Nuclear and Cytoplasmic Functions of cIAP1: Comparison
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Cellular inhibitor of apoptosis 1 (cIAP1) is a cell signaling regulator of the IAP family. Through its E3-ubiquitine ligase activity, it has the ability to activate intracellular signaling pathways, modify signal transduction pathways by changing protein-protein interaction networks, and stop signal transduction by promoting the degradation of critical components of signaling pathways. Thus, cIAP1 appears to be a potent determinant of the response of cells, enabling their rapid adaptation to changing environmental conditions or intra- or extracellular stresses. It is expressed in almost all tissues, found in the cytoplasm, membrane and/or nucleus of cells. cIAP1 regulates innate immunity by controlling signaling pathways mediated by tumor necrosis factor receptor superfamily (TNFRs), some cytokine receptors and pattern recognition-receptors (PRRs). Although less documented, cIAP1 has also been involved in the regulation of cell migration and in the control of transcriptional programs. 

  • IAPs
  • signaling pathways
  • innate immunity
  • ubiquitination
  • TNFα
  • NF-κB
  • cell migration
  • E2F1

1. Introduction

IAPs (Inhibitors of Apoptosis) form a family of proteins highly conserved during evolution. The named “IAP” was chosen by Lois Miller’s teams, who described a new class of proteins encoded by the Cydia pomonella granulosis virus (CpGV) genome and were able to protect infected insect cells from apoptosis to allow viral spread [1]. Since then, based on sequence homologies, IAP homologs have been identified in insects, yeasts, nematodes, fish and mammals. However, although they are able to inhibit or delay cell death when overexpressed, the main cellular function for most of them is not an inhibition of apoptosis. Among the eight described mammal homologs, XIAP (X-linked IAP) [2], cIAP1 (cellular IAP1), cIAP2, ML-IAP (Melanoma IAP) [3] and ILP-2 (IAP-like protein 2) [4] are enzymes of the ubiquitination reaction involved in proteostasis and the regulation of the assembly of intracellular signaling platforms.
XIAP has the greatest ability to inhibit apoptosis by directly interacting with initiator and effector caspases and blocking their activity [5][6][7]. Upon apoptotic stimuli, XIAP is neutralized by Smac (Second mitochondria derived activator of caspase), which is contained into the mitochondrial intermembrane space and released into the cytosol during the early phase of apoptotic intrinsic pathway [8][9][10]. Based on these observations, Smac mimetics have been developed in order to counteract the anti-apoptotic activity of IAPs in tumors. However, Smac as well as Smac mimetics are also able to bind and neutralize other IAPs such as cIAP1, cIAP2 and ML-IAP with high affinities [11].
cIAP1 and its paralogous cIAP2 are most studied for their ability to regulate innate immunity and inflammation [12]. By controlling the scaffolding and kinase activities of RIPK1, cIAPs dictate the response of cells to tumor necrosis factor receptor (TNFR) superfamily stimulation [13]. They have also been involved in the control of the inflammatory response mediated by pattern recognition (PRRs) and cytokine receptors [14]. In addition, cIAP1 can control intracellular signaling pathways that drive cell motility and migration, regulate cell cycle cell proliferation and transcriptional programs [15].
The expression of cIAP1, cIAP2 and XIAP is preferentially induced under stressful conditions such as hypoxia, endoplasmic reticular stress and DNA damage. Regulation can occur at a transcriptional level via HIF-1α, NF-κB or E2F1-dependent mechanisms [16][17] or at translational level due to the presence of an internal ribosome entry site (IRES)-dependent mechanism of translation initiation [18][19][20]. Moreover, the stability of cIAPs is regulated by heat shock proteins (HSPs) [21]. Thus, these pleiotropic proteins appeared to act as potent regulators of the adaptive response of cells to a changing environment or in response to environmental or intracellular stresses such as pathogen attack, hypoxic-ischemic injury or DNA damage [22]. Consistent with their role in regulating homeostasis, dysregulations of cIAPs have been observed in cancer, neurodegenerative disorders and inflammatory diseases. Moreover, the oncogenic properties of cIAP1 were clearly demonstrated in mouse models of hepatocarcinoma, osteosarcoma and breast cancer [23][24][25].

