1. XIAP Loss Triggers RIPK3- and Caspase-8-Driven IL-1β Activation and Cell Death as a Consequence of TLR-MyD88-Induced cIAP1-TRAF2 Degradation.
- Author
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Lawlor KE, Feltham R, Yabal M, Conos SA, Chen KW, Ziehe S, Graß C, Zhan Y, Nguyen TA, Hall C, Vince AJ, Chatfield SM, D'Silva DB, Pang KC, Schroder K, Silke J, Vaux DL, Jost PJ, and Vince JE
- Subjects
- Animals, Caspase 8 genetics, Cell Death, Inhibitor of Apoptosis Proteins deficiency, Inhibitor of Apoptosis Proteins genetics, Interleukin-1beta genetics, Mice, Mice, Knockout, Myeloid Differentiation Factor 88 genetics, Proteolysis, Receptor-Interacting Protein Serine-Threonine Kinases genetics, TNF Receptor-Associated Factor 2 genetics, Toll-Like Receptors genetics, Caspase 8 metabolism, Inhibitor of Apoptosis Proteins metabolism, Interleukin-1beta metabolism, Myeloid Differentiation Factor 88 metabolism, Receptor-Interacting Protein Serine-Threonine Kinases metabolism, TNF Receptor-Associated Factor 2 metabolism, Toll-Like Receptors metabolism
- Abstract
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., (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2017
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