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Τρίτη 18 Ιουλίου 2017

XIAP Loss Triggers RIPK3- and Caspase-8-Driven IL-1β Activation and Cell Death as a Consequence of TLR-MyD88-Induced cIAP1-TRAF2 Degradation

Publication date: 18 July 2017
Source:Cell Reports, Volume 20, Issue 3
Author(s): Kate E. Lawlor, Rebecca Feltham, Monica Yabal, Stephanie A. Conos, Kaiwen W. Chen, Stephanie Ziehe, Carina Graß, Yifan Zhan, Tan A. Nguyen, Cathrine Hall, Angelina J. Vince, Simon M. Chatfield, Damian B. D'Silva, Kenneth C. Pang, Kate Schroder, John Silke, David L. Vaux, Philipp J. Jost, James E. Vince
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.

Graphical abstract

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Teaser

Lawlor et al. find that TLR signaling induces TNF and TNFR2 to trigger degradation of the IAP family member cIAP1. In the absence of XIAP, these events induce TLR-RIPK3-caspase-8-driven NLRP3 and IL-1β activation and cell death.


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