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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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“Abbreviations mtDNA: Mitochondrial DNA; ddPCR: Droplet digital PCR; siRNA: Small interfering RNA; qRT-PCR: Quantitative real-time polymerase chain reaction; shRNA: Short hairpin RNA; CQ: Chloroquine; CsA: Cyclosporin A; ROS: Reactive oxygen species; IFNs: Type I interferons; cGAS: Cyclic GMP-AMP synthase; STING: Stimu…”
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“Other studies also demonstrated caspases to suppress cGAS/STING- dependent mtDNA sensing and block downstream type I interferon production and inflammation in both mice and humans [74, 75].”
BackgroundMetallo-alginate hydrogel can potentiate microwave tumor ablation for synergistic cancer treatment
Zhu, Y., Yang, Z., Pan, Z., Hao, Y., Wang, C., Dong, Z., Li, Q., Han, Y., Tian, L., Feng, L., et al. (2022) · Science Advances · doi:10.1126/sciadv.abo5285 · Cited by 155
Tumor cells suppress radiation-induced immunity by hijacking caspase 9 signaling
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Durante, M., & Formenti, S. C. (2018) · Frontiers in Oncology · doi:10.3389/fonc.2018.00192 · Cited by 156
“Cytosolic leakage of mtDNA also results in activation of the cGAS–STING pathway (121, 122).”
BackgroundOrganellar homeostasis and innate immune sensing
Harapas, C. R., Idiiatullina, E., Al‐Azab, M., Hrovat-Schaale, K., Reygaerts, T., Steiner, A., Laohamonthonkul, P., Davidson, S., Yu, C., Booty, L. M., et al. (2022) · Nature reviews. Immunology · doi:10.1038/s41577-022-00682-8 · Cited by 152
DNA sensor cGAS-mediated immune recognition
Xia, P., Wang, S., Gao, P., Gao, G., & Fan, Z. (2016) · Protein & Cell · doi:10.1007/s13238-016-0320-3 · Cited by 154
“However, apoptotic caspases inhibit type I IFN production (Rongvaux et al., 2014; White et al., 2014).”
BackgroundInfluentialRodriguez-Ruiz, M. E., Buqué, A., Hensler, M., Chen, J., Bloy, N., Petroni, G., Sato, A., Yamazaki, T., Fucikova, J., & Galluzzi, L. (2019) · OncoImmunology · doi:10.1080/2162402x.2019.1655964 · Cited by 147
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“Next, we examined whether aging affected STING activation during IR. mtDNA has been recognized as an important endogenous DAMPs, which can be detected by STING-dependent sensors (White et al., 2014).”
BackgroundTranslating nucleic acid-sensing pathways into therapies
Junt, T., & Barchet, W. (2015) · Nature reviews. Immunology · doi:10.1038/nri3875 · Cited by 153
“…sensing of mitochondrial DNA through STING can elicit IFN-dependent inflammation following cell death in the absence of apoptotic caspases 9,123 , and efficient B cell responses to T cell-independent type 2 antigens seem to rely on BCR-dependent reactivation of endogenous retroviruses and…”
Wang, C., Sun, Z., Zhao, C., Zhang, Z., Wang, H., Liu, Y., Guo, Y., Zhang, B., Gu, L., Yu, Y., et al. (2021) · Journal of Controlled Release · doi:10.1016/j.jconrel.2021.01.036 · Cited by 145
Cell death in chronic inflammation: breaking the cycle to treat rheumatic disease
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Mitochondrial cristae architecture protects against mtDNA release and inflammation
He, B., Yu, H., Liu, S., Wan, H., Fu, S., Liu, S., Yang, J. J., Zhang, Z., Huang, H., Li, Q., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.111774 · Cited by 157
Type-I-interferons in infection and cancer: Unanticipated dynamics with therapeutic implications
Musella, M., Manic, G., Maria, R. D., Vitale, I., & Sistigu, A. (2017) · OncoImmunology · doi:10.1080/2162402x.2017.1314424 · Cited by 147
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“…lacks immunogenicity, mitochondrial outer membrane permeabilization can trigger caspase-independent cell death in the absence of caspases, which can activate antitumor immunity and significantly enhance antitumor activity, as has been validated in the mouse rectal cancer CT26 [143, 144, 163, 164].”
miR-25/93 mediates hypoxia-induced immunosuppression by repressing cGAS
Wu, M.-Z., Cheng, W., Chen, S.-F., Nieh, S., O’Connor, C., Liu, C., Tsai, W., Wu, C.-J., Martin, L., Lin, Y., et al. (2017) · Nature Cell Biology · doi:10.1038/ncb3615 · Cited by 139
“Recent studies have demonstrated that the cGAS-dependent DNA sensing pathway can also recognize mtDNA released by apoptosis 27–28 .”
