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XIAP loss triggers RIPK3- and caspase-8-driven IL-1beta activation and cell death as a consequence of TLR-MyD88-induced cIAP1-TRAF2 degradation


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; Vince, JE
2017-07-18
Cell Reports
Journal Article
20
3
668-682
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-1beta 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-1beta 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-1beta activation. In contrast to TLR-MyD88, TLR-TRIF-induced interferon (IFN)beta 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-1beta. This mechanism may explain why XIAP-deficient patients can exhibit symptoms reminiscent of patients with activating inflammasome mutations.
Elsevier
Inflammation; Immunology; Cell Signalling and Cell Death
10.1016/j.celrep.2017.06.073
28723569
Refer to article for additional funding acknowledgements
https://creativecommons.org/licenses/by-nc-nd/4.0/

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