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 Reports

Monica Yabal¹  Stephanie Ziehe¹  Carina Graß¹  Philipp J. Jost¹  Kate Schroder²  Kaiwen W. Chen²  James E. Vince³  Tan A. Nguyen³  Yifan Zhan³  Cathrine Hall³  Stephanie A. Conos³  Damian B. D’Silva³  David L. Vaux³  Simon M. Chatfield³  Kenneth C. Pang³  John Silke³  Angelina J. Vince³  Kate E. Lawlor³  Rebecca Feltham³ 

[1] III. Medical Department for Hematology and Oncology, Klinikum rechts der Isar, Technische Universität München, 81675 Munich, Germany;Institute for Molecular Bioscience and Centre for Inflammation and Disease Research, The University of Queensland, St. Lucia, QLD 4072, Australia;The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia;

关键词: Toll-like receptor;    NLRP3;    RIPK3;    caspase-8;    TNFR2;    XIAP;    cIAP1;    necroptosis;    interferon;    autoinflammatory disease;   

DOI  :  10.1016/j.celrep.2017.06.073

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown