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

By Michael J. White, K. McArthur, D. Metcalf, Rachael M. Lane, J. Cambier, Marco J. Herold, M. V. van Delft, S. Bedoui, G. Lessene, Matthew E. Ritchie and 2 more. Cell, 2014

921 citations recorded by the source corpus.

SUMMARY 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.

Subfields: Immunology, Infectious Diseases, Public Health, Environmental and Occupational Health

View Paper: https://www.semanticscholar.org/paper/59f36fca80a22f8d6ebeebe9da8fb42d893a08d5

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Citations in the corpus

BAK/BAX macropores facilitate mitochondrial herniation and mtDNA efflux during apoptosis (2018, methodology): “mtDNA depletion and assessment of mtDNA content was carried out as described (6).”
Mitochondrial DNA in inflammation and immunity (2020, positive): “Three independent studies were the first to show that mtDNA released from mitochondria is able to activate cGAS-STING signalling [37 – 39].”
Mitochondrial dysfunction: mechanisms and advances in therapy (2024, background): “181,182 Nonetheless, this regulatory schema is not absolute.”
Mitochondria in the regulation of innate and adaptive immunity (2015, positive): “…demonstrate that Bakand Bax-mediated mitochondrial damage in the absence of activating the downstream apoptotic caspases triggers the release of mitochondrial DNA (mtDNA), which cyclic GMP-AMP synthase (cGAS)/STING-mediated cytosolic DNA sensing pathway (Rongvaux et al., 2014; White et al., 2014).”
TDP-43 Triggers Mitochondrial DNA Release via mPTP to Activate cGAS/STING in ALS (2020, methodology): “To ascertain the source of DNA activating cGAS in response to TDP-43, we immunoprecipitated FLAG-tagged cGAS from HEK293T cells overexpressing WT or ALS mutant TDP-43 (A315T or Q331K; Figure S2A), directly followed by qPCR for the detection of mitochondrial or nuclear DNA (White et al., 2014).”
Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018 (2018, background): “Of note, lysosome-dependent cell death does not necessarily involve MOMP and caspases, and does not necessarily manifest with an apoptotic morphotype [782].”