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Apoptotic Caspases Suppress mtDNA-Induced STING-Mediated Type I IFN Production
Open accessAbstract
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, 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 measuredIn the citing paper
“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]
In the citing paper
“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
In the citing paper
“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
In the citing paper
“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
In the citing paper
“Finally, ABT-737 (an experimental inhibitor of multiple BCL2 family members) is known for its ability to drive robust type I IFN secretion by cancer cells downstream of mtDNA-driven CGAS activation, especially in the context of caspases inhibition (Rongvaux et al., 2014; White et al., 2014).”
From Immunomodulation by targeted anticancer agents (2021) · cites this paper as White et al., 2014
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“The same pro-apoptotic caspases stimulated by cGAS-STING operate to inhibit their activation: During intrinsic apoptosis, initiator and effector caspases (Caspase 9 and Caspase 3) result in cleavage of cGAS, STING and IRF3, thus limiting further STING signaling (88, 89).”
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“The mtDNA is sensed by the cGAS-STING axis leading to sustained production of type I IFN response and autoimmunity (Ablasser et al , 2014; Rongvaux et al , 2014; White et al , 2014; Gao et al , 2015; West et al , 2015).”
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“Previous studies have evidenced that genomic and mtDNA, released upon cell injury (36), activate the STING pathway (4, 58, 59).”
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“Additionally, caspases actively suppress the innate immune response to danger-associated molecular patterns (DAMPs) such as mitochondrial DNA (mtDNA) and reactive oxygen species (ROS), which are released from damaged mitochondria during apoptosis (White et al, 2014; Riley et al, 2018).”
Metadata
- 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
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2014-12
- Volume
- 159
- Issue
- 7
- Pages
- 1549-1562
- ISSN
- 0092-8674 (ISSN-L)
- 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
- 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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