2. Cytoplasmic Functions of cIAP1

2.1. Role for cIAP1 in Regulating Innate Immunity

2.1.1. Regulation of TNFα Signaling Pathways in Immune and Non-Immune Cells

The tumor necrosis factor alpha (TNFα) is the master regulator of tissue homeostasis by coordinating the inflammatory response and regulating the immune system (for review, see [26]). Dysregulated TNFR-signaling pathways or sustained production of TNFα has been involved in the pathogenesis of many chronic inflammatory diseases and anti-TNFα therapy has demonstrated efficiency in the treatment of severe forms of rheumatoid arthritis, Crohn’s disease, ulcerative colitis, psoriasis, psoriatic arthritis, ankylosing spondylitis and juvenile idiopathic arthritis. Conversely, neutralizing TNFα can also result in the onset of autoimmune disease supporting its pleiotropic functions in regulating the immune system [26][27]. It is produced within minutes of injury or stress, mainly by monocytes and macrophages, and it exerts its activity in transmembrane or soluble, secreted forms. TNFα is endowed with multiples functions depending on the cellular and environmental context. Its predominant activity is to trigger the production of pro-inflammatory cytokines and chemokines. It can also stimulate the survival and differentiation of immune cells, promote their recruitment to the site of damage, and enhance the adhesion of endothelial cells. Under specific conditions, survival signals can switch to cell death signals. For example, TNFα can help in killing infected cells in order to contain the infection and ensure tissue integrity; it takes part in the maintenance of peripheral immune tolerance by participating to the deletion of activated T-cells [28]; it can promote the death of irreversibly damaged cells in order to ensure tissue homeostasis [26].
TNFα is recognized by TNFR1 expressed in all human tissues and by TNFR2, whose expression is limited to immune cells, neurons, endothelial cells, cardiomyocytes, and osteoclast precursors. It is generally admitted that TNFR1 can trigger a strong inflammatory response and/or cell death, while TNFR2 induces cell death protection and a moderate inflammation. The response to TNFR1 stimulation is orchestrated by the presence of different checkpoints. The kinase RIP1 is critical in determining the inflammatory response or cell death. It is recruited into the surface receptor-associated intracellular complex via homotypic interaction thanks to the death-domain (DD) exhibited by both the receptor (intracellular side) and RIP1 [29]. In the receptor-associated signaling complex, so-called complex I, RIP1 acts as a scaffold for the recruitment of kinase complexes including TAK1/TAB2/TAB3 and IκB kinase (IKK) complex that promote MAPK and NF-kB-mediated transcriptional programs [30] (Figure 1). This scaffolding function is fully dependent on non-degradative poly-ubiquitination including K11, K63-linked, linear and hybrid-polyubiquitination [31][32]. On the other hand, thanks to its kinase activity, RIP1 can promote the assembly of a secondary cytoplasmic complexes including complex-II, ripoptosome and necrosome that result in apoptotic or necroptotic cell death [33] (Figure 1). Necroptosis is associated with a massive release of cytokines, chemokines and damage-associated molecular patterns (DAMPs) recognized by pattern recognition receptors (PRRs) that trigger the innate immune response [34][35]. The role of TNFα in chronic inflammatory diseases has been explained by its capacity to activate this immunogenic cell death [27].
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Figure 1. Regulation of signaling pathways by cIAP1. The cIAP1-TRAF2 E3-Ubiquitin ligase complex regulates the cellular content of NIK by mediating its ubiquitin-proteasome dependent degradation. The recruitment of cIAP1/TRAF2 to TNFR2, CD30, CD40 or BAFF-R releases NIK that in turn stimulates the non-canonical NF-κB signaling pathway. In the TLR4-associated signaling complex, cIAP1 induces the ubiquitination and degradation of TRAF3. cIAP1/TRAF2 forms a secondary cytoplasmic complex leading to NF-kB / MAPK activation. In TNFR1-associated complex, cIAP1 induces the ubiquitination of RIP1 and other components of the complex, resulting in the assembly of the signaling platform driving NF-κB and MAPK activation. cIAP1-mediated ubiquitination of RIP1 inhibits its kinase activity required for the assembly of cytoplasmic RIP-containing platforms leading to apoptotic or necrotic cell death. cIAP1 controls the cycle of activation of cdc42. The recruitment of cIAP1/TRAF2 to TNFR-associated signaling complex releases cdc42 for activation. BAFF-R: B-cell activating factor receptor; CD40-R: Cluster of differentiation 40 receptor, IKKα, β or γ: Inhibitor of κB kinase α, β or γ; LUBAC: linear ubiquitin chain assembly complex; Myd88: Myeloid differentiation primary response 88; NIK: NF-κB-inducing kinase; Rho-GDI: Rho-guanine-nucleotide dissociation inhibitors; TAB1, 2 or 3: transforming growth factor-activated kinase1-binding protein 1, 2, and 3; TAK1:tumor growth factor-β-activated kinase 1; TLR 4: toll-like receptor 4; TNFR2: tumor necrosis factor Receptor 2, TRADD: TNFR-associated death domain; TRIF: toll–interleukin 1 receptor domain-containing adaptor inducing IFN-β.
cIAP1 takes part in this regulation. It constitutes an essential survival factor in intestinal epithelial cells, neutrophils, macrophages and activated T cells, allowing them to resist to TNFR1-mediated cell death when exposed to an acute inflammatory environment [36][37][38][39][40]. Depletion of cIAPs prevents TNFα-mediated NF-κB and MAPK activation and sensitizes cells to TNFα-mediated cell death [41][42][43][44]. In mice, deletion of cIAP1 as well as cIAP2 or XIAP did not lead to obvious phenotypic abnormalities. A moderate inflammation in lungs and intestines was observed in cIAP1−/− KO mice [45]. However, double deletion of cIAP1 and cIAP2 or cIAP1 and XIAP in mice leads to embryonic lethality in TNFR1 and RIP1-dependent manner [42] and the specific depletion of cIAP1, -2 and XIAP in myeloid lineage or keratinocytes causes a severe local inflammation and TNFR1 or RIP1-dependent cell death [38][46][47]. By controlling the stability, scaffold function and kinase activity of RIP1, cIAPs have the ability to control the intensity and duration of the TNFR1-mediated inflammatory response: (i) they activate the scaffold function by promoting the conjugation of K11 and K63-linked poly-ubiquitin chains on components of complex I that include RIP1 [48][49][50][51]; (ii) they can stop the TNFR1-mediating signaling pathway by the promotion of ubiquitin-dependent degradation of RIP1 [48]; (iii) alternatively, cIAP-mediated ubiquitination of RIP1 represses its kinase activity necessary for the assembly of cell-death-mediated complexes-II [48] and then prevents TNF-mediated cytotoxicity and necroptosis-associated massive inflammation [52] (Figure 1). In addition to controlling the scaffold function, kinase activity and stability of RIP1, cIAP1 can regulate the TNFα-mediated NF-κB activating signalling pathway by the ubiquitination of NEMO/IKKγ (NF-κB essential modulator/IκB kinase-γ), the regulatory subunit of IKK complex [53].
TNFR2 plays a role in promoting the differentiation and stabilization of regulatory T cells, and mutation in TNFR2 has been involved in the pathogenesis of several autoimmune diseases [27]. In endothelial cells, it participates in tissue regeneration. Since the TNFR2 protein does not harbor DD (death- domain), it cannot recruit RIP1, but it can directly bind the molecular adaptors TRAF2 and TRAF3. TRAF2 recruits cIAP1 into the TNFR2-associated signaling complex. As observed in the TNFR1-associated signaling complex, cIAP1 can promote K63-linked polyubiquitinatin at the TNFR2-signaling complex [54], resulting in the recruitment and activation of kinase complexes that drive MAPK and canonical NF-κB. However, TNFR2 stimulation likely leads to cIAPs-dependent canonical NF-κB activation [54] (see below).