The induction and consequences of Influenza A virus-induced cell death
Atkin‐Smith, G. K., Duan, M., Chen, W., & Poon, I. K. H. (2018) · Cell Death and Disease · doi:10.1038/s41419-018-1035-6 · Cited by 141
Mechanisms of mitochondrial DNA escape and its relationship with different metabolic diseases
Pérez-Treviño, P., Velasquez-Esparza, M. M., & Garcı́a, N. (2020) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2020.165761 · Cited by 134
The extracellular matrix integrates mitochondrial homeostasis
Zhang, H., Tsui, C. K., Garcia, G., Joe, L. K., Wu, H., Maruichi, A., Fan, W., Pandovski, S., Yoon, P. H., Webster, B. M., et al. (2024) · Cell · doi:10.1016/j.cell.2024.05.057 · Cited by 139
Innate Sensing of DNA Virus Genomes
Ma, Z., Ni, G., & Damania, B. (2018) · Annual Review of Virology · doi:10.1146/annurev-virology-092917-043244 · Cited by 140
Emerging Role of Mitochondrial DNA as a Major Driver of Inflammation and Disease Progression
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Mitochondria and the hallmarks of cancer
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Crashing the computer: apoptosis vs. necroptosis in neuroinflammation
Heckmann, B. L., Tummers, B., & Green, D. R. (2018) · Cell Death and Differentiation · doi:10.1038/s41418-018-0195-3 · Cited by 136
Mitochondria at the interface between neurodegeneration and neuroinflammation
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cGAS‐cGAMP‐STING: The three musketeers of cytosolic DNA sensing and signaling
Tao, J., Zhou, X., & Jiang, Z. (2016) · IUBMB Life · doi:10.1002/iub.1566 · Cited by 135
“Meanwhile, as a balance, the mtDNA-induced type I IFN response can be prevented by the activation of apoptotic caspases 3/7/9 though the detailed inhibitory mechanism remains to be determined (110,111), indicating that the inhibitors of caspases have the potential to serve as antiviral therapies.”
BackgroundHu, Q., Shi, H., Zeng, T., Liu, H., Su, Y., Cheng, X., Ye, J., Yin, Y., Liu, M., Zheng, H. W., et al. (2019) · Arthritis Research & Therapy · doi:10.1186/s13075-018-1800-z · Cited by 134
“THP-1 SN were concentrated by trichloroacetic acid precipitation [23].”
BackgroundMethodThe cGAS‐STING pathway: The role of self‐DNA sensing in inflammatory lung disease
Ma, R., Serrano, T. P. O., Davis, J., Prigge, A. D., & Ridge, K. M. (2020) · The FASEB Journal · doi:10.1096/fj.202001607r · Cited by 138
Interferons and the immunogenic effects of cancer therapy
Minn, A. J. (2015) · Trends in Immunology · doi:10.1016/j.it.2015.09.007 · Cited by 130
“The propensity to undergo MOMP is promoted by pro-apoptotic BCL-2 proteins BAX and BAK and antagonized by anti-apoptotic BCL-2 and BCL-XL.”
BackgroundInfluentialPan, J., 宁波大学农产品质量安全危害因子与风险防控国家重点实验室, 浙. 宁. 3., Fei, C.-J., Hu, Y., Wu, X., Nie, L., Chen, J., 宁波大学梅山校区海洋学院生物化学与分子生物学实验室, 浙. 宁. 3., & 浙江省海洋生物工程重点实验室, 浙. 宁. 3. (2023) · 动物学研究 · doi:10.24272/j.issn.2095-8137.2022.464 · Cited by 138
The Antisocial Network: Cross Talk Between Cell Death Programs in Host Defense
Snyder, A. G., & Oberst, A. (2021) · Annual Review of Immunology · doi:10.1146/annurev-immunol-112019-072301 · Cited by 129
Activation and Regulation of DNA-Driven Immune Responses
Paludan, S. R. (2015) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.00061-14 · Cited by 128
“The stimulation of the mitochondrial Bak/Bax-mediated apoptosis pathway leads to the release of mitochondrial DNA with the potential to stimulate the cGAS-STING pathway (97, 98).”
BackgroundGasdermins mediate cellular release of mitochondrial DNA during pyroptosis and apoptosis
de Torre‐Minguela, C., Gómez, A. I., Couillin, I., & Pelegrı́n, P. (2021) · The FASEB Journal · doi:10.1096/fj.202100085r · Cited by 140
Mitochondrial pores at the crossroad between cell death and inflammatory signaling
Flores‐Romero, H., Dadsena, S., & García‐Sáez, A. J. (2023) · Molecular Cell · doi:10.1016/j.molcel.2023.02.021 · Cited by 131
Reinert, L. S., Rashidi, A. S., Tran, D. N., Katzilieris-Petras, G., Hvidt, A. K., Gohr, M., Fruhwürth, S., Bodda, C., Thomsen, M. K., Vendelbo, M. H., et al. (2021) · Journal of Clinical Investigation · doi:10.1172/jci136824 · Cited by 118
“Indeed, several studies have described a link between the cGAS29 STING pathway, PCD pathways, and negative regulation of IFN-I (49, 56-58).”
BackgroundIngelsson, B., Appelgren, D., Strid, T., Söderberg, A., Bergh, A.-C., Loitto, V. M., Lotfi, K., Segelmark, M., Spyrou, G., & Rosén, A. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1711950115 · Cited by 132
“This finding underlines the interferogenic characteristics of mtDNA previously reported by others (5, 6, 24).”
Cytosolic sensing of immuno-stimulatory DNA, the enemy within
Dhanwani, R., Takahashi, M., & Sharma, S. (2018) · Current Opinion in Immunology · doi:10.1016/j.coi.2017.11.004 · Cited by 123
Mitochondria and Inflammation: Cell Death Heats Up
Vringer, E., & Tait, S. W. G. (2019) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2019.00100 · Cited by 124
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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