Apoptotic Caspases Suppress mtDNA-Induced STING-Mediated Type I IFN Production

• Activation of Bak and Bax, essential mediators of apoptosis, triggers mtDNA release
• mtDNA stimulates the cGAS/STING pathway to induce IFN-β production
• Activation of the apoptotic caspase cascade blocks the cGAS/STING pathway
• Inhibition or genetic deletion of caspases causes apoptotic cells to secrete IFN-β

SummaryActivated 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.

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