2.1.2. Regulation of the Non-Canonical NF-κB Signaling Pathway in Immune Cells, Osteoclasts and Endothelial Cells

The best characterized substrate of the cIAP1/TRAF2 E3-ubiquitine ligase complex is NF-κB-inducing kinase (NIK), an essential mediator of the non-canonical NF-κB signaling pathway [55][56][57].
The non-canonical NF-κB signaling pathway is characterized by inducible processing of the p100 subunit in active p52 which, when heterodimerized with RelB, acts as a transcription factor. The processing of p100 is triggered following its phosphorylation by the IKKα homodimer, itself activated by NIK [58]. cIAP1 regulates the NF-kB alternative pathway by controlling the cellular content of NIK. In the resting condition, NIK is recruited to the cIAP1/TRAF2 complex via TRAF3. The complex is stabilized by direct binding of NIK with the BIR2 domain of cIAP1 in IBM-dependent manner [55][59][57]. cIAP1 promotes the ubiquitin-mediated proteasomal degradation of NIK, turning off the non-canonical NF-κB signaling pathway [55][56][57] (Figure 24). Stimulation of TNFR2, CD30, CD40, BAFF-R (B-cell-activating factor) or FN14 leads to the recruitment of TRAF2/TRAF3/cIAP1 complex to membrane-associated signaling complex [60][61][62][63][64]. TRAF2 induced cIAP1 activation via K63-linked ubiquitination. In turn, cIAP1 catalyzes K43-linked ubiquitination of TRAF2/3 and their degradation by the proteasome system, resulting in upregulation of NIK and activation of non-canonical NF-κB signaling [55].
/media/item_content/202203/622edc38a91b8biomolecules-12-00322-g004.png
Figure 2. Regulation of signaling pathways by cIAP1. The cIAP1-TRAF2 E3-Ubiquitin ligase complex regulates the cellular content of NIK by mediating its ubiquitin-proteasome dependent degradation. The recruitment of cIAP1/TRAF2 to TNFR2, CD30, CD40 or BAFF-R releases NIK that in turn stimulates the non-canonical NF-κB signaling pathway. In the TLR4-associated signaling complex, cIAP1 induces the ubiquitination and degradation of TRAF3. cIAP1/TRAF2 forms a secondary cytoplasmic complex leading to NF-kB / MAPK activation. In TNFR1-associated complex, cIAP1 induces the ubiquitination of RIP1 and other components of the complex, resulting in the assembly of the signaling platform driving NF-κB and MAPK activation. cIAP1-mediated ubiquitination of RIP1 inhibits its kinase activity required for the assembly of cytoplasmic RIP-containing platforms leading to apoptotic or necrotic cell death. cIAP1 controls the cycle of activation of cdc42. The recruitment of cIAP1/TRAF2 to TNFR-associated signaling complex releases cdc42 for activation. BAFF-R: B-cell activating factor receptor; CD40-R: Cluster of differentiation 40 receptor, IKKα, β or γ: Inhibitor of κB kinase α, β or γ; LUBAC: linear ubiquitin chain assembly complex; Myd88: Myeloid differentiation primary response 88; NIK: NF-κB-inducing kinase; Rho-GDI: Rho-guanine-nucleotide dissociation inhibitors; TAB1, 2 or 3: transforming growth factor-activated kinase1-binding protein 1, 2, and 3; TAK1:tumor growth factor-β-activated kinase 1; TLR 4: toll-like receptor 4; TNFR2: tumor necrosis factor Receptor 2, TRADD: TNFR-associated death domain; TRIF: toll–interleukin 1 receptor domain-containing adaptor inducing IFN-β.
Non-canonical NF-κB signaling is essential for the activation, survival and differentiation of immune cells such as B-cells, macrophages and dendritic cells. Deletion of cIAP1 and cIAP2 in mice maintained B-cells survival and maturation independent of BAFF-R stimulation [62], and can account for B-cell transformation [65][66][67]. It's demonstrated that cIAP1-mediated degradation of TRAF2 is essential for the full activity of macrophages in response to CD40 stimulation [68]. IAP antagonists can also favor osteoclasts differentiation in a NIK-dependent manner, supporting the critical role of the non-canonical NF-κB signaling pathway in osteoclastogenesis [69].

2.1.3. Regulation of PRR Signaling Pathways

The presence of pathogens in an organism is sensed by cell surface and intracellular receptors able to recognize a wide variety of pathogen-associated molecular patterns (PAMPs) and danger signals (DAMPs). Among them, the cell surface membrane TLR4, which recognizes bacteria lipopolysaccharides (LPS) can elicit distinct signaling pathways leading to either pro-inflammatory or interferon response. TLR4 engagement induces the recruitment of several cytoplasmic adaptor proteins thanks to the presence, in both the receptors and adaptors, of a homotypic interacting domain. The adaptor MyD88 (myeloid differentiation factor 88) has been involved in NF-κB and MAPK-dependent production of pro-inflammatory cytokines, whereas the adaptor TRIF (TIR-domain-containing adaptor-inducing IFN-b) is required for the IFN response. The cIAP1/TRAF2 E3-ubiquitine ligase complex is a potent determinant of the response to TLR4 stimulation. MyD-88 can directly recruit the adaptor TRAF3 which can bind the TRAF2/cIAP1 complex. In the MyD88-containing TLR4 complex (so-called Myddosome), the cIAP1/TRAF2 E3-ubiquitin ligase complex induces the ubiquitination and degradation of TRAF3, which results in the assembly of a secondary cytoplasmic signaling platform containing TRAF2/cIAP1, TAK1/TAB1–3 and IKK complexes leading to the activation of MAPK (Mitogen-activated protein kinases) and NF-κB (nuclear factor-kappa B)-signaling pathways [70][71][72] (Figure 1). Depletion of TRAF3 can also turn-off the IFN response that is involved in the TRAF6/TRAF3 complex.
In some situations, such as a sustained infection, the presence of pathogens resistant to inflammatory defense, or in some pathological conditions, TLR4, just like TLR3, which senses virus-derived nucleic acids, can also trigger RIP1-dependent cell death through a direct binding of RIP1 to the adaptor TRIF. cIAP1 constitutes a powerful survival factor in infected cells by preventing the assembly of ripoptosome and necrosome as explained above [35][47].
Supporting the role of IAPs in controlling the strength and duration of the inflammatory response, Jin et al. showed that the cIAP1/TRAF2 complex can limit inflammation by promoting the ubiquitin-proteasome dependent degradation of c-Rel and IRF5 (interferon-responsive factor 5), two critical transcription factors involved in TLR-mediated NF-κB-dependent inflammatory and IFN response respectively. Depletion of TRAF2 in macrophages promoted colitis characterized by enhanced leukocyte infiltration in colon, mucosal damage and pro-inflammatory cytokines production in an animal model [73].

