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mitochondrial DNA cGAS

Alessandra Zevini, David Olagnier, John Hiscott
Detection of evolutionarily conserved molecules on microbial pathogens by host immune sensors represents the initial trigger of the immune response against infection. Cytosolic receptors sense viral and intracellular bacterial genomes, as well as nucleic acids produced during replication. Once activated, these sensors trigger multiple signaling cascades, converging on the production of type I interferons and proinflammatory cytokines. Although distinct classes of receptors are responsible for the RNA and DNA sensing, the downstream signaling components are physically and functionally interconnected...
January 7, 2017: Trends in Immunology
Kirsten E Wiens, Joel D Ernst
Type I interferons (including IFNαβ) are innate cytokines that may contribute to pathogenesis during Mycobacterium tuberculosis (Mtb) infection. To induce IFNβ, Mtb must gain access to the host cytosol and trigger stimulator of interferon genes (STING) signaling. A recently proposed model suggests that Mtb triggers STING signaling through bacterial DNA binding cyclic GMP-AMP synthase (cGAS) in the cytosol. The aim of this study was to test the generalizability of this model using phylogenetically distinct strains of the Mtb complex (MTBC)...
August 2016: PLoS Pathogens
Elizabeth C Carroll, Lei Jin, Andres Mori, Natalia Muñoz-Wolf, Ewa Oleszycka, Hannah B T Moran, Samira Mansouri, Craig P McEntee, Eimear Lambe, Else Marie Agger, Peter Andersen, Colm Cunningham, Paul Hertzog, Katherine A Fitzgerald, Andrew G Bowie, Ed C Lavelle
The cationic polysaccharide chitosan is an attractive candidate adjuvant capable of driving potent cell-mediated immunity, but the mechanism by which it acts is not clear. We show that chitosan promotes dendritic cell maturation by inducing type I interferons (IFNs) and enhances antigen-specific T helper 1 (Th1) responses in a type I IFN receptor-dependent manner. The induction of type I IFNs, IFN-stimulated genes and dendritic cell maturation by chitosan required the cytoplasmic DNA sensor cGAS and STING, implicating this pathway in dendritic cell activation...
March 15, 2016: Immunity
Song Liu, Min Feng, Wenxian Guan
Recent studies have revealed the diverse pathophysiological functions of mitochondria beyond traditional energetic metabolism in cells. Mitochondria-released damage-associated molecular patterns, particularly mitochondrial deoxyribonucleic acid (mtDNA), play a central role in host immune defenses against foreign pathogens. Newly discovered cGAS-STING signaling is responsible for microbial DNA recognition, and potentially participates in mitochondrial DNA sensing. Inappropriate inflammatory signaling mediated by mtDNA is implicated in various human diseases, especially infectious/inflammatory disease and cancer...
August 15, 2016: International Journal of Cancer. Journal International du Cancer
Thirumala-Devi Kanneganti, Mondira Kundu, Douglas R Green
In addition to their roles in cellular metabolism and apoptosis, mitochondria function as signaling platforms in the innate immune response. In Nature, West et al. (2015) demonstrate that mitochondrial stress triggers a type I interferon response and confers viral resistance via release of mtDNA and activation of the cGAS-STING pathway.
June 2, 2015: Cell Metabolism
A Phillip West, William Khoury-Hanold, Matthew Staron, Michal C Tal, Cristiana M Pineda, Sabine M Lang, Megan Bestwick, Brett A Duguay, Nuno Raimundo, Donna A MacDuff, Susan M Kaech, James R Smiley, Robert E Means, Akiko Iwasaki, Gerald S Shadel
Mitochondrial DNA (mtDNA) is normally present at thousands of copies per cell and is packaged into several hundred higher-order structures termed nucleoids. The abundant mtDNA-binding protein TFAM (transcription factor A, mitochondrial) regulates nucleoid architecture, abundance and segregation. Complete mtDNA depletion profoundly impairs oxidative phosphorylation, triggering calcium-dependent stress signalling and adaptive metabolic responses. However, the cellular responses to mtDNA instability, a physiologically relevant stress observed in many human diseases and ageing, remain poorly defined...
April 23, 2015: Nature
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
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)...
December 18, 2014: Cell
Michael J White, Kate McArthur, Donald Metcalf, Rachael M Lane, John C Cambier, Marco J Herold, Mark F van Delft, Sammy Bedoui, Guillaume Lessene, Matthew E Ritchie, David C S Huang, Benjamin T Kile
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...
December 18, 2014: Cell
Ming Zeng, Zeping Hu, Xiaolei Shi, Xiaohong Li, Xiaoming Zhan, Xiao-Dong Li, Jianhui Wang, Jin Huk Choi, Kuan-wen Wang, Tiana Purrington, Miao Tang, Maggy Fina, Ralph J DeBerardinis, Eva Marie Y Moresco, Gabriel Pedersen, Gerald M McInerney, Gunilla B Karlsson Hedestam, Zhijian J Chen, Bruce Beutler
Multivalent molecules with repetitive structures including bacterial capsular polysaccharides and viral capsids elicit antibody responses through B cell receptor (BCR) crosslinking in the absence of T cell help. We report that immunization with these T cell-independent type 2 (TI-2) antigens causes up-regulation of endogenous retrovirus (ERV) RNAs in antigen-specific mouse B cells. These RNAs are detected via a mitochondrial antiviral signaling protein (MAVS)-dependent RNA sensing pathway or reverse-transcribed and detected via the cGAS-cGAMP-STING pathway, triggering a second, sustained wave of signaling that promotes specific immunoglobulin M production...
December 19, 2014: Science
Takayuki Suzuki, Hiroyuki Oshiumi, Moeko Miyashita, Hussein Hassan Aly, Misako Matsumoto, Tsukasa Seya
Cytoplasmic viral RNA and DNA are recognized by RIG-I-like receptors and DNA sensors that include DAI, IFI16, DDX41, and cGAS. The RNA and DNA sensors evoke innate immune responses through the IPS-1 and STING adaptors. IPS-1 and STING activate TBK1 kinase. TBK1 is phosphorylated in its activation loop, leading to IRF3/7 activation and Type I interferon (IFN) production. IPS-1 and STING localize to the mitochondria and endoplasmic reticulum, respectively, whereas it is unclear where phosphorylated TBK1 is localized in response to cytoplasmic viral DNA...
2013: PloS One
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