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.

doi:10.1016/j.cell.2014.11.036

Cited by 983interferon and immune responsesCell death mechanisms and regulationInflammasome and immune disorders

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

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White, Michael J., McArthur, Kate, Metcalf, Donald, Lane, Rachael M., Cambier, John C., Herold, Marco J., van Delft, Mark F., Bedoui, Sammy +4 more·2014·Cell

DOI 10.1016/j.cell.2014.11.036PMC PMC4520319

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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.

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In the absence of active caspases, mitochondrial DNA released after mitochondrial outer membrane permeabilization triggers type I interferon responses in a cGAS-STING-dependent manner.
“In the absence of active caspases, mtDNA released following mitochondrial outer membrane permeabilization triggers type I interferon responses in a cGAS–STING-dependent manner143,144”
From The role of mitochondria in rheumatic diseases (2022) · cites this paper as [144]
Experimental — accuracy not yet measured
CASP8 inhibits necroptosis; CASP3 drives PS exposure, boosts PGE2 secretion, and inhibits type I IFN signaling from mitochondrial DNA upon MOMP.
“These include: (1) the prominent ability of CASP8 to inhibit necroptosis (see above), which is generally associated with the establishment of robust inflammatory responses linked to NF-κB activation [496 925–928]; (2) the capacity of CASP3 to drive PS exposure (see above), which generally supports the phagocytic removal of dying and dead cells while delivering anti-inflammatory signals to”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [932]
mtDNA activates immunity through TLR9 and cGAS pathways.
“MtDNA has been reported to activate immunity through two distinct pathways, namely Toll-like receptor 9 (TLR9; Zhang et al, 2010;Oka et al, 2012;Liu et al, 2015), and cGAS activation (White et al, 2014;West et al, 2015).”
From Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency (2018) · cites this paper as White et al, 2014
Cytosolic mtDNA activates cGAS and promotes STING-IRF3-dependent signaling.
“Thus, cytosolic mtDNA activates the DNA sensor cGAS and promotes STING-IRF3-dependent signaling (Rongvaux et al, 2014;White et al, 2014;West et al, 2015).”
From Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency (2018) · cites this paper as White et al, 2014
These age-related retrotransposon events are attenuated by caloric restriction.
“Interestingly, these events were attenuated by caloric restriction (White et al., 2014), an intervention which has been shown to extend lifespan in a plethora of organisms and decrease the burden of senescent cells (Fontana et al., 2018; Mercken et al., 2012).”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as White et al., 2014

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“It has long been considered that the highly regulated caspase-dependent apoptosis is immunologically silent, in which the effector caspases including caspase-3, -7, and -9, were necessary to inhibit mtDNA triggered activation of STING (White et al., 2014; West et al., 2015).”
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Self-citation
Apoptotic Caspases Prevent the Induction of Type I Interferons by Mitochondrial DNA
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Apoptotic caspases silence spontaneous innate immune signals by specifically cleaving activated mitochondrial antiviral signalling protein (MAVS)Preprint
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Apoptotic Caspases: Multiple or Mistaken Identities?
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Self-citation

Authors: White, M. J., McArthur, K., Metcalf, D., Lane, R. M., Cambier, J. C., Herold, M. J., van Delft, M. F., Bedoui, S., Lessene, G., Ritchie, M. E., Huang, D. C. S., & Kile, B. T.
Affiliations: The University of Melbourne (AU)
Walter and Eliza Hall Institute of Medical Research (AU)
National Jewish Health (US)
Corresponding author: White, Michael J.
Kile, Benjamin T.
ORCID: McArthur, Kate
Cambier, John C.
Herold, Marco J.
Bedoui, Sammy
Ritchie, Matthew E.
Huang, David C.S.
Kile, Benjamin T.
Venue: Cell
Publisher: Elsevier BV
Published: 2014-12
Volume: 159
Issue: 7
Pages: 1549-1562
ISSN: 0092-8674 (ISSN-L)
DOI: 10.1016/j.cell.2014.11.036
PMC: PMC4520319
OpenAlex: W2028107828
Cited by: 983
References: 68
Citations by year: 2026: 89 · 2025: 88 · 2024: 118 · 2023: 107 · 2022: 111 · 2021: 94 · 2020: 93 · 2019: 61 · 2018: 76 · 2017: 63 · 2016: 39 · 2015: 40
FWCI: 21.61
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 382 d)
Locations: Cell (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion)
Funders: National Institute of Allergy and Infectious Diseases (R21AI099346)
Topics: Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
Keywords: caspases, apoptosis, type I interferon, STING, cGAS, mitochondrial DNA, Bak, Bax, caspase-9, Apaf-1, caspase-3, caspase-7, interferon-beta, hematopoietic stem cells
MeSH terms: STING Protein, Animals, Crosses, Genetic, DNA, Mitochondrial, Female, Hematopoietic Stem Cells, Interferon Type I, Male, Membrane Proteins, Mice, Inbred C57BL, Signal Transduction, Apoptosis, Caspases, Caspase 9

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

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