2.2. Role for cIAP1 in Cell Motility and Migration

Cell shape and cell motility are controlled by small GTPases of the Rho family. These proteins are critical regulators of the dynamic reorganization of the actin cytoskeleton [74][75][76]. They control cell architecture, focal adhesion complexes and local contraction by promoting the generation of stress fibers or membrane protrusions such as lamellopodia or filopodia [77]. They switch between a cytoplasmic, inactive GDP-bound state and a membrane-associated, active GTP-bound state, providing energy required for cytoskeleton rearrangement. RhoGTPase activation is mediated by guanine-nucleotide exchange factors (GEFs), which catalyze the transfer of GDP-bound to GTP-bound forms. Once activated, RhoGTPases are either recycled in inactive state by the action of GTPase-activation proteins (GAPs) or subjected to UPS-mediated degradation. The activation cycle of Rho GTPase is controlled by molecular chaperones such as guanine-nucleotide dissociation inhibitors (GDIs) which stabilize Rho GTPases in their cytosolic inactive state [77]. A relationship between IAPs and RhoGTPases was suggested in 2004 in a study showing that drosophila DIAP1 can interact with Rac1 and compensate for the migration defect triggered by the expression of a dominant negative form of this GTPase [78]. In mammals, in vitro assays have demonstrated that cIAP1, cIAP2 and XIAP are able to directly interact with the three most studied RhoGTPases [79][80][81][82] RhoA, Rac1 and cdc42, which promote lamellopodia, stress fibers or filopidia, respectively. In a study analysing the influence of cIAP1 on cell shape and migration, it's demonstrated that cIAP1 can directly bind cdc42. It stabilizes cdc42 in its GDP-, inactive-state by promoting its association with its molecular chaperone RhoGDI. Deletion of cIAP1 deregulated the activation cycle of cdc42 by promoting its activation and then degradation [79]. Accordingly, cIAP1−/− fibroblasts display an enhanced ability to migrate and exhibit filopodia. TNFα has the ability to induce cdc42 activation and actin reorganisation [75][76]. Upon TNFα stimulation, cIAP1 is recruited to the membrane receptor-associated complex, releasing cdc42 and promoting its activation [79] (Figure 1). The ubiquitination of cdc42 by cIAP1 has not been demonstrated; however, the ability of XIAP to ubiquitinate cdc42 and of XIAP and cIAP1 to ubiquitinate Rac1 has been observed [80][83]. Single or combined deletion of cIAP1, cIAP2 or XIAP differently affects cell shape, actin distribution and migratory capacity. They appear to have specific and distinct activity on each of the Rho proteins, suggesting that IAPs could regulate the spatiotemporal and sequential activation of Rho proteins [84]. Additional analysis will be required to decipher the regulation of the Rho proteins by IAPs.

3. Conclusions

cIAP1 mainly exerts its activity by controlling the cell fate of its protein partners. Thanks to their ability to promote the conjugation of ubiquitin chains of different types, they can modulate the stability, localization and/or the activity of intracellular proteins and can change the composition of signaling platforms by modifying the intermolecular binding affinities. Thus, IAPs have the ability to control the implementation of signaling pathways and their regulations in time and space. To date, more than 30 cIAP substrates have been identified (recently reviewed in [15]). A database search for proteins containing IBM-like sequences found many proteins with different cellular functions [85], greatly expanding the number of potential IAP-binding partners. The identified IAP substrates are involved in various cellular processes essential for maintaining cell homeostasis (innate immune response, DNA damage response, cell cycle regulation). For most of them, the type and site of ubiquitination have not been determined. However, this is an important issue to address since they determine the cellular fate of the substrate [48]. The ultimate function of IAPs is to allow cells to adapt to their changing environment, to help implement an appropriate response to combat endogenous or exogenous stress or microbial aggression, and to restore homeostasis. Although loss of cIAP1 in mice has been associated with locale inflammation in lung, intestines or skin [45][46], deletion or mutation of the BIRC2/3 gene has not been associated with chronic inflammatory disease but has with cancer development. More in-depth studies of the implication of cIAPs in these pathologies deserve to be carried out. Most studies have focused on analyzing the role of cIAPs in innate immunity and in regulating cell surface receptor signaling pathways. However, consistent with their nuclear expression in cells in many tissues, their functions in the nucleus, in particular as a transcriptional regulator, may have been underestimated. The expression of cIAP1 is ubiquitous and its regulation mechanisms are still poorly understood. The last observations suggest that cIAP1 and TRAF2 require each other and form an E3-ubiquitin ligase complex. cIAP1 E3-ligase activity is stimulated by K63-linked ubiquitination that can be mediated by TRAF2 or TRAF6 [55][70]. The stability of cIAP1 can be controlled by phosphorylation [86], and its regulation by S-nitrosylation and oxidation processes have also been reported [87][88]. One important issue to address concerns the mechanisms of regulation of the subcellular localization of cIAP1. Smac mimetics designed to block XIAP anti-apoptotic activity are also potent inhibitors of cIAP1 by promoting its proteasome-mediated degradation. They have been developed as anticancer agents. However, because of the ability of cIAP1 to regulate RIP1 activities, numerous preclinical studies are exploring their potential in the treatment of inflammatory and infectious disease.

