Cyclic GMP-AMP Synthase Is a Cytosolic DNA Sensor That Activates the Type I Interferon Pathway

Sun, Lijun; Wu, Jiaxi; Du, Fenghe; Chen, Xiang; Chen, Zhijian J.

doi:10.1126/science.1232458

Cited by 3,336 publications

(3,095 citation statements)

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“…Finally, the fact that both dsDNA (Sun et al , 2013; Gao et al , 2013) and RNA:DNA hybrids (Mankan et al , 2014) can bind and activate the cytoplasmic nucleic acid sensor cGAS prompted us to consider the origin of the cGAS ligand present in RNase H2‐deficient cells. Abrogated RNase H2 function could give rise to cytosolic accumulation of RNA:DNA heteroduplexes as a consequence of reduced RNA:DNA degradation of structures such as R‐loops or active retroelements/endogenous retroviruses (Chon et al , 2013; Rigby et al , 2014; Moelling & Broecker, 2015).…”

Section: Resultsmentioning

confidence: 99%

Ribonuclease H2 mutations induce a cGAS/STING‐dependent innate immune response

et al. 2016

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Aicardi–Goutières syndrome (AGS) provides a monogenic model of nucleic acid‐mediated inflammation relevant to the pathogenesis of systemic autoimmunity. Mutations that impair ribonuclease (RNase) H2 enzyme function are the most frequent cause of this autoinflammatory disorder of childhood and are also associated with systemic lupus erythematosus. Reduced processing of either RNA:DNA hybrid or genome‐embedded ribonucleotide substrates is thought to lead to activation of a yet undefined nucleic acid‐sensing pathway. Here, we establish Rnaseh2b A174T/A174T knock‐in mice as a subclinical model of disease, identifying significant interferon‐stimulated gene (ISG) transcript upregulation that recapitulates the ISG signature seen in AGS patients. The inflammatory response is dependent on the nucleic acid sensor cyclic GMP‐AMP synthase (cGAS) and its adaptor STING and is associated with reduced cellular ribonucleotide excision repair activity and increased DNA damage. This suggests that cGAS/STING is a key nucleic acid‐sensing pathway relevant to AGS, providing additional insight into disease pathogenesis relevant to the development of therapeutics for this childhood‐onset interferonopathy and adult systemic autoimmune disorders.

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Section: Resultsmentioning

confidence: 99%

Ribonuclease H2 mutations induce a cGAS/STING‐dependent innate immune response

et al. 2016

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“…3d–f). Cyclic GMP-AMP synthase (cGAS) can sense cytosolic DNA and produce cyclic GMP-AMP (cGAMP), which subsequently activates STING, leading to induction of type I IFNs 22 . Additional studies in cGAS −/− mice showed CTL response was partially dependent on cGAS.…”

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confidence: 99%

A STING-activating nanovaccine for cancer immunotherapy

et al. 2017

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Generation of tumor-specific T cells is critically important for cancer immunotherapy1,2. A major challenge in achieving a robust T cell response is the spatio-temporal orchestration of antigen cross-presentation in antigen presenting cells (APCs) with innate stimulation. Here we report a minimalist nanovaccine by a simple physical mixture of an antigen with a synthetic polymeric nanoparticle, PC7A NP, which generated a strong cytotoxic T cell response with low systemic cytokine expression. Mechanistically, PC7A NP achieved efficient cytosolic delivery of tumor antigens to APCs in draining lymph nodes leading to increased surface presentation while simultaneously activating type I interferon-stimulated genes. This effect was dependent on STING but not Toll-like receptor or MAVS pathway. Nanovaccine produced potent tumor growth inhibition in melanoma, colon cancer, and human papilloma virus-E6/E7 tumor models. Combination of PC7A nanovaccine with an anti-PD-1 antibody showed great synergy with 100% survival over 60 days in a TC-1 tumor model. Rechallenging of these tumor-free animals with TC-1 cells led to complete inhibition of tumor growth, suggesting generation of long-term antitumor memory. The STING-activating nanovaccine offers a simple, safe and robust strategy in boosting anti-tumor immunity for cancer immunotherapy.

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“…Intracellular dsDNA arising during viral or bacterial infection constitutes a very potent danger signal that stimulates innate immune responses characterized by the production of proinflammatory cytokines and type I IFNs (1). Cyclic GMP-AMP synthase (cGAS) has been identified as a cytosolic DNA receptor responsible for the induction of an antiviral and proinflammatory gene expression profile (2)(3)(4). Upon dsDNA binding, cGAS catalyzes the production of the second messenger molecule cGAMP(29-59), a unique cyclic dinucleotide molecule containing one 29-59 phosphodiester linkage in addition to a canonical 39-59 linkage (5)(6)(7)(8).…”

mentioning

confidence: 99%

TREX1 Deficiency Triggers Cell-Autonomous Immunity in a cGAS-Dependent Manner

Ablasser

Hemmerling

Schmid-Burgk

et al. 2014

The Journal of Immunology

211

142

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Cytosolic detection of DNA is crucial for the initiation of antiviral immunity but can also cause autoimmunity in the context of endogenous nucleic acids being sensed. Mutations in the human 3′ repair exonuclease 1 (TREX1) have been linked to the type I IFN–associated autoimmune disease Aicardi–Goutières syndrome. The exact mechanisms driving unabated type I IFN responses in the absence of TREX1 are only partly understood, but it appears likely that accumulation of endogenous DNA species triggers a cell-autonomous immune response by activating a cytosolic DNA receptor. In this article, we demonstrate that knocking out the DNA sensor cyclic GMP–AMP synthase completely abrogates spontaneous induction of IFN-stimulated genes in TREX1-deficient cells. These findings indicate a key role of cyclic GMP–AMP synthase for the initiation of self-DNA–induced autoimmune disorders, thus providing important implications for novel therapeutic approaches.

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Cyclic GMP-AMP Synthase Is a Cytosolic DNA Sensor That Activates the Type I Interferon Pathway

Cited by 3,336 publications

References 23 publications

Ribonuclease H2 mutations induce a cGAS/STING‐dependent innate immune response

Ribonuclease H2 mutations induce a cGAS/STING‐dependent innate immune response

A STING-activating nanovaccine for cancer immunotherapy

TREX1 Deficiency Triggers Cell-Autonomous Immunity in a cGAS-Dependent Manner

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