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• W2738117029 abstract "•TLR-MyD88 engagement triggers cIAP1 and TRAF2 degradation•TLR-induced cIAP1 and TRAF2 degradation results from TNF and TNFR2 induction•Upon XIAP loss, TNFR2-induced cIAP1 removal induces RIPK3-caspase-8-induced IL-1β•A TLR-TRIF-IFNβ axis protects from cIAP1 degradation and consequent cell death X-linked Inhibitor of Apoptosis (XIAP) deficiency predisposes people to pathogen-associated hyperinflammation. Upon XIAP loss, Toll-like receptor (TLR) ligation triggers RIPK3-caspase-8-mediated IL-1β activation and death in myeloid cells. How XIAP suppresses these events remains unclear. Here, we show that TLR-MyD88 causes the proteasomal degradation of the related IAP, cIAP1, and its adaptor, TRAF2, by inducing TNF and TNF Receptor 2 (TNFR2) signaling. Genetically, we define that myeloid-specific cIAP1 loss promotes TLR-induced RIPK3-caspase-8 and IL-1β activity in the absence of XIAP. Importantly, deletion of TNFR2 in XIAP-deficient cells limited TLR-MyD88-induced cIAP1-TRAF2 degradation, cell death, and IL-1β activation. In contrast to TLR-MyD88, TLR-TRIF-induced interferon (IFN)β inhibited cIAP1 loss and consequent cell death. These data reveal how, upon XIAP deficiency, a TLR-TNF-TNFR2 axis drives cIAP1-TRAF2 degradation to allow TLR or TNFR1 activation of RIPK3-caspase-8 and IL-1β. This mechanism may explain why XIAP-deficient patients can exhibit symptoms reminiscent of patients with activating inflammasome mutations. X-linked Inhibitor of Apoptosis (XIAP) deficiency predisposes people to pathogen-associated hyperinflammation. Upon XIAP loss, Toll-like receptor (TLR) ligation triggers RIPK3-caspase-8-mediated IL-1β activation and death in myeloid cells. How XIAP suppresses these events remains unclear. Here, we show that TLR-MyD88 causes the proteasomal degradation of the related IAP, cIAP1, and its adaptor, TRAF2, by inducing TNF and TNF Receptor 2 (TNFR2) signaling. Genetically, we define that myeloid-specific cIAP1 loss promotes TLR-induced RIPK3-caspase-8 and IL-1β activity in the absence of XIAP. Importantly, deletion of TNFR2 in XIAP-deficient cells limited TLR-MyD88-induced cIAP1-TRAF2 degradation, cell death, and IL-1β activation. In contrast to TLR-MyD88, TLR-TRIF-induced interferon (IFN)β inhibited cIAP1 loss and consequent cell death. These data reveal how, upon XIAP deficiency, a TLR-TNF-TNFR2 axis drives cIAP1-TRAF2 degradation to allow TLR or TNFR1 activation of RIPK3-caspase-8 and IL-1β. This mechanism may explain why XIAP-deficient patients can exhibit symptoms reminiscent of patients with activating inflammasome mutations. Mammalian Inhibitor of Apoptosis (IAP) proteins include the RING domain ubiquitin E3 ligases X-linked IAP (XIAP), cellular IAP1 (cIAP1), and cIAP2 (Vaux and Silke, 2005Vaux D.L. Silke J. IAPs, RINGs and ubiquitylation.Nat. Rev. Mol. Cell Biol. 2005; 6: 287-297Crossref PubMed Scopus (528) Google Scholar). Despite XIAP being best characterized for its role in inhibiting apoptosis, mutations in XIAP, which result in XIAP deficiency, cause a hereditary disorder classified as X-linked lymphoproliferative syndrome type 2 (XLP-2) (Rigaud et al., 2006Rigaud S. Fondanèche M.C. Lambert N. Pasquier B. Mateo V. Soulas P. Galicier L. Le Deist F. Rieux-Laucat F. Revy P. et al.XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome.Nature. 2006; 444: 110-114Crossref PubMed Scopus (557) Google Scholar). Clinically, XIAP-deficient patients can present with a range of symptoms, including fevers, hepatosplenomegaly, cytopenia, and inflammatory bowel disease. Within their first decade of life, many XIAP-deficient patients also develop hemophagocytic lymphohistiocytosis (HLH), a potentially fatal hyperinflammatory disease that is often triggered by an infectious agent, such as Epstein-Barr virus (Aguilar and Latour, 2015Aguilar C. Latour S. X-linked inhibitor of apoptosis protein deficiency: more than an X-linked lymphoproliferative syndrome.J. Clin. Immunol. 