References

  1. Crook, N.E.; Clem, R.J.; Miller, L.K. An apoptosis-inhibiting baculovirus gene with a zinc finger-like motif. J. Virol. 1993, 67, 2168–2174.
  2. Liston, P.; Roy, N.; Tamai, K.; Lefebvre, C.; Baird, S.; Cherton-Horvat, G.; Farahani, R.; McLean, M.; Ikeda, J.E.; MacKenzie, A.; et al. Suppression of apoptosis in mammalian cells by NAIP and a related family of IAP genes. Nature 1996, 379, 349–353.
  3. Vucic, D.; Stennicke, H.R.; Pisabarro, M.T.; Salvesen, G.S.; Dixit, V.M. ML-IAP, a novel inhibitor of apoptosis that is preferentially expressed in human melanomas. Curr. Biol. 2000, 10, 1359–1366.
  4. Vucic, D.; Kaiser, W.J.; Harvey, A.J.; Miller, L.K. Inhibition of reaper-induced apoptosis by interaction with inhibitor of apoptosis proteins (IAPs). Proc. Natl. Acad. Sci. USA 1997, 94, 10183–10188.
  5. Deveraux, Q.L.; Takahashi, R.; Salvesen, G.S.; Reed, J.C. X-linked IAP is a direct inhibitor of cell-death proteases. Nature 1997, 388, 300–304.
  6. Takahashi, R.; Deveraux, Q.; Tamm, I.; Welsh, K.; Assa-Munt, N.; Salvesen, G.S.; Reed, J.C. A single BIR domain of XIAP sufficient for inhibiting caspases. J. Biol. Chem. 1998, 273, 7787–7790.
  7. Chai, J.; Shiozaki, E.; Srinivasula, S.M.; Wu, Q.; Datta, P.; Alnemri, E.S.; Shi, Y. Structural basis of caspase-7 inhibition by XIAP. Cell 2001, 104, 769–780.
  8. Chai, J.; Du, C.; Wu, J.W.; Kyin, S.; Wang, X.; Shi, Y. Structural and biochemical basis of apoptotic activation by Smac/DIABLO. Nature 2000, 406, 855–862.
  9. Hegde, R.; Srinivasula, S.M.; Zhang, Z.; Wassell, R.; Mukattash, R.; Cilenti, L.; DuBois, G.; Lazebnik, Y.; Zervos, A.S.; Fernandes-Alnemri, T.; et al. Identification of Omi/HtrA2 as a mitochondrial apoptotic serine protease that disrupts inhibitor of apoptosis protein-caspase interaction. J. Biol. Chem. 2002, 277, 432–438.
  10. Verhagen, A.M.; Silke, J.; Ekert, P.G.; Pakusch, M.; Kaufmann, H.; Connolly, L.M.; Day, C.L.; Tikoo, A.; Burke, R.; Wrobel, C.; et al. HtrA2 promotes cell death through its serine protease activity and its ability to antagonize inhibitor of apoptosis proteins. J. Biol. Chem. 2002, 277, 445–454.
  11. Morrish, E.; Brumatti, G.; Silke, J. Future Therapeutic Directions for Smac-Mimetics. Cells 2020, 9, 406.
  12. Uren, A.G.; Pakusch, M.; Hawkins, C.J.; Puls, K.L.; Vaux, D.L. Cloning and expression of apoptosis inhibitory protein homologs that function to inhibit apoptosis and/or bind tumor necrosis factor receptor-associated factors. Proc. Natl. Acad. Sci. USA 1996, 93, 4974–4978.
  13. Peltzer, N.; Darding, M.; Walczak, H. Holding RIPK1 on the Ubiquitin Leash in TNFR1 Signaling. Trends Cell Biol. 2016, 26, 445–461.
  14. Estornes, Y.; Bertrand, M.J. IAPs, regulators of innate immunity and inflammation. Semin. Cell Dev. Biol. 2015, 39, 106–114.
  15. Dumetier, B.; Zadoroznyj, A.; Dubrez, L. IAP-Mediated Protein Ubiquitination in Regulating Cell Signaling. Cells 2020, 9, 1118.
  16. Wang, D.; Berglund, A.E.; Kenchappa, R.S.; MacAulay, R.J.; Mulé, J.J.; Etame, A.B. BIRC3 is a biomarker of mesenchymal habitat of glioblastoma, and a mediator of survival adaptation in hypoxia-driven glioblastoma habitats. Sci. Rep. 2017, 7, 9350.
  17. Allègre, J.; Cartier, J.; Glorian, V.; Droin, N.; Dumetier, B.; Kayaci, C.; Berthelet, J.; Gemble, S.; Vuillier, C.; Maillet, L.; et al. E2F1 binds to the peptide-binding groove within the BIR3 domain of cIAP1 and requires cIAP1 for chromatin binding. PLoS ONE 2018, 13, e0206253.
  18. Warnakulasuriyarachchi, D.; Cerquozzi, S.; Cheung, H.H.; Holcik, M. Translational induction of the inhibitor of apoptosis protein HIAP2 during endoplasmic reticulum stress attenuates cell death and is mediated via an inducible internal ribosome entry site element. J. Biol. Chem. 2004, 279, 17148–17157.
  19. Riley, A.; Jordan, L.E.; Holcik, M. Distinct 5′ UTRs regulate XIAP expression under normal growth conditions and during cellular stress. Nucleic Acids Res. 2010, 38, 4665–4674.
  20. Van Eden, M.E.; Byrd, M.P.; Sherrill, K.W.; Lloyd, R.E. Translation of cellular inhibitor of apoptosis protein 1 (c-IAP1) mRNA is IRES mediated and regulated during cell stress. RNA 2004, 10, 469–481.
  21. Didelot, C.; Lanneau, D.; Brunet, M.; Bouchot, A.; Cartier, J.; Jacquel, A.; Ducoroy, P.; Cathelin, S.; Decologne, N.; Chiosis, G.; et al. Interaction of heat-shock protein 90 beta isoform (HSP90 beta) with cellular inhibitor of apoptosis 1 (c-IAP1) is required for cell differentiation. Cell Death Differ. 2008, 15, 859–866.
  22. Marivin, A.; Berthelet, J.; Plenchette, S.; Dubrez, L. The Inhibitor of Apoptosis (IAPs) in Adaptive Response to Cellular Stress. Cells 2012, 1, 711–737.
  23. Zender, L.; Spector, M.S.; Xue, W.; Flemming, P.; Cordon-Cardo, C.; Silke, J.; Fan, S.T.; Luk, J.M.; Wigler, M.; Hannon, G.J.; et al. Identification and validation of oncogenes in liver cancer using an integrative oncogenomic approach. Cell 2006, 125, 1253–1267.
  24. Ma, O.; Cai, W.W.; Zender, L.; Dayaram, T.; Shen, J.; Herron, A.J.; Lowe, S.W.; Man, T.K.; Lau, C.C.; Donehower, L.A. MMP13, Birc2 (cIAP1), and Birc3 (cIAP2), amplified on chromosome 9, collaborate with p53 deficiency in mouse osteosarcoma progression. Cancer Res. 2009, 69, 2559–2567.
