Journal article
Apoptotic caspases suppress mtDNA-induced STING-mediated type i IFN production
MJ White, K McArthur, D Metcalf, RM Lane, JC Cambier, MJ Herold, MF Van Delft, S Bedoui, G Lessene, ME Ritchie, DCS Huang, BT Kile
Cell | Published : 2014
Abstract
Activated caspases are a hallmark of apoptosis induced by the intrinsic pathway, but they are dispensable for cell death and the apoptotic clearance of cells in vivo. This has led to the suggestion that caspases are activated not just to kill but to prevent dying cells from triggering a host immune response. Here, we show that the caspase cascade suppresses type I interferon (IFN) production by cells undergoing Bak/Bax-mediated apoptosis. Bak and Bax trigger the release of mitochondrial DNA. This is recognized by the cGAS/STING-dependent DNA sensing pathway, which initiates IFN production. Activated caspases attenuate this response. Pharmacological caspase inhibition or genetic deletion of c..
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Awarded by National Institute of Allergy and Infectious Diseases
Funding Acknowledgements
The authors thank J. Corbin and L. Di Rago for excellent technical assistance; K. Franks, E. Lanera, K. McGregor, S. Ross, K. Stoev, L. Wilkins, and E. Kryan for outstanding animal husbandry; S. Monard for expert flow cytometry assistance; T. Mak for Apaf1<SUP>+/-</SUP> mice; R. Flavell for Casp3<SUP>+/-</SUP> Casp7<SUP>+/-</SUP> mice; C. Thompson for Bak<SUP>+/</SUP> and Bax<SUP>+/</SUP> mice; P. Crack for Ifnar1<SUP>+/</SUP> mice; D. Fairlie and E. Lee for Bim variants; K. Aumann and C. De Nardo for manuscript assistance; and A. Strasser, J. Choi, S. Best, A. Rongvaux, and R. Flavell for insightful discussions. This work was supported by Project Grants (516725 and 575535), Program Grants (461219, 461221, and 1016647), Fellowships (D.C.S.H. and B.T.K.), and an Independent Research Institutes Infrastructure Support Scheme Grant (361646) from the Australian National Health and Medical Research Council; a scholarship from the Leukemia Foundation of Australia (M.J.W.), fellowships from the Cancer Council of Victoria (M.J.W. and D.M.); an Australian Postgraduate Award scholarship (K.M.); a fellowship from the Sylvia and Charles Viertel Foundation (B.T.K.); the Australian Cancer Research Fund; and a Victorian State Government Operational Infrastructure Support Grant.