Apoptotic caspases suppress mtDNA-Induced STING-mediated type I IFN production
- Author(s)
- White, MJ; McArthur, K; Metcalf, D; Lane, RM; Cambier, JC; Herold, MJ; van Delft, MF; Bedoui, S; Lessene, G; Ritchie, ME; Huang, DC; Kile, BT;
- Details
- Publication Year 2014-12-18,Volume 159,Issue #7,Page 1549-62
- Journal Title
- Cell
- Publication Type
- Journal Article
- 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 caspase-9, Apaf-1, or caspase-3/7 causes dying cells to secrete IFN-beta. In vivo, this precipitates an elevation in IFN-beta levels and consequent hematopoietic stem cell dysfunction, which is corrected by loss of Bak and Bax. Thus, the apoptotic caspase cascade functions to render mitochondrial apoptosis immunologically silent.
- Publisher
- Cell Press
- Research Division(s)
- Chemical Biology; Cancer And Haematology; Molecular Genetics Of Cancer
- Publisher's Version
- https://doi.org/10.1016/j.cell.2014.11.036
- NHMRC Grants
- NHMRC/516725, NHMRC/575535, NHMRC/461219, NHMRC/461221, NHMRC/1016647,
- Terms of Use/Rights Notice
- Copyright © 2014 Elsevier Inc. All rights reserved.
Creation Date: 2014-12-23 09:57:14
Last Modified: 2014-12-23 10:02:55