2015; 35: 331-338Crossref PubMed Scopus (67) Google Scholar, Marsh et al., 2010Marsh R.A. Madden L. Kitchen B.J. Mody R. McClimon B. Jordan M.B. Bleesing J.J. Zhang K. Filipovich A.H. XIAP deficiency: a unique primary immunodeficiency best classified as X-linked familial hemophagocytic lymphohistiocytosis and not as X-linked lymphoproliferative disease.Blood. 2010; 116: 1079-1082Crossref PubMed Scopus (200) Google Scholar, Rigaud et al., 2006Rigaud S. Fondanèche M.C. Lambert N. Pasquier B. Mateo V. Soulas P. Galicier L. Le Deist F. Rieux-Laucat F. Revy P. et al.XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome.Nature. 2006; 444: 110-114Crossref PubMed Scopus (557) Google Scholar). In view of the lack of monoclonal lymphoproliferation and the prevalence of HLH that is associated with XIAP loss, it has been suggested that XIAP deficiency should be reclassified as an X-linked HLH disease (Marsh et al., 2010Marsh R.A. Madden L. Kitchen B.J. Mody R. McClimon B. Jordan M.B. Bleesing J.J. Zhang K. Filipovich A.H. XIAP deficiency: a unique primary immunodeficiency best classified as X-linked familial hemophagocytic lymphohistiocytosis and not as X-linked lymphoproliferative disease.Blood. 2010; 116: 1079-1082Crossref PubMed Scopus (200) Google Scholar). Intriguingly, recurrent X-linked HLH is accentuated by dramatically elevated and sustained levels of the cytokine interleukin (IL)-18, which are comparable to the levels of IL-18 observed in other inflammatory conditions featuring the related entity, macrophage activation syndrome (Wada et al., 2014Wada T. Kanegane H. Ohta K. Katoh F. Imamura T. Nakazawa Y. Miyashita R. Hara J. Hamamoto K. Yang X. et al.Sustained elevation of serum interleukin-18 and its association with hemophagocytic lymphohistiocytosis in XIAP deficiency.Cytokine. 2014; 65: 74-78Crossref PubMed Scopus (87) Google Scholar). Both IL-18 and IL-1β secretion are markers of inflammasome activation. Inflammasomes are large protein complexes that recruit and activate caspase-1 to cleave precursor IL-1β and IL-18 to their mature bioactive fragments and induce a lytic form of cell death, termed pyroptosis (de Zoete et al., 2014de Zoete M.R. Palm N.W. Zhu S. Flavell R.A. Inflammasomes.Cold Spring Harb. Perspect. Biol. 2014; 6: a016287Crossref Scopus (229) Google Scholar). Other than the pathological association of X-linked HLH with IL-18, a recent case report documented use of anti-IL-1 therapy in an XIAP-deficient patient (Christiansen et al., 2016Christiansen M. Ammann S. Speckmann C. Mogensen T.H. XIAP deficiency and MEFV variants resulting in an autoinflammatory lymphoproliferative syndrome.BMJ Case Rep. 2016; 2016 (bcr2016216922)PubMed Google Scholar). Consistent with these studies, we and others have reported how the inflammasome sensor protein NOD-like Receptor Protein 3 (NLRP3) can spontaneously form in the absence of IAPs, and in particular XIAP, to activate caspase-1 upon pathogen ligand-induced Toll-like receptor (TLR) stimulation (Lawlor et al., 2015Lawlor 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: 6282Crossref PubMed Scopus (407) Google Scholar, Vince et al., 2012Vince 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: 215-227Abstract Full Text Full Text PDF PubMed Scopus (384) Google Scholar, Wicki et al., 2016Wicki S. Gurzeler U. Wei-Lynn Wong W. Jost P.J. Bachmann D. Kaufmann T. Loss of XIAP facilitates switch to TNFα-induced necroptosis in mouse neutrophils.Cell Death Dis. 2016; 7: e2422Crossref PubMed Scopus (58) Google Scholar, Yabal et al., 2014Yabal M. Müller N. Adler H. Knies N. Groß C.J. Damgaard R.B. Kanegane H. Ringelhan M. Kaufmann T. Heikenwälder M. et al.XIAP restricts TNF- and RIP3-dependent