Apoptotic caspases prevent the induction of type i interferons by mitochondrial DNA

Anthony Rongvaux, Ruaidhrí Jackson, Christian C D Harman, Tuo Li, A. Phillip West, Marcel R. De Zoete, Youtong Wu, Brian Yordy, Saquib A. Lakhani, Chia Yi Kuan, Tadatsugu Taniguchi, Gerald S. Shadel, Zhijian J. Chen, Akiko Iwasaki, Richard A. Flavell

Research output: Contribution to journalArticle

221 Citations (Scopus)

Abstract

The mechanism by which cells undergo death determines whether dying cells trigger inflammatory responses or remain immunologically silent. Mitochondria play a central role in the induction of cell death, as well as in immune signaling pathways. Here, we identify a mechanism by which mitochondria and downstream proapoptotic caspases regulate the activation of antiviral immunity. In the absence of active caspases, mitochondrial outer membrane permeabilization by Bax and Bak results in the expression of type I interferons (IFNs). This induction is mediated by mitochondrial DNA-dependent activation of the cGAS/STING pathway and results in the establishment of a potent state of viral resistance. Our results show that mitochondria have the capacity to simultaneously expose a cell-intrinsic inducer of the IFN response and to inactivate this response in a caspase-dependent manner. This mechanism provides a dual control, which determines whether mitochondria initiate an immunologically silent or a proinflammatory type of cell death.

Original languageEnglish (US)
Pages (from-to)1563-1577
Number of pages15
JournalCell
Volume159
Issue number7
DOIs
StatePublished - Dec 18 2014

Fingerprint

Mitochondria
Caspases
Mitochondrial DNA
Interferons
Cell death
Cell Death
Chemical activation
Interferon Inducers
Interferon Type I
Mitochondrial Membranes
Helper-Inducer T-Lymphocytes
Antiviral Agents
Immunity
Membranes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Rongvaux, A., Jackson, R., Harman, C. C. D., Li, T., West, A. P., De Zoete, M. R., ... Flavell, R. A. (2014). Apoptotic caspases prevent the induction of type i interferons by mitochondrial DNA. Cell, 159(7), 1563-1577. https://doi.org/10.1016/j.cell.2014.11.037

Apoptotic caspases prevent the induction of type i interferons by mitochondrial DNA. / Rongvaux, Anthony; Jackson, Ruaidhrí; Harman, Christian C D; Li, Tuo; West, A. Phillip; De Zoete, Marcel R.; Wu, Youtong; Yordy, Brian; Lakhani, Saquib A.; Kuan, Chia Yi; Taniguchi, Tadatsugu; Shadel, Gerald S.; Chen, Zhijian J.; Iwasaki, Akiko; Flavell, Richard A.

In: Cell, Vol. 159, No. 7, 18.12.2014, p. 1563-1577.

