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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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TFAM downregulation promotes autophagy and ESCC survival through mtDNA stress-mediated STING pathway
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“the caspase cascade suppresses mtDNA-induced type I IFN response, as shown in primary mouse embryonic fibroblasts or human peripheral blood cells [5, 6].”
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Airway Epithelial cGAS Is Critical for Induction of Experimental Allergic Airway Inflammation
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A small molecule interacts with VDAC2 to block mouse BAK-driven apoptosis
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“Activation of this pathway results in the release of type I interferon (IFN) and other immune cytokines, promoting dendritic cell maturation and enhancing the quantity and function of cytotoxic T cells 28 e 31 .”
BackgroundVRK2 is involved in the innate antiviral response by promoting mitostress-induced mtDNA release
He, W.-R., Cao, L.-B., Yang, Y.-L., Hua, D., Hu, M., & Shu, H. (2021) · Cellular and Molecular Immunology · doi:10.1038/s41423-021-00673-0 · Cited by 62
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“This conclusion is supported by the observation that the genetic deletion of caspase-9, caspase-3/7, or Apaf-1 leads to type I IFN production by dying cells [280].”
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“As another example, in cells undergoing apoptosis leaky mitochondria release DNA capable of inducing cytokines in a cGAS-dependent manner, an event that is normally prevented by the action of apoptotic caspases [48, 49].”
BackgroundCaspases control antiviral innate immunity
Chen, H., Ning, X., & Jiang, Z. (2017) · Cellular and Molecular Immunology · doi:10.1038/cmi.2017.44 · Cited by 59
Therapeutic approaches targeting CD95L/CD95 signaling in cancer and autoimmune diseases
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“In addition, several reports indicate that MOMP can initiate multiple inflammatory signaling, for example the cGAS/STING [30, 31] or the NF-κB pathways [32].”
BackgroundCell death in skin function, inflammation, and disease
Anderton, H., & Alqudah, S. (2022) · Biochemical Journal · doi:10.1042/bcj20210606 · Cited by 64
ARF1 prevents aberrant type I interferon induction by regulating STING activation and recycling
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“Treatment with ABT-737 and Q-VD-OPH (ABT/QVD), to damage mitochondria and promote mtDNA release 33 , was used as a positive control.”
Mitochondrial fidelity and metabolic agility control immune cell fate and function
Sack, M. N. (2018) · Journal of Clinical Investigation · doi:10.1172/jci120845 · Cited by 54
Microtubule-Based Mitochondrial Dynamics as a Valuable Therapeutic Target in Cancer
Vona, R., Mileo, A. M., & Matarrese, P. (2021) · Cancers · doi:10.3390/cancers13225812 · Cited by 58
Putting the STING back into BH3-mimetic drugs for TP53-mutant blood cancers
Diepstraten, S. T., Yuan, Y., Marca, J. E. L., Young, S., Chang, C. W. T., Whelan, L., Ross, A. M., Fischer, K. C., Pomilio, G., Morris, R., et al. (2024) · Cancer Cell · doi:10.1016/j.ccell.2024.04.004 · Cited by 56
The mitochondria in lung fibrosis: friend or foe?
Malsin, E. S., & Kamp, D. W. (2018) · Translational research · doi:10.1016/j.trsl.2018.05.005 · Cited by 56
Hu, Q., Knight, P. H., Ren, Y., Ren, H., Zheng, J., Wu, X., Ren, J., & Sawyer, R. G. (2018) · Acta Physiologica · doi:10.1111/apha.13194 · Cited by 55
“Two laboratories in 2014 independently demonstrated that mtDNA liberation following Bas/Bak‐induced apoptosis activates the cGAS‐STING pathway with resulting enhancement of type I IFNs responses and IFN‐ stimulated gene expression.(33,34) Chen et al(35) also suggested that PUMA (a proapoptotic protein) can stimulate t…”
BackgroundJin, S., Guo, Y., Song, D., Zhu, Z., Zhang, Z., Sun, Y., Yang, T., Guo, Z., & Wang, X. (2019) · Inorganic Chemistry · doi:10.1021/acs.inorgchem.9b00708 · Cited by 56
Wang, X., Wang, Y., Cao, A., Luo, Q., Chen, D., Zhao, W., Xu, J., Li, Q., Bu, X., & Quan, J. (2023) · Nature Communications · doi:10.1038/s41467-023-41892-5 · Cited by 54
“Moreover, mitochondrial DNA stress invoked by a variety of cellular insults also promotes the in fl ammatory response through triggering cGAS activity 32 – 35 .”
Karniely, S., Weekes, M. P., Antrobus, R., Rorbach, J., Haute, L. V., Umrania, Y., Smith, D. L., Stanton, R. J., Minczuk, M. A., Lehner, P. J., et al. (2016) · mBio · doi:10.1128/mbio.00029-16 · Cited by 56
“Within cells, mtDNA released from mitochondria during apoptosis is sensed by the cytosolic cGAS DNA sensor and leads to the induction of type I interferons (92–94).”