cell death and inflammasome activation.Cell Rep. 2014; 7: 1796-1808Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar). In macrophages, dendritic cells, and neutrophils, TLR ligation and IAP loss stimulate the formation and activation of a large receptor-interacting protein kinase (RIPK) complex, termed the ripoptosome (Feoktistova et al., 2011Feoktistova M. Geserick P. Kellert B. Dimitrova D.P. Langlais C. Hupe M. Cain K. MacFarlane M. Häcker 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: 449-463Abstract Full Text Full Text PDF PubMed Scopus (649) Google Scholar, Tenev et al., 2011Tenev T. Bianchi K. Darding M. Broemer M. Langlais C. Wallberg F. Zachariou A. Lopez J. MacFarlane M. Cain K. Meier P. The Ripoptosome, a signaling platform that assembles in response to genotoxic stress and loss of IAPs.Mol. Cell. 2011; 43: 432-448Abstract Full Text Full Text PDF PubMed Scopus (602) Google Scholar), that is responsible for triggering NLRP3 and IL-1β activity. The ripoptosome complex is principally comprised of RIPK1, FADD, and caspase-8, and it was first described to induce apoptotic cell death upon TLR activation, tumor necrosis factor (TNF) receptor 1 (TNFR1) ligation, or genotoxic stress (Feoktistova et al., 2011Feoktistova M. Geserick P. Kellert B. Dimitrova D.P. Langlais C. Hupe M. Cain K. MacFarlane M. Häcker 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: 449-463Abstract Full Text Full Text PDF PubMed Scopus (649) Google Scholar, Tenev et al., 2011Tenev T. Bianchi K. Darding M. Broemer M. Langlais C. Wallberg F. Zachariou A. Lopez J. MacFarlane M. Cain K. Meier P. The Ripoptosome, a signaling platform that assembles in response to genotoxic stress and loss of IAPs.Mol. Cell. 2011; 43: 432-448Abstract Full Text Full Text PDF PubMed Scopus (602) Google Scholar). The cIAPs act to inhibit this complex by ubiquitylating RIPK1 and recruiting LUBAC to induce a pro-survival nuclear factor κB (NF-κB) signal. In some cell types, including macrophages, XIAP prevents ripoptosome formation and caspase-8 activation (Lawlor et al., 2015Lawlor 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: 6282Crossref PubMed Scopus (407) Google Scholar, Yabal et al., 2014Yabal M. Müller N. Adler H. Knies N. Groß C.J. Damgaard R.B. Kanegane H. Ringelhan M. Kaufmann T. Heikenwälder M. et al.XIAP restricts TNF- and RIP3-dependent cell death and inflammasome activation.Cell Rep. 2014; 7: 1796-1808Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar), although the mechanism remains elusive. However, what is clear is that macrophages and dendritic cells lacking IAPs, including XIAP, undergo caspase-8-mediated apoptotic cell death upon TLR ligand or TNF exposure in a largely RIPK3-dependent manner (Lawlor et al., 2015Lawlor 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: 6282Crossref PubMed Scopus (407) Google Scholar, Vince et al., 2012Vince 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: 215-227Abstract Full Text Full Text PDF PubMed Scopus (384) Google Scholar, Yabal et al., 2014Yabal M. Müller N. Adler H. Knies N. Groß C.J. Damgaard R.B. Kanegane H. Ringelhan M. Kaufmann T. Heikenwälder M. et al.XIAP restricts TNF- and RIP3-dependent cell death and inflammasome activation.Cell Rep. 2014; 7: 1796-1808Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar). This is in line with recent reports indicating that RIPK3 can recruit RIPK1 to activate caspase-8 (Mandal et al., 2014Mandal P. Berger S.B. Pillay S. Moriwaki K. Huang C. Guo H. Lich J.D. Finger J. Kasparcova V. Votta B. et al.RIP3 induces apoptosis independent of pronecrotic kinase activity.Mol. Cell. 2014; 56: 481-495Abstract Full Text Full Text PDF PubMed Scopus (387) Google Scholar, Newton et al., 2014Newton K. Dugger D.L. Wickliffe K.E. Kapoor N. de Almagro M.C. Vucic D. Komuves L. Ferrando R.E. French D.M. Webster J. et al.Activity of protein kinase RIPK3 determines whether cells die by necroptosis or apoptosis.Science. 