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      Targeting STING with covalent small-molecule inhibitors

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          Cyclic GMP-AMP containing mixed phosphodiester linkages is an endogenous high-affinity ligand for STING.

          The presence of microbial or self DNA in the cytoplasm of mammalian cells is a danger signal detected by the DNA sensor cyclic-GMP-AMP (cGAMP) synthase (cGAS), which catalyzes the production of cGAMP that in turn serves as a second messenger to activate innate immune responses. Here we show that endogenous cGAMP in mammalian cells contains two distinct phosphodiester linkages, one between 2'-OH of GMP and 5'-phosphate of AMP, and the other between 3'-OH of AMP and 5'-phosphate of GMP. This molecule, termed 2'3'-cGAMP, is unique in that it binds to the adaptor protein STING with a much greater affinity than cGAMP molecules containing other combinations of phosphodiester linkages. The crystal structure of STING bound to 2'3'-cGAMP revealed the structural basis of this high-affinity binding and a ligand-induced conformational change in STING that may underlie its activation. Copyright © 2013 Elsevier Inc. All rights reserved.
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            Atg9a controls dsDNA-driven dynamic translocation of STING and the innate immune response.

            Microbial nucleic acids are critical for the induction of innate immune responses, a host defense mechanism against infection by microbes. Recent studies have indicated that double-stranded DNA (dsDNA) induces potent innate immune responses via the induction of type I IFN (IFN) and IFN-inducible genes. However, the regulatory mechanisms underlying dsDNA-triggered signaling are not fully understood. Here we show that the translocation and assembly of the essential signal transducers, stimulator of IFN genes (STING) and TANK-binding kinase 1 (TBK1), are required for dsDNA-triggered innate immune responses. After sensing dsDNA, STING moves from the endoplasmic reticulum (ER) to the Golgi apparatus and finally reaches the cytoplasmic punctate structures to assemble with TBK1. The addition of an ER-retention signal to the C terminus of STING dampens its ability to induce antiviral responses. We also show that STING co-localizes with the autophagy proteins, microtubule-associated protein 1 light chain 3 (LC3) and autophagy-related gene 9a (Atg9a), after dsDNA stimulation. The loss of Atg9a, but not that of another autophagy-related gene (Atg7), greatly enhances the assembly of STING and TBK1 by dsDNA, leading to aberrant activation of the innate immune response. Hence Atg9a functions as a regulator of innate immunity following dsDNA stimulation as well as an essential autophagy protein. These results demonstrate that dynamic membrane traffic mediates the sequential translocation and assembly of STING, both of which are essential processes required for maximal activation of the innate immune response triggered by dsDNA.
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              IRF3 and Type I Interferons Fuel a Fatal Response to Myocardial Infarction

              Interferon regulatory factor 3 (IRF3) and type I interferons (IFNs) protect against infections 1 and cancer 2 , but excessive IRF3 activation and type I IFN production cause auto-inflammatory conditions such as Aicardi Goutieres Syndrome 3,4 and STING-associated vasculopathy of infancy (SAVI) 3 . Myocardial infarction (MI) elicits inflammation 5 , but the dominant molecular drivers of MI-associated inflammation remain unclear. Here, we show that ischemic cell death in the heart fuels a fatal response to myocardial infarction by activating IRF3 and type I IFN production. In mice, single cell RNA-Seq analysis of 4,215 leukocytes isolated from infarcted and non-infarcted hearts revealed that MI provokes activation of an IRF3-interferon axis in a distinct population of interferon inducible cells (IFNICs that were classified as cardiac macrophages). Mice genetically deficient in cGAS, its adaptor STING, IRF3, or the type I interferon receptor IFNAR exhibited impaired interferon stimulated gene (ISG) expression and, in the case of mice deficient in IRF3 or IFNAR, improved survival after MI as compared to controls. Interruption of IRF3-dependent signaling resulted in decreased cardiac expression of inflammatory cytokines and chemokines and decreased cardiac inflammatory cell infiltration, as well as in attenuated ventricular dilation and improved cardiac function. Similarly, treatment of mice with an IFNAR neutralizing antibody after MI ablated the IFN response and improved left ventricular dysfunction and survival. These results identify IRF3 and the type I interferon response as a potential therapeutic target for post-MI cardioprotection.
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                Author and article information

                Journal
                Nature
                Nature
                Springer Nature
                0028-0836
                1476-4687
                July 4 2018
                Article
                10.1038/s41586-018-0287-8
                29973723
                02d1894e-6b12-41a5-96e4-b4c483b3bd0e
                © 2018

                http://www.springer.com/tdm

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