Defects of mitochondrial RNA turnover lead to the accumulation of double-stranded RNA in vivo
Pajak, A., Laine, I., Clemente, P., Fissi, N. E., Schober, F. A., Maffezzini, C., Calvo‐Garrido, J., Wibom, R., Filograna, R., Dhir, A., et al. (2019) · PLoS Genetics · doi:10.1371/journal.pgen.1008240 · Cited by 55
The crosstalk between the caspase family and the cGAS‒STING signaling pathway
Xiong, Y., Tang, Y.-D., & Zheng, C. (2021) · Journal of Molecular Cell Biology · doi:10.1093/jmcb/mjab071 · Cited by 54
“…TBK1 phosphorylation, and IRF3 phosphorylation and dimerization, suggesting that caspase-3, caspase-7, and caspase-9 are negative regulators of mtDNA-induced damage-associated molecular pattern signaling and could downregulate cGAS/STING/TBK1/IRF3-mediated IFN-a/b production (White et al., 2014).”
Ding, L., Qian, J., Yu, X., Wu, Q., Mao, J., Liu, X., Wang, Y., Guo, D., Su, R., Xie, H., et al. (2023) · Cancer Letters · doi:10.1016/j.canlet.2023.216568 · Cited by 54
Gasdermins as evolutionarily conserved executors of inflammation and cell death
Chen, K. W., & Brož, P. (2024) · Nature Cell Biology · doi:10.1038/s41556-024-01474-z · Cited by 59
“For example, caspase-3 and -7 were reported to cleave and inactivate cGAS (cyclic GMP-AMP synthase) and IRF3 (interferon regulatory factor 3) to restrict activation of type I interferon by endogenous mitochondrial DNA during apoptosis 69–71 .”
Saas, P., Daguindau, É., & Perruche, S. (2016) · Stem Cells · doi:10.1002/stem.2361 · Cited by 53
Immunometabolism of pro-repair cells
Singer, B. D., & Chandel, N. S. (2019) · Journal of Clinical Investigation · doi:10.1172/jci124613 · Cited by 53
Mitochondrial DNA in cell death and inflammation
Heilig, R., Lee, J., & Tait, S. W. G. (2023) · Biochemical Society Transactions · doi:10.1042/bst20221525 · Cited by 56
Cell death and thymic tolerance
Daley, S. R., Teh, C. E., Hu, D. Y., Strasser, A., & Gray, D. H. D. (2017) · Immunological Reviews · doi:10.1111/imr.12532 · Cited by 52
cGAS-STING Activation in the Tumor Microenvironment and Its Role in Cancer Immunity
Pépin, G., & Gantier, M. P. (2017) · Advances in experimental medicine and biology · doi:10.1007/978-981-10-5987-2_8 · Cited by 53
Liang, S., Li, Y., Jiang, H., Tao, Y., Qian, Z., Li, L., Cai, F., Ma, L., & Yu, Y. (2017) · Journal of Cancer · doi:10.7150/jca.21018 · Cited by 54
“The aspartic acid-directed cysteine proteases (Caspases) are central to the apoptotic mechanisms [6, 7].”
BackgroundAn emerging role for calcium signalling in innate and autoimmunity via the cGAS-STING axis
Mathavarajah, S., Salsman, J., & Dellaire, G. (2019) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2019.04.003 · Cited by 53
The BCL-2 protein family: from discovery to drug development
Croce, C. M., Vaux, D. L., Strasser, A., Opferman, J. T., Czabotar, P. E., & Fesik, S. W. (2025) · Cell Death and Differentiation · doi:10.1038/s41418-025-01481-z · Cited by 56
“…grow in size and shape on the mitochondrial outer membrane [105, 106] to form pores that release factors from inside, initially proteins such as Cyto-chrome c to initiate apoptosis [107, 108], or if left unchecked, very large structures such as mtDNA to initiate cGAS/STING signaling [109 – 112].”
Endogenous Nucleic Acid Recognition by RIG-I-Like Receptors and cGAS
Lee, J., Chiang, C., & Gack, M. U. (2019) · Journal of Interferon & Cytokine Research · doi:10.1089/jir.2019.0015 · Cited by 50
Host Protective Immune Responses against Influenza A Virus Infection
Jung, H. E., & Lee, H. K. (2020) · Viruses · doi:10.3390/v12050504 · Cited by 55
cGAS‐STING pathway: post‐translational modifications and functions in sterile inflammatory diseases
Hong, Z., Ma, T., Liu, X., & Wang, C. (2021) · FEBS Journal · doi:10.1111/febs.16137 · Cited by 52
Zhao, X., Yu, M., Zhao, Y., Zheng, Y., Meng, L., Du, K., Xie, Z., Lv, H., Zhang, W. Y., Liu, J., et al. (2022) · Journal of Neurology · doi:10.1007/s00415-022-11146-3 · Cited by 51
Wang, W., Wu, S., Cen, Z., Zhang, Y., Chen, Y., Huang, Y., Cillo, A. R., Prokopec, J. S., Quarato, G., Vignali, D. A. A., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.111582 · Cited by 50
“However, this hypothesis is contrary to the fact that the pro-inflammatory effects of apoptotic cells occurred only under caspase-inhibited conditions (Giampazolias et al., 2017; Riley et al., 2018; Rongvaux et al., 2014; White et al., 2014).”