  25. Cheng, L.; Zhou, Z.; Flesken-Nikitin, A.; Toshkov, I.A.; Wang, W.; Camps, J.; Ried, T.; Nikitin, A.Y. Rb inactivation accelerates neoplastic growth and substitutes for recurrent amplification of cIAP1, cIAP2 and Yap1 in sporadic mammary carcinoma associated with p53 deficiency. Oncogene 2010, 29, 5700–5711.
  26. Holbrook, J.; Lara-Reyna, S.; Jarosz-Griffiths, H.; McDermott, M. Tumour necrosis factor signalling in health and disease. F1000Res 2019, 8.
  27. Tseng, W.Y.; Huang, Y.S.; Lin, H.H.; Luo, S.F.; McCann, F.; McNamee, K.; Clanchy, F.; Williams, R. TNFR signalling and its clinical implications. Cytokine 2018, 101, 19–25.
  28. Zhang, M.; Wang, J.; Jia, L.; Huang, J.; He, C.; Hu, F.; Yuan, L.; Wang, G.; Yu, M.; Li, Z. Transmembrane TNF-α promotes activation-induced cell death by forward and reverse signaling. Oncotarget 2017, 8, 63799–63812.
  29. He, S.; Wang, X. RIP kinases as modulators of inflammation and immunity. Nat. Immunol. 2018, 19, 912–922.
  30. Annibaldi, A.; Meier, P. Checkpoints in TNF-Induced Cell Death: Implications in Inflammation and Cancer. Trends Mol. Med. 2018, 24, 49–65.
  31. Emmerich, C.H.; Bakshi, S.; Kelsall, I.R.; Ortiz-Guerrero, J.; Shpiro, N.; Cohen, P. Lys63/Met1-hybrid ubiquitin chains are commonly formed during the activation of innate immune signalling. Biochem. Biophys. Res. Commun. 2016, 474, 452–461.
  32. Witt, A.; Vucic, D. Diverse ubiquitin linkages regulate RIP kinases-mediated inflammatory and cell death signaling. Cell Death Differ. 2017, 24, 1160–1171.
  33. Schwarzer, R.; Laurien, L.; Pasparakis, M. New insights into the regulation of apoptosis, necroptosis, and pyroptosis by receptor interacting protein kinase 1 and caspase-8. Curr. Opin. Cell Biol. 2020, 63, 186–193.
  34. Frank, D.; Vince, J.E. Pyroptosis versus necroptosis: Similarities, differences, and crosstalk. Cell Death Differ. 2019, 26, 99–114.
  35. Lawlor, K.E.; Khan, N.; Mildenhall, A.; Gerlic, M.; Croker, B.A.; D’Cruz, A.A.; Hall, C.; Kaur Spall, S.; Anderton, H.; Masters, S.L.; et al. RIPK3 promotes cell death and NLRP3 inflammasome activation in the absence of MLKL. Nat. Commun. 2015, 6, 6282.
  36. Chen, K.W.; Lawlor, K.E.; von Pein, J.B.; Boucher, D.; Gerlic, M.; Croker, B.A.; Bezbradica, J.S.; Vince, J.E.; Schroder, K. Cutting Edge: Blockade of Inhibitor of Apoptosis Proteins Sensitizes Neutrophils to TNF- but Not Lipopolysaccharide-Mediated Cell Death and IL-1β Secretion. J. Immunol. 2018, 200, 3341–3346.
  37. Grabinger, T.; Bode, K.J.; Demgenski, J.; Seitz, C.; Delgado, M.E.; Kostadinova, F.; Reinhold, C.; Etemadi, N.; Wilhelm, S.; Schweinlin, M.; et al. Inhibitor of Apoptosis Protein-1 Regulates Tumor Necrosis Factor-Mediated Destruction of Intestinal Epithelial Cells. Gastroenterology 2017, 152, 867–879.
  38. Wong, W.W.; Vince, J.E.; Lalaoui, N.; Lawlor, K.E.; Chau, D.; Bankovacki, A.; Anderton, H.; Metcalf, D.; O’Reilly, L.; Jost, P.J.; et al. cIAPs and XIAP regulate myelopoiesis through cytokine production in an RIPK1- and RIPK3-dependent manner. Blood 2014, 123, 2562–2572.
  39. Liu, H.; Liao, R.; He, K.; Zhu, X.; Li, P.; Gong, J. The SMAC mimetic birinapant attenuates lipopolysaccharide-induced liver injury by inhibiting the tumor necrosis factor receptor-associated factor 3 degradation in Kupffer cells. Immunol. Lett. 2017, 185, 79–83.
  40. Gentle, I.E.; Moelter, I.; Lechler, N.; Bambach, S.; Vucikuja, S.; Häcker, G.; Aichele, P. Inhibitors of apoptosis proteins (IAPs) are required for effective T-cell expansion/survival during antiviral immunity in mice. Blood 2014, 123, 659–668.
  41. Varfolomeev, E.; Goncharov, T.; Fedorova, A.V.; Dynek, J.N.; Zobel, K.; Deshayes, K.; Fairbrother, W.J.; Vucic, D. c-IAP1 and c-IAP2 are critical mediators of tumor necrosis factor alpha (TNFalpha)-induced NF-kappaB activation. J. Biol. Chem. 2008, 283, 24295–24299.
  42. Moulin, M.; Anderton, H.; Voss, A.K.; Thomas, T.; Wong, W.W.; Bankovacki, A.; Feltham, R.; Chau, D.; Cook, W.D.; Silke, J.; et al. IAPs limit activation of RIP kinases by TNF receptor 1 during development. EMBO J. 2012, 31, 1679–1691.
  43. Feoktistova, M.; Geserick, P.; Kellert, B.; Dimitrova, D.P.; Langlais, C.; Hupe, M.; Cain, K.; MacFarlane, M.; Hacker, G.; Leverkus, M. cIAPs block Ripoptosome formation, a RIP1/caspase-8 containing intracellular cell death complex differentially regulated by cFLIP isoforms. Mol. Cell 2011, 43, 449–463.
  44. Moen, I.N.; Westhrin, M.; Håland, E.; Haug, M.; Nonstad, U.; Klaharn, M.; Standal, T.; Starheim, K.K. Smac-mimetics reduce numbers and viability of human osteoclasts. Cell Death Discov. 2021, 7, 36.
  45. Zhang, J.; Webster, J.D.; Dugger, D.L.; Goncharov, T.; Roose-Girma, M.; Hung, J.; Kwon, Y.C.; Vucic, D.; Newton, K.; Dixit, V.M. Ubiquitin Ligases cIAP1 and cIAP2 Limit Cell Death to Prevent Inflammation. Cell Rep. 2019, 27, 2679–2689.e2673.
  46. Anderton, H.; Rickard, J.A.; Varigos, G.A.; Lalaoui, N.; Silke, J. Inhibitor of Apoptosis Proteins (IAPs) Limit RIPK1-Mediated Skin Inflammation. J. Investig. Dermatol. 2017, 137, 2371–2379.