Research output: Contribution to journalArticle

Rongvaux, A, Jackson, R, Harman, CCD, Li, T, West, AP, De Zoete, MR, Wu, Y, Yordy, B, Lakhani, SA, Kuan, CY, Taniguchi, T, Shadel, GS, Chen, ZJ, Iwasaki, A & Flavell, RA 2014, 'Apoptotic caspases prevent the induction of type i interferons by mitochondrial DNA', Cell, vol. 159, no. 7, pp. 1563-1577. https://doi.org/10.1016/j.cell.2014.11.037
Rongvaux A, Jackson R, Harman CCD, Li T, West AP, De Zoete MR et al. Apoptotic caspases prevent the induction of type i interferons by mitochondrial DNA. Cell. 2014 Dec 18;159(7):1563-1577. https://doi.org/10.1016/j.cell.2014.11.037
Rongvaux, Anthony ; Jackson, Ruaidhrí ; Harman, Christian C D ; Li, Tuo ; West, A. Phillip ; De Zoete, Marcel R. ; Wu, Youtong ; Yordy, Brian ; Lakhani, Saquib A. ; Kuan, Chia Yi ; Taniguchi, Tadatsugu ; Shadel, Gerald S. ; Chen, Zhijian J. ; Iwasaki, Akiko ; Flavell, Richard A. / Apoptotic caspases prevent the induction of type i interferons by mitochondrial DNA. In: Cell. 2014 ; Vol. 159, No. 7. pp. 1563-1577.
@article{384aeca1aa344858961b3bafdd212632,
title = "Apoptotic caspases prevent the induction of type i interferons by mitochondrial DNA",
abstract = "The mechanism by which cells undergo death determines whether dying cells trigger inflammatory responses or remain immunologically silent. Mitochondria play a central role in the induction of cell death, as well as in immune signaling pathways. Here, we identify a mechanism by which mitochondria and downstream proapoptotic caspases regulate the activation of antiviral immunity. In the absence of active caspases, mitochondrial outer membrane permeabilization by Bax and Bak results in the expression of type I interferons (IFNs). This induction is mediated by mitochondrial DNA-dependent activation of the cGAS/STING pathway and results in the establishment of a potent state of viral resistance. Our results show that mitochondria have the capacity to simultaneously expose a cell-intrinsic inducer of the IFN response and to inactivate this response in a caspase-dependent manner. This mechanism provides a dual control, which determines whether mitochondria initiate an immunologically silent or a proinflammatory type of cell death.",
author = "Anthony Rongvaux and Ruaidhr{\'i} Jackson and Harman, {Christian C D} and Tuo Li and West, {A. Phillip} and {De Zoete}, {Marcel R.} and Youtong Wu and Brian Yordy and Lakhani, {Saquib A.} and Kuan, {Chia Yi} and Tadatsugu Taniguchi and Shadel, {Gerald S.} and Chen, {Zhijian J.} and Akiko Iwasaki and Flavell, {Richard A.}",
year = "2014",
month = "12",
day = "18",
doi = "10.1016/j.cell.2014.11.037",
language = "English (US)",
volume = "159",
pages = "1563--1577",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "7",

}

TY - JOUR

T1 - Apoptotic caspases prevent the induction of type i interferons by mitochondrial DNA

AU - Rongvaux, Anthony

AU - Jackson, Ruaidhrí

AU - Harman, Christian C D

AU - Li, Tuo

AU - West, A. Phillip

AU - De Zoete, Marcel R.

AU - Wu, Youtong

AU - Yordy, Brian

AU - Lakhani, Saquib A.

AU - Kuan, Chia Yi

AU - Taniguchi, Tadatsugu

AU - Shadel, Gerald S.

AU - Chen, Zhijian J.

AU - Iwasaki, Akiko

AU - Flavell, Richard A.

PY - 2014/12/18

Y1 - 2014/12/18

N2 - The mechanism by which cells undergo death determines whether dying cells trigger inflammatory responses or remain immunologically silent. Mitochondria play a central role in the induction of cell death, as well as in immune signaling pathways. Here, we identify a mechanism by which mitochondria and downstream proapoptotic caspases regulate the activation of antiviral immunity. In the absence of active caspases, mitochondrial outer membrane permeabilization by Bax and Bak results in the expression of type I interferons (IFNs). This induction is mediated by mitochondrial DNA-dependent activation of the cGAS/STING pathway and results in the establishment of a potent state of viral resistance. Our results show that mitochondria have the capacity to simultaneously expose a cell-intrinsic inducer of the IFN response and to inactivate this response in a caspase-dependent manner. This mechanism provides a dual control, which determines whether mitochondria initiate an immunologically silent or a proinflammatory type of cell death.

AB - The mechanism by which cells undergo death determines whether dying cells trigger inflammatory responses or remain immunologically silent. Mitochondria play a central role in the induction of cell death, as well as in immune signaling pathways. Here, we identify a mechanism by which mitochondria and downstream proapoptotic caspases regulate the activation of antiviral immunity. In the absence of active caspases, mitochondrial outer membrane permeabilization by Bax and Bak results in the expression of type I interferons (IFNs). This induction is mediated by mitochondrial DNA-dependent activation of the cGAS/STING pathway and results in the establishment of a potent state of viral resistance. Our results show that mitochondria have the capacity to simultaneously expose a cell-intrinsic inducer of the IFN response and to inactivate this response in a caspase-dependent manner. This mechanism provides a dual control, which determines whether mitochondria initiate an immunologically silent or a proinflammatory type of cell death.

UR - http://www.scopus.com/inward/record.url?scp=84919898250&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84919898250&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2014.11.037

DO - 10.1016/j.cell.2014.11.037

M3 - Article

C2 - 25525875

AN - SCOPUS:84919898250

VL - 159

SP - 1563

EP - 1577

JO - Cell

JF - Cell

SN - 0092-8674

IS - 7

ER -