Apoptotic caspases suppress mtDNA-induced STING-mediated type i IFN production

Michael J. White, Kate McArthur, Donald Metcalf, Rachael M. Lane, John C. Cambier, Marco J. Herold, Mark F. van Delft, Sammy Bedoui, Guillaume Lessene, Matthew E. Ritchie, David C. S. Huang, Benjamin T. Kile

Research output: Contribution to journalArticleResearchpeer-review

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-β. In vivo, this precipitates an elevation in IFN-β 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.

Original languageEnglish
Pages (from-to)1549-1562
Number of pages14
JournalCell
Volume159
Issue number7
DOIs
Publication statusPublished - 18 Dec 2014
Externally publishedYes

Cite this

White, Michael J. ; McArthur, Kate ; Metcalf, Donald ; Lane, Rachael M. ; Cambier, John C. ; Herold, Marco J. ; van Delft, Mark F. ; Bedoui, Sammy ; Lessene, Guillaume ; Ritchie, Matthew E. ; Huang, David C. S. ; Kile, Benjamin T. / Apoptotic caspases suppress mtDNA-induced STING-mediated type i IFN production. In: Cell. 2014 ; Vol. 159, No. 7. pp. 1549-1562.
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title = "Apoptotic caspases suppress mtDNA-induced STING-mediated type i IFN production",
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-β. In vivo, this precipitates an elevation in IFN-β 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.",
author = "White, {Michael J.} and Kate McArthur and Donald Metcalf and Lane, {Rachael M.} and Cambier, {John C.} and Herold, {Marco J.} and {van Delft}, {Mark F.} and Sammy Bedoui and Guillaume Lessene and Ritchie, {Matthew E.} and Huang, {David C. S.} and Kile, {Benjamin T.}",
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White, MJ, McArthur, K, Metcalf, D, Lane, RM, Cambier, JC, Herold, MJ, van Delft, MF, Bedoui, S, Lessene, G, Ritchie, ME, Huang, DCS & Kile, BT 2014, 'Apoptotic caspases suppress mtDNA-induced STING-mediated type i IFN production' Cell, vol. 159, no. 7, pp. 1549-1562. https://doi.org/10.1016/j.cell.2014.11.036

Apoptotic caspases suppress mtDNA-induced STING-mediated type i IFN production. / White, Michael J.; McArthur, Kate; Metcalf, Donald; Lane, Rachael M.; Cambier, John C.; Herold, Marco J.; van Delft, Mark F.; Bedoui, Sammy; Lessene, Guillaume; Ritchie, Matthew E.; Huang, David C. S.; Kile, Benjamin T.

In: Cell, Vol. 159, No. 7, 18.12.2014, p. 1549-1562.

Research output: Contribution to journalArticleResearchpeer-review

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White MJ, McArthur K, Metcalf D, Lane RM, Cambier JC, Herold MJ et al. Apoptotic caspases suppress mtDNA-induced STING-mediated type i IFN production. Cell. 2014 Dec 18;159(7):1549-1562. https://doi.org/10.1016/j.cell.2014.11.036