  47. Lawlor, K.E.; Feltham, R.; Yabal, M.; Conos, S.A.; Chen, K.W.; Ziehe, S.; Graß, C.; Zhan, Y.; Nguyen, T.A.; Hall, C.; et al. XIAP Loss Triggers RIPK3- and Caspase-8-Driven IL-1β Activation and Cell Death as a Consequence of TLR-MyD88-Induced cIAP1-TRAF2 Degradation. Cell Rep. 2017, 20, 668–682.
  48. Annibaldi, A.; Wicky John, S.; Vanden Berghe, T.; Swatek, K.N.; Ruan, J.; Liccardi, G.; Bianchi, K.; Elliott, P.R.; Choi, S.M.; Van Coillie, S.; et al. Ubiquitin-Mediated Regulation of RIPK1 Kinase Activity Independent of IKK and MK2. Mol. Cell 2018, 69, 566–580.e565.
  49. Ea, C.K.; Deng, L.; Xia, Z.P.; Pineda, G.; Chen, Z.J. Activation of IKK by TNFalpha requires site-specific ubiquitination of RIP1 and polyubiquitin binding by NEMO. Mol. Cell 2006, 22, 245–257.
  50. O’Donnell, M.A.; Legarda-Addison, D.; Skountzos, P.; Yeh, W.C.; Ting, A.T. Ubiquitination of RIP1 regulates an NF-kappaB-independent cell-death switch in TNF signaling. Curr. Biol. 2007, 17, 418–424.
  51. Dynek, J.N.; Goncharov, T.; Dueber, E.C.; Fedorova, A.V.; Izrael-Tomasevic, A.; Phu, L.; Helgason, E.; Fairbrother, W.J.; Deshayes, K.; Kirkpatrick, D.S.; et al. c-IAP1 and UbcH5 promote K11-linked polyubiquitination of RIP1 in TNF signalling. EMBO J. 2010, 29, 4198–4209.
  52. Vince, J.E.; Wong, W.W.; Gentle, I.; Lawlor, K.E.; Allam, R.; O’Reilly, L.; Mason, K.; Gross, O.; Ma, S.; Guarda, G.; et al. Inhibitor of apoptosis proteins limit RIP3 kinase-dependent interleukin-1 activation. Immunity 2012, 36, 215–227.
  53. Tang, E.D.; Wang, C.Y.; Xiong, Y.; Guan, K.L. A role for NF-kappaB essential modifier/IkappaB kinase-gamma (NEMO/IKKgamma) ubiquitination in the activation of the IkappaB kinase complex by tumor necrosis factor-alpha. J. Biol. Chem. 2003, 278, 37297–37305.
  54. Borghi, A.; Haegman, M.; Fischer, R.; Carpentier, I.; Bertrand, M.J.M.; Libert, C.; Afonina, I.S.; Beyaert, R. The E3 ubiquitin ligases HOIP and cIAP1 are recruited to the TNFR2 signaling complex and mediate TNFR2-induced canonical NF-κB signaling. Biochem. Pharm. 2018, 153, 292–298.
  55. Vallabhapurapu, S.; Matsuzawa, A.; Zhang, W.; Tseng, P.H.; Keats, J.J.; Wang, H.; Vignali, D.A.; Bergsagel, P.L.; Karin, M. Nonredundant and complementary functions of TRAF2 and TRAF3 in a ubiquitination cascade that activates NIK-dependent alternative NF-kappaB signaling. Nat. Immunol. 2008, 9, 1364–1370.
  56. Varfolomeev, E.; Blankenship, J.W.; Wayson, S.M.; Fedorova, A.V.; Kayagaki, N.; Garg, P.; Zobel, K.; Dynek, J.N.; Elliott, L.O.; Wallweber, H.J.; et al. IAP antagonists induce autoubiquitination of c-IAPs, NF-kappaB activation, and TNFalpha-dependent apoptosis. Cell 2007, 131, 669–681.
  57. Zarnegar, B.J.; Wang, Y.; Mahoney, D.J.; Dempsey, P.W.; Cheung, H.H.; He, J.; Shiba, T.; Yang, X.; Yeh, W.C.; Mak, T.W.; et al. Noncanonical NF-kappaB activation requires coordinated assembly of a regulatory complex of the adaptors cIAP1, cIAP2, TRAF2 and TRAF3 and the kinase NIK. Nat. Immunol. 2008, 9, 1371–1378.
  58. Sun, S.C. Non-canonical NF-κB signaling pathway. Cell Res. 2011, 21, 71–85.
  59. Lee, S.; Challa-Malladi, M.; Bratton, S.B.; Wright, C.W. Nuclear factor-κB-inducing kinase (NIK) contains an amino-terminal inhibitor of apoptosis (IAP)-binding motif (IBM) that potentiates NIK degradation by cellular IAP1 (c-IAP1). J. Biol. Chem. 2014, 289, 30680–30689.
  60. Csomos, R.A.; Wright, C.W.; Galban, S.; Oetjen, K.A.; Duckett, C.S. Two distinct signalling cascades target the NF-kappaB regulatory factor c-IAP1 for degradation. Biochem. J. 2009, 420, 83–91.
  61. Matsuzawa, A.; Tseng, P.H.; Vallabhapurapu, S.; Luo, J.L.; Zhang, W.; Wang, H.; Vignali, D.A.; Gallagher, E.; Karin, M. Essential cytoplasmic translocation of a cytokine receptor-assembled signaling complex. Science 2008, 321, 663–668.
  62. Gardam, S.; Turner, V.M.; Anderton, H.; Limaye, S.; Basten, A.; Koentgen, F.; Vaux, D.L.; Silke, J.; Brink, R. Deletion of cIAP1 and cIAP2 in murine B lymphocytes constitutively activates cell survival pathways and inactivates the germinal center response. Blood 2011, 117, 4041–4051.
  63. Varfolomeev, E.; Goncharov, T.; Maecker, H.; Zobel, K.; Komuves, L.G.; Deshayes, K.; Vucic, D. Cellular inhibitors of apoptosis are global regulators of NF-kappaB and MAPK activation by members of the TNF family of receptors. Sci. Signal. 2012, 5, ra22.
  64. Vince, J.E.; Chau, D.; Callus, B.; Wong, W.W.; Hawkins, C.J.; Schneider, P.; McKinlay, M.; Benetatos, C.A.; Condon, S.M.; Chunduru, S.K.; et al. TWEAK-FN14 signaling induces lysosomal degradation of a cIAP1-TRAF2 complex to sensitize tumor cells to TNFalpha. J. Cell Biol. 2008, 182, 171–184.
  65. Hatem, J.; Schrank-Hacker, A.M.; Watt, C.D.; Morrissette, J.J.; Rubin, A.I.; Kim, E.J.; Nasta, S.D.; Wasik, M.A.; Bogusz, A.M. Marginal zone lymphoma-derived interfollicular diffuse large B-cell lymphoma harboring 20q12 chromosomal deletion and missense mutation of BIRC3 gene: A case report. Diagn. Pathol. 2016, 11, 137.
  66. Rosebeck, S.; Lim, M.S.; Elenitoba-Johnson, K.S.; McAllister-Lucas, L.M.; Lucas, P.C. API2-MALT1 oncoprotein promotes lymphomagenesis via unique program of substrate ubiquitination and proteolysis. World J. Biol. Chem. 2016, 7, 128–137.