2014; 343: 1357-1360Crossref PubMed Scopus (458) Google Scholar). In situations where ripoptosome-induced caspase-8 activity is insufficient, RIPK1 associates with RIPK3, triggering RIPK3 phosphorylation of mixed-lineage kinase domain-like (MLKL) and necroptosis (Murphy and Vince, 2015Murphy J.M. Vince J.E. Post-translational control of RIPK3 and MLKL mediated necroptotic cell death.F1000Res. 2015; 4 (F1000 Faculty Rev-1297)PubMed Google Scholar), as well as NLRP3 inflammasome activation (Conos et al., 2017Conos S.A. Chen K.W. De Nardo D. Hara H. Whitehead L. Núñez G. Masters S.L. Murphy J.M. Schroder K. Vaux D.L. et al.Active MLKL triggers the NLRP3 inflammasome in a cell-intrinsic manner.Proc. Natl. Acad. Sci. USA. 2017; 114: E961-E969Crossref PubMed Scopus (246) Google Scholar, Gutierrez et al., 2017Gutierrez K.D. Davis M.A. Daniels B.P. Olsen T.M. Ralli-Jain P. Tait S.W. Gale Jr., M. Oberst A. MLKL Activation Triggers NLRP3-Mediated Processing and Release of IL-1β Independently of Gasdermin-D.J. Immunol. 2017; 198: 2156-2164Crossref PubMed Scopus (123) Google Scholar, Kang et al., 2013Kang T.B. Yang S.H. Toth B. Kovalenko A. Wallach D. Caspase-8 blocks kinase RIPK3-mediated activation of the NLRP3 inflammasome.Immunity. 2013; 38: 27-40Abstract Full Text Full Text PDF PubMed Scopus (326) Google Scholar, Kang et al., 2015Kang S. Fernandes-Alnemri T. Rogers C. Mayes L. Wang Y. Dillon C. Roback L. Kaiser W. Oberst A. Sagara J. et al.Caspase-8 scaffolding function and MLKL regulate NLRP3 inflammasome activation downstream of TLR3.Nat. Commun. 2015; 6: 7515Crossref PubMed Scopus (173) Google Scholar, Lawlor et al., 2015Lawlor 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: 6282Crossref PubMed Scopus (407) Google Scholar). Recently, we documented how, upon IAP antagonist treatment or IAP deficiency, TLR and TNFR1 signal to ripoptosome-associated RIPK3 to promote caspase-8 auto-proteolysis and drive IL-1β and IL-18 activation in macrophages (Lawlor et al., 2015Lawlor 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: 6282Crossref PubMed Scopus (407) Google Scholar, Vince et al., 2012Vince 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: 215-227Abstract Full Text Full Text PDF PubMed Scopus (384) Google Scholar). Activated caspase-8 triggered IL-1β secretion by inducing both NLRP3 inflammasome formation and by directly processing precursor IL-1β. Importantly, XIAP deficiency alone was sufficient to allow ripoptosome-mediated IL-1β activation in response to TLR ligands. The mechanism by which this occurs remains of outstanding interest, and it is considered important for not only defining the causes of X-linked HLH but also how pathogen ligands can act to modulate innate immune cell inflammatory and cell death responses. Here we now document that multiple pathogen TLR ligands that signal through MyD88 induce TRAF2-dependent cIAP1 degradation that can activate non-canonical NF-κB signaling. More importantly, we demonstrate that XIAP deficiency results in enhanced TLR-induced cIAP1 loss, leading to heightened IL-1β production and cell death signaling. TLR-induced degradation of cIAP1 and TRAF2 was critically dependent on TLR-induced TNFR2 signaling, as TNFR2 loss blocked cIAP1 degradation, apoptotic cell death, and NLRP3-driven inflammatory responses. These results show how TLR and TNF receptor (TNFR) superfamily members can cooperate to regulate cell death and inflammation generated by pathogen ligands, and they document how this crosstalk might contribute to the autoinflammatory disease observed in XIAP-deficient patients. Consistent with previous findings (Lawlor et al., 2015Lawlor 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: 6282Crossref PubMed Scopus (407) Google Scholar, Vince et al., 2012Vince 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: 215-227Abstract Full Text Full Text PDF PubMed Scopus (384) Google Scholar, Yabal et al., 2014Yabal M. Müller N. Adler H. Knies N. Groß C.J. Damgaard R.B. Kanegane H. Ringelhan M. Kaufmann T. Heikenwälder M. et al.XIAP restricts TNF- and RIP3-dependent cell death and inflammasome activation.Cell Rep. 2014; 7: 1796-1808Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar), we observed secretion of IL-1β in XIAP-deficient (Xiap−/−), but not wild-type (WT), bone marrow-derived macrophages (BMDMs) upon stimulation with lipopolysaccharide (LPS) (Figure 1A). On the other hand, LPS-induced TNF levels were comparable between WT and Xiap−/− cells (Figure 1B). Treatment of Xiap−/− BMDMs with IAP antagonists (Smac-mimetics) that show functional affinity against the cIAPs (cIAP1 and cIAP2; 711, 851, and 883; Lawlor et al., 2015Lawlor 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: 6282Crossref PubMed Scopus (407) Google Scholar) resulted in enhanced LPS-induced IL-1β processing and secretion, and cell death, in XIAP-deficient cells but did not trigger IL-1β activation or death in WT BMDMs (Figures 1A, 1C, and 1D). In contrast, IAP antagonists that functionally inhibited all three IAPs, XIAP, cIAP1, and cIAP2 (030, 031, and Cp. A; Lawlor et al., 2015Lawlor 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: 6282Crossref PubMed Scopus (407) Google Scholar) elicited significant LPS-induced IL-1β processing and secretion, even from WT macrophages (Figure 1D). TLR engagement and IAP loss activate caspase-8, which can directly process IL-1β and induce formation of the NLRP3-caspase-1 inflammasome (Lawlor et al., 2015Lawlor 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: 6282Crossref PubMed Scopus (407) Google Scholar, Vince et al., 2012Vince 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: 215-227Abstract Full Text Full Text PDF PubMed Scopus (384) Google Scholar, Yabal et al., 2014Yabal M. Müller N. Adler H. Knies N. Groß C.J. Damgaard R.B. Kanegane H. Ringelhan M. Kaufmann T. Heikenwälder M. et al.XIAP restricts TNF- and RIP3-dependent cell death and inflammasome activation.Cell Rep. 2014; 7: 1796-1808Abstract Full Text Full Text PDF PubMed Scopus (184) Google Scholar). Consistent with this, the secretion of IL-1β upon LPS stimulation and XIAP loss coincided with caspase-8 and caspase-1 processing (Figure 1D). These results show that XIAP cooperates with cIAPs to prevent spontaneous TLR-induced NLRP3 inflammasome and IL-1β responses (Figure 1E). In light of the results using IAP antagonist compounds, we considered whether TLR signaling might deplete cellular cIAP1 to promote inflammatory responses. In line with this idea, stimulation of BMDMs with Pam3CSK4 (P3Cys; TLR1/2), CpG (TLR9), or R837 (TLR7) induced a substantial reduction in total cellular cIAP1, as well as its binding partner TRAF2, within 4–8 hr (Figures 2A–2D and S1A). In comparison, LPS (TLR4) was less efficient at inducing cIAP1 loss, particularly when cells were treated with higher concentrations (Figures 2A–2D and S1A). However, despite this less prominent cIAP1 degradation in response to LPS treatment, LPS-induced degradation of TRAF2 was comparable to the other TLR ligands. Therefore, multiple TLR family members are able to induce cIAP1 and TRAF2 depletion. TRAF2 helps recruit cIAP1 into TNFR superfamily (TNFRSF) complexes, such as TNFR2 and FN14 (Brown et al., 2003Brown S.A. Richards C.M. Hanscom H.N. Feng S.L. Winkles J.A. The Fn14 cytoplasmic tail binds tumour-necrosis-factor-receptor-associated factors 1, 2, 3 and 5 and mediates nuclear factor-kappaB activation.Biochem. J. 2003; 371: 395-403Crossref PubMed Scopus (156) Google Scholar, Rothe et al., 1995Rothe M. Pan M.G. Henzel W.J. Ayres T.M. Goeddel D.V. The TNFR2-TRAF signaling complex contains two