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

KE Lawlor; R Feltham; M Yabal; SA Conos; KW Chen; S Ziehe; C Graß; Y Zhan; TA Nguyen; C Hall; AJ Vince; SM Chatfield; DB D'Silva; KC Pang; K Schroder; J Silke; DL Vaux; PJ Jost; JE Vince

Journal article

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

KE Lawlor, R Feltham, M Yabal, SA Conos, KW Chen, S Ziehe, C Graß, Y Zhan, TA Nguyen, C Hall, AJ Vince, SM Chatfield, DB D'Silva, KC Pang, K Schroder, J Silke, DL Vaux, PJ Jost, JE Vince

Cell Reports | CELL PRESS | Published : 2017

DOI: 10.1016/j.celrep.2017.06.073

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,..

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University of Melbourne Researchers

Rebecca Feltham Author

Ken Chung-Ren Pang Author

John Silke Author

David Vaux Author

Grants

Awarded by José Carreras Leukämie-Stiftung

Funding Acknowledgements

We thank F. Moghaddas, L. Lindqvist, and B. Croker for comments on the manuscript and A. Mildenhall for technical assistance; R. Crawley, L. Wilkins, C. Yates, S. Oliver, C. Stivila, and N. Lynch for animal care; J. Corbin for Advia cell counts; TetraLogic Pharmaceuticals and Novartis for Smac mimetic compounds; S. Monard and staff for cell sorting; L. Wong for RT- PCR primer sequences and discussions; B. Kile for Ifnar1 -/- mice; and D. De Nardo for advice and reagents; This work was supported by National Health and Medical Research Project grants (1051210, 1101405, 1064591, and 1081272), fellowships to J.E.V. (1052598), a Program Grant to D.L.V. (461221), and operational infrastructure grants through the Australian Government IRISS (9000220) and the Victorian State Government OIS. P.J.J. was supported by a Max Eder-Program grant from the Deutsche Krebshilfe (program 111738), and P.J.J. and M.Y. were supported by grants from the Deutsche Jose Carreras Leukamie Stiftung (DJCLS R 12/22), the DFG (FOR2036), and the Else Kroner-Fresenius-Stiftung (2014_A185).