  67. Matthews, G.M.; de Matos Simoes, R.; Dhimolea, E.; Sheffer, M.; Gandolfi, S.; Dashevsky, O.; Sorrell, J.D.; Mitsiades, C.S. NF-κB dysregulation in multiple myeloma. Semin. Cancer Biol. 2016, 39, 68–76.
  68. Dupoux, A.; Cartier, J.; Cathelin, S.; Filomenko, R.; Solary, E.; Dubrez-Daloz, L. cIAP1-dependent TRAF2 degradation regulates the differentiation of monocytes into macrophages and their response to CD40 ligand. Blood 2009, 113, 175–185.
  69. Yang, C.; Davis, J.L.; Zeng, R.; Vora, P.; Su, X.; Collins, L.I.; Vangveravong, S.; Mach, R.H.; Piwnica-Worms, D.; Weilbaecher, K.N.; et al. Antagonism of inhibitor of apoptosis proteins increases bone metastasis via unexpected osteoclast activation. Cancer Discov. 2013, 3, 212–223.
  70. Tseng, P.H.; Matsuzawa, A.; Zhang, W.; Mino, T.; Vignali, D.A.; Karin, M. Different modes of ubiquitination of the adaptor TRAF3 selectively activate the expression of type I interferons and proinflammatory cytokines. Nat. Immunol. 2010, 11, 70–75.
  71. Xiao, Y.; Jin, J.; Chang, M.; Chang, J.H.; Hu, H.; Zhou, X.; Brittain, G.C.; Stansberg, C.; Torkildsen, Ø.; Wang, X.; et al. Peli1 promotes microglia-mediated CNS inflammation by regulating Traf3 degradation. Nat. Med. 2013, 19, 595–602.
  72. Busca, A.; Konarski, Y.; Gajanayaka, N.; O’Hara, S.; Angel, J.; Kozlowski, M.; Kumar, A. cIAP1/2-TRAF2-SHP-1-Src-MyD88 Complex Regulates Lipopolysaccharide-Induced IL-27 Production through NF-κB Activation in Human Macrophages. J. Immunol. 2018, 200, 1593–1606.
  73. Jin, J.; Xiao, Y.; Hu, H.; Zou, Q.; Li, Y.; Gao, Y.; Ge, W.; Cheng, X.; Sun, S.C. Proinflammatory TLR signalling is regulated by a TRAF2-dependent proteolysis mechanism in macrophages. Nat. Commun. 2015, 6, 5930.
  74. Mathew, S.J.; Haubert, D.; Kronke, M.; Leptin, M. Looking beyond death: A morphogenetic role for the TNF signalling pathway. J. Cell Sci. 2009, 122, 1939–1946.
  75. Peppelenbosch, M.; Boone, E.; Jones, G.E.; van Deventer, S.J.; Haegeman, G.; Fiers, W.; Grooten, J.; Ridley, A.J. Multiple signal transduction pathways regulate TNF-induced actin reorganization in macrophages: Inhibition of Cdc42-mediated filopodium formation by TNF. J. Immunol. 1999, 162, 837–845.
  76. Puls, A.; Eliopoulos, A.G.; Nobes, C.D.; Bridges, T.; Young, L.S.; Hall, A. Activation of the small GTPase Cdc42 by the inflammatory cytokines TNF(alpha) and IL-1, and by the Epstein-Barr virus transforming protein LMP1. J. Cell Sci. 1999, 112 Pt 17, 2983–2992.
  77. Murali, A.; Rajalingam, K. Small Rho GTPases in the control of cell shape and mobility. Cell. Mol. Life Sci. CMLS 2014, 71, 1703–1721.
  78. Geisbrecht, E.R.; Montell, D.J. A role for Drosophila IAP1-mediated caspase inhibition in Rac-dependent cell migration. Cell 2004, 118, 111–125.
  79. Marivin, A.; Berthelet, J.; Cartier, J.; Paul, C.; Gemble, S.; Morizot, A.; Boireau, W.; Saleh, M.; Bertoglio, J.; Solary, E.; et al. cIAP1 regulates TNF-mediated cdc42 activation and filopodia formation. Oncogene 2014, 33, 5534–5545.
  80. Oberoi, T.K.; Dogan, T.; Hocking, J.C.; Scholz, R.P.; Mooz, J.; Anderson, C.L.; Karreman, C.; Meyer Zu Heringdorf, D.; Schmidt, G.; Ruonala, M.; et al. IAPs regulate the plasticity of cell migration by directly targeting Rac1 for degradation. EMBO J. 2011, 31, 14–28.
  81. Oberoi-Khanuja, T.K.; Rajalingam, K. Ubiquitination of Rac1 by inhibitors of apoptosis (IAPs). Methods Mol. Biol. 2014, 1120, 43–54.
  82. Hornburger, M.C.; Mayer, B.A.; Leonhardt, S.; Willer, E.A.; Zahler, S.; Beyerle, A.; Rajalingam, K.; Vollmar, A.M.; Furst, R. A novel role for inhibitor of apoptosis (IAP) proteins as regulators of endothelial barrier function by mediating RhoA activation. FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol. 2014, 28, 1938–1946.
  83. Murali, A.; Shin, J.; Yurugi, H.; Krishnan, A.; Akutsu, M.; Carpy, A.; Macek, B.; Rajalingam, K. Ubiquitin-dependent regulation of Cdc42 by XIAP. Cell Death Dis. 2017, 8, e2900.
  84. Dubrez, L.; Rajalingam, K. IAPs and cell migration. Semin. Cell Dev. Biol. 2015, 39, 124–131.
  85. Sweeney, M.C.; Wang, X.; Park, J.; Liu, Y.; Pei, D. Determination of the sequence specificity of XIAP BIR domains by screening a combinatorial peptide library. Biochemistry 2006, 45, 14740–14748.
  86. He, W.; Wang, Q.; Srinivasan, B.; Xu, J.; Padilla, M.T.; Li, Z.; Wang, X.; Liu, Y.; Gou, X.; Shen, H.M.; et al. A JNK-mediated autophagy pathway that triggers c-IAP degradation and necroptosis for anticancer chemotherapy. Oncogene 2014, 33, 3004–3013.
  87. Lee, S.; Lee, J.Y.; Lee, E.W.; Park, S.; Kang, D.H.; Min, C.; Lee, D.J.; Kang, D.; Song, J.; Kwon, J.; et al. Absence of Cytosolic 2-Cys Prx Subtypes I and II Exacerbates TNF-α-Induced Apoptosis via Different Routes. Cell Rep. 2019, 26, 2194–2211.e2196.
  88. Romagny, S.; Bouaouiche, S.; Lucchi, G.; Ducoroy, P.; Bertoldo, J.B.; Terenzi, H.; Bettaieb, A.; Plenchette, S. S-Nitrosylation of cIAP1 Switches Cancer Cell Fate from TNFα/TNFR1-Mediated Cell Survival to Cell Death. Cancer Res. 2018, 78, 1948–1957.
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