novel proteins related to baculoviral inhibitor of apoptosis proteins.Cell. 1995; 83: 1243-1252Abstract Full Text PDF PubMed Scopus (1056) Google Scholar). Signaling from TNFR2 and FN14 also promotes the degradation of TRAF2 and cIAP1 in a proteasomal and/or lysosomal manner to trigger activation of non-canonical NF-κB (Fotin-Mleczek et al., 2002Fotin-Mleczek M. Henkler F. Samel D. Reichwein M. Hausser A. Parmryd I. Scheurich P. Schmid J.A. Wajant H. Apoptotic crosstalk of TNF receptors: TNF-R2-induces depletion of TRAF2 and IAP proteins and accelerates TNF-R1-dependent activation of caspase-8.J. Cell Sci. 2002; 115: 2757-2770PubMed Google Scholar, Li et al., 2009Li L. Soetandyo N. Wang Q. Ye Y. The zinc finger protein A20 targets TRAF2 to the lysosomes for degradation.Biochim. Biophys. Acta. 2009; 1793: 346-353Crossref PubMed Scopus (69) Google Scholar, Varfolomeev et al., 2012Varfolomeev E. Goncharov T. Maecker H. Zobel K. Kömüves L.G. Deshayes K. Vucic D. Cellular inhibitors of apoptosis are global regulators of NF-κB and MAPK activation by members of the TNF family of receptors.Sci. Signal. 2012; 5: ra22Crossref PubMed Scopus (153) Google Scholar, Vince et al., 2008Vince 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: 171-184Crossref PubMed Scopus (207) Google Scholar). Consistent with TRAF2 being required for the recruitment of cIAP1 into receptor-signaling complexes, we observed that cIAP1 levels in TRAF2-deficient BMDMs stimulated with the TLR ligands LPS or P3Cys did not decline, but rather they increased over time (Figure 2E). Treatment of BMDMs with the proteasomal inhibitor MG132 also prevented P3Cys-mediated cIAP1 and TRAF2 depletion, whereas the caspase inhibitor QVD-OPh was not sufficient to prevent their loss (Figures 2F and 2G). The inhibitor of lysosomal function, Bafilomycin A1, partly reduced the loss of TRAF2, but it had no impact on cIAP1 degradation (Figures 2F and 2G). Therefore, TLR ligation stimulates the degradation of cIAP1 and TRAF2 in a manner that is largely dependent on the proteasome. In unstimulated cells, a cIAP/TRAF2/TRAF3 complex associates with NF-κB-inducing kinase (NIK), and it allows cIAPs to target NIK for proteasomal degradation, thereby preventing non-canonical NF-κB2/p100 processing to the active p52 subunit. Hence, TNFRSF-induced cIAP1-TRAF2 loss, or IAP antagonist treatment, can trigger non-canonical NF-κB (Sun, 2012Sun S.C. The noncanonical NF-κB pathway.Immunol. Rev. 2012; 246: 125-140Crossref PubMed Scopus (504) Google Scholar, Varfolomeev et al., 2007Varfolomeev 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: 669-681Abstract Full Text Full Text PDF PubMed Scopus (1008) Google Scholar, Vince et al., 2007Vince J.E. Wong W.W. Khan N. Feltham R. Chau D. Ahmed A.U. Benetatos C.A. Chunduru S.K. Condon S.M. McKinlay M. et al.IAP antagonists target cIAP1 to induce TNFalpha-dependent apoptosis.Cell. 2007; 131: 682-693Abstract Full Text Full Text PDF PubMed Scopus (888) Google Scholar). Our results therefore suggested that NF-κB2/p100 might be involved in TLR-induced cytokine production. Consistent with this idea, the production of a subset of cytokines was diminished in NF-κB2-deficient BMDMs compared to WT cells in response to LPS or P3Cys treatment (Figures 2H, S1B, and S1C). Immunoblotting also revealed increased non-canonical NF-κB activation upon LPS or P3Cys treatment, as measured by p100 processing to p52 and stabilization of NIK (Figures S1D and S1E). These data imply that TLR-induced non-canonical activity in macrophages is important for optimal cytokine production. Based on the above data, we hypothesized that TLR-induced depletion of cIAP1 is required for efficient NLRP3 inflammasome activation and cell death in the absence of XIAP. However, our results demonstrated that LPS treatment in WT BMDMs is often less efficient at degrading