Kong, Y., & Xu, S. (2018) · Oncology Reports · doi:10.3892/or.2018.6381 · Cited by 50
“Additionally, cysteinyl aspartate specific proteinases (caspases) play important roles during apoptosis (58).”
BackgroundSanta, P., Garreau, A., Serpas, L., Ferrière, A., Blanco, P., Soni, C., & Sisirak, V. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.629922 · Cited by 56
“Accordingly, once in the cytosol, unmodified mtDNA stimulates the cGAS-STING pathway (73, 74), while its oxidized counterpart acquires the capacity to activate the NLR family pyrin domain containing 3 (NLRP3) inflammasome (75).”
BackgroundThe abscopal effect: a sense of DNA damage is in the air
Lippert, T. P., & Greenberg, R. A. (2021) · Journal of Clinical Investigation · doi:10.1172/jci148274 · Cited by 53
cGAS/STING: novel perspectives of the classic pathway
Gao, M., He, Y., Tang, H., Chen, X., Liu, S., & Tao, Y. (2020) · Molecular Biomedicine · doi:10.1186/s43556-020-00006-z · Cited by 50
“The engagement of cGAS and subsequent mtDNA-induced STINGmediated type I IFN production can be suppressed by apoptotic caspase 9 and downstream caspase 3 and 7, rendering mitochondrial apoptosis immunologically silent [108, 110] (Fig.”
BackgroundMitochondrial DNA and the STING pathway are required for hepatic stellate cell activation
Arumugam, S., Li, B., Boodapati, S. L. T., Nathanson, M. H., Sun, B., Ouyang, X., & Mehal, W. Z. (2023) · Hepatology · doi:10.1097/hep.0000000000000388 · Cited by 51
“Binding between cGAS and DNA involves extensive ionic interactions between the positively charged surface of cGAS and negatively charged DNA.”
Secretion of mitochondrial DNA via exosomes promotes inflammation in Behçet's syndrome
Konaka, H., Kato, Y., Hirano, T., Tsujimoto, K., Park, J., Koba, T., Aoki, W., Matsuzaki, Y., Taki, M., Koyama, S., et al. (2023) · The EMBO Journal · doi:10.15252/embj.2022112573 · Cited by 49
“…by inducing the production of various cytokines, including type I interferon recognized via cyclic GMP-AMP synthase (Rong-vaux et al , 2014; White et al , 2014), proinflammatory cytokines via toll-like receptor (TLR) 9 (Zhang et al , 2010; Oka et al , 2012), and IL-1 b and IL-18 via NLR…”
BackgroundMethodTopoisomerase 1 Inhibition Promotes Cyclic GMP-AMP Synthase-Dependent Antiviral Responses
Pépin, G., Nejad, C., Ferrand, J., Thomas, B. J., Stunden, H. J., Sanij, E., Foo, C. H., Stewart, C. R., Cain, J. E., Bardin, P. G., et al. (2017) · mBio · doi:10.1128/mbio.01611-17 · Cited by 50
“regularly interspaced short palindromic repeat(s) (CRISPR) and were derived from a parental cGaswt/wt-immortalized MEF line (used as a matched control) (12).”
Gao, M., Dang, F., & Deng, C. (2019) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2019.172528 · Cited by 49
Balancing life and death: BCL‐2 family members at diverse ER–mitochondrial contact sites
Means, R. E., & Katz, S. G. (2021) · FEBS Journal · doi:10.1111/febs.16241 · Cited by 50
Antimicrobial Peptides Mediate Apoptosis by Changing Mitochondrial Membrane Permeability
Wang, H., Zhang, C., Li, M., Liu, C., Wang, J., Ou, X., & Han, Y. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232112732 · Cited by 51
Novel insight into cGAS-STING pathway in ischemic stroke: from pre- to post-disease
Ma, X., Xin, D., She, R., Liu, D., Ge, J., & Mei, Z. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1275408 · Cited by 52
Control of innate immunity by the cGAS‐STING pathway
Mosallanejad, K., & Kagan, J. C. (2022) · Immunology and Cell Biology · doi:10.1111/imcb.12555 · Cited by 52
Zou, W.-W., & Xu, S. (2017) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2017.09.144 · Cited by 47
Mitochondrial DNA and Exercise: Implications for Health and Injuries in Sports
Zanini, G., De Gaetano, A., Selleri, V., Savino, G., Cossarizza, A., Pinti, M., Mattioli, A. V., & Nasi, M. (2021) · Cells · doi:10.3390/cells10102575 · Cited by 46
Liu, J., Zhang, X., & Wang, H. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.113680 · Cited by 46
Acute kidney injury in diabetes mellitus: Epidemiology, diagnostic, and therapeutic concepts
Gui, Y., Palanza, Z., Fu, H., & Zhou, D. F. (2023) · The FASEB Journal · doi:10.1096/fj.202201340rr · Cited by 51
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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