomal degradation (Oberoi et al. 2012). Therefore, regulation of Rac1 stability provides another modality for the modulation of cell migration.

Elevated expression of XIAP in numerous tumor types in combination with its prosurvival functions makes XIAP an attractive target for therapeutic intervention in cancer (Fulda and Vucic 2012). Several clinical trials have targeted XIAP in cancer, either via antisense RNA or by using IAP antagonists (smac mimetics), in the hope of stimulating and/or enhancing tumor cell death (Fulda and Vucic 2012). However, results of these trials were not encouraging and, coupled with a lack of clear predictive biomarkers, IAP antagonists and XIAP antisense reagents have not reached their potential as a cancer treatment option through the activation of cell death.

The recent discovery of the role of XIAP in NOD2 signaling and the development of XIAP-selective antagonists indicate that targeting XIAP in NOD2-mediated inflammatory diseases could be beneficial. IAP antagonists that are selective for XIAP are well positioned for intervention in NOD2-mediated pathologies because, unlike pan-IAP antagonists, they do not activate cell death, c-IAP1/2 autoubiquitination and proteasomal degradation, or NF-κB signaling (Goncharov et al. 2018). In addition, RIPK2 is a dedicated and specific adaptor for the NOD1/NOD2 pathways. Accordingly, XIAP-selective antagonists do not compromise other inflammatory pathways such as TNF signaling (Goncharov et al. 2018). XIAP selectivity is possible because of the uniqueness of the XIAP BIR2 domain that binds to the kinase domain of RIPK2. XIAP-selective antagonists break the direct physical interaction between XIAP and RIPK2. Disruption of XIAP-RIPK2 binding prevents RIPK2 ubiquitination and the assembly of the NOD2 signaling complex, thereby precluding production of inflammatory cytokines (Damgaard et al. 2013; Goncharov et al. 2018).

Previous drug discovery efforts that used pan IAP antagonists have produced reagents with favorable potency and pharmacological properties allowing clinical trials in cancer patients (Fulda and Vucic 2012). Identification of XIAP mutations-associated pathologies urges a cautious approach in targeting XIAP (Aguilar and Latour 2015). Nevertheless, XIAP-selective antagonists have shown no adverse effects and display great efficacy in NOD2-RIPK2 pathway inhibition (Goncharov et al. 2018). Thus, future optimization of XIAP-selective antagonists could yield promising agents for therapeutic intervention in NOD2-mediated diseases such as Crohn's disease, sarcoidosis, and Blau syndrome.

Footnotes

Editors: Kim Newton, James M. Murphy, and Edward A. Miao

Additional Perspectives on Cell Survival and Cell Death available at www.cshperspectives.org

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