cIAP1 when compared to other TLR ligands, even though it can trigger IL-1β secretion in Xiap−/− BMDMs (Figures 1 and 2). We therefore compared cIAP1 levels in TLR-stimulated WT and XIAP-deficient BMDMs. Remarkably, we observed that LPS-induced cIAP1 degradation was typically enhanced in XIAP-deficient macrophages compared to WT cells and this correlated with caspase-8 processing and cell death, while P3Cys-induced cIAP1 loss was moderately accelerated in Xiap−/− BMDMs (Figures 3A–3C and S2A–S2C). We also observed that, in the absence of XIAP, IL-1β secretion and cell death occurred more efficiently at lower cell densities (Figures S3A–S3E). Higher concentrations of LPS (100–1,000 ng/mL) did not significantly alter TNF secretion by Xiap−/− BMDMs, but it did result in reduced levels of precursor, cleaved, and secreted IL-1β (Figures 3B and 3D–3F). This phenomenon probably reflects increased TRIF-induced type I interferon (IFN) production and the inhibition of IL-1β gene transcription (Guarda et al., 2011Guarda G. Braun M. Staehli F. Tardivel A. Mattmann C. Förster I. Farlik M. Decker T. Du Pasquier R.A. Romero P. Tschopp J. Type I interferon inhibits interleukin-1 production and inflammasome activation.Immunity. 2011; 34: 213-223Abstract Full Text Full Text PDF PubMed Scopus (681) Google Scholar, Masters et al., 2010Masters S.L. Mielke L.A. Cornish A.L. Sutton C.E. O’Donnell J. Cengia L.H. Roberts A.W. Wicks I.P. Mills K.H. Croker B.A. Regulation of interleukin-1beta by interferon-gamma is species specific, limited by suppressor of cytokine signalling 1 and influences interleukin-17 production.EMBO Rep. 2010; 11: 640-646Crossref PubMed Scopus (57) Google Scholar). Interestingly, the TLR3 ligand Poly(I:C) failed to induce cIAP1 loss in either WT or XIAP-deficient BMDMs, and it did not result in detectable IL-1β secretion or cell death, thus correlating an inability to degrade cIAP1 with a lack of NLRP3 and cell death responses (Figures 3A, 3D, and S2A). In contrast to IL-1β secretion, TNF secretion in response to all TLR ligands tested was comparable between WT and XIAP-deficient cells (Figures 3E and S3D). Hence, the loss of XIAP can promote LPS-induced cIAP1 degradation, which correlates with IL-1β maturation, caspase-8 cleavage, and enhanced cell death. The degradation of cIAP1 induced by TLR ligands was only partial (Figure 2). Therefore, prompted by our Smac-mimetic results (Figure 1), we reasoned that genetic loss of cIAP1 should cause more pronounced NLRP3 inflammasome activation upon TLR ligation than that observed upon XIAP loss alone. To test this idea, we generated mice lacking cIAP1 in myeloid cells on an XIAP-deficient background (cIAP1LysMcreXiap−/−). Distinct from the defective generation of BMDMs from cIAP1LysMcreXiap−/−cIAP2−/− mice (Lawlor et al., 2015Lawlor 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: 6282Crossref PubMed Scopus (407) Google Scholar, Wong et al., 2014Wong 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: 2562-2572Crossref PubMed Scopus (125) Google Scholar), cIAP1LysMcreXiap−/− bone marrow yielded normal numbers of BMDMs (Figure 4A). As predicted, based on our published results using chemical IAP antagonists (Conos et al., 2017Conos S.A. Chen K.W. De Nardo D. Hara H. Whitehead L. Núñez G. Masters S.L. Murphy J.M. Schroder K. Vaux D.L. et al.Active MLKL triggers the NLRP3 inflammasome in a cell-intrinsic manner.Proc. Natl. Acad. Sci. USA. 2017; 114: E961-E969Crossref PubMed Scopus (246) Google Scholar, Lawlor et al., 2015Lawlor K.E. Khan N. Mildenhall A. Gerlic M. C" @default.
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• W2738117029 title "XIAP Loss Triggers RIPK3- and Caspase-8-Driven IL-1β Activation and Cell Death as a Consequence of TLR-MyD88-Induced cIAP1-TRAF2 Degradation" @default.
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