Blog
About

1
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: not found

      STING: infection, inflammation and cancer

      Nature Reviews. Immunology

      Nature Publishing Group UK

      Innate immunity, Infection, Inflammatory diseases, Cytokines

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Key Points

          • Stimulator of interferon genes (STING) is activated by binding to cyclic dinucleotides (CDNs), which results in potent cytokine production. CDNs are produced by certain intracellular bacteria and are generated by the cyclic GMP–AMP synthase (cGAS) following binding to cytosolic DNA species, such as viral DNA.

          • STING-inducible innate immune molecules are essential for protection of the host against pathogens and are important for the stimulation of adaptive immunity.

          • Self-DNA, for example from the nucleus or mitochondria, can leak into the cytosolic compartment and stimulate STING activity to cause autoinflammatory disease. Certain mutations in the gene encoding STING can cause the protein to become permanently active and similarly induce autoinflammatory responses.

          • STING can be activated in phagocytes by DNA released from engulfed tumour cells and drive the production of cytokines necessary for generating robust antitumour T cell responses.

          • DNA-damaging agents can cause the release of nuclear DNA into the cytosol that stimulates STING-dependent cytokine production and phagocyte infiltration. This may be essential for eliminating damaged cells and generating antitumour T cell responses, but chronic stimulation may also promote inflammation-aggravated cancer.

          • STING agonists exert potent antitumour activity and may be effective, novel adjuvants in vaccine formulations. In contrast, inhibitors of STING signalling may be beneficial for the treatment of autoinflammatory disease, such as systemic lupus erythematosus (SLE), Aicardi–Goutières syndrome (AGS) and STING-associated vasculopathy with onset in infancy (SAVI).

          Supplementary information

          The online version of this article (doi:10.1038/nri3921) contains supplementary material, which is available to authorized users.

          Abstract

          Activation of STING (stimulator of interferon genes) by cytosolic aberrant DNA species or cyclic dinucleotides triggers transcription of numerous innate immune genes. In this Review, the author summarizes recent insights into the regulation of STING signalling and its role in autoinflammatory disease and cancer.

          Supplementary information

          The online version of this article (doi:10.1038/nri3921) contains supplementary material, which is available to authorized users.

          Abstract

          The rapid detection of microbial agents is essential for the effective initiation of host defence mechanisms against infection. Understanding how cells detect cytosolic DNA to trigger innate immune gene transcription has important implications — not only for comprehending the immune response to pathogens but also for elucidating the causes of autoinflammatory disease involving the sensing of self-DNA and the generation of effective antitumour adaptive immunity. The discovery of the STING (stimulator of interferon genes)-controlled innate immune pathway, which mediates cytosolic DNA-induced signalling events, has recently provided important insights into these processes, opening the way for the development of novel immunization regimes, as well as therapies to treat autoinflammatory disease and cancer.

          Supplementary information

          The online version of this article (doi:10.1038/nri3921) contains supplementary material, which is available to authorized users.

          Related collections

          Most cited references 104

          • Record: found
          • Abstract: found
          • Article: not found

          Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway.

          The presence of DNA in the cytoplasm of mammalian cells is a danger signal that triggers host immune responses such as the production of type I interferons. Cytosolic DNA induces interferons through the production of cyclic guanosine monophosphate-adenosine monophosphate (cyclic GMP-AMP, or cGAMP), which binds to and activates the adaptor protein STING. Through biochemical fractionation and quantitative mass spectrometry, we identified a cGAMP synthase (cGAS), which belongs to the nucleotidyltransferase family. Overexpression of cGAS activated the transcription factor IRF3 and induced interferon-β in a STING-dependent manner. Knockdown of cGAS inhibited IRF3 activation and interferon-β induction by DNA transfection or DNA virus infection. cGAS bound to DNA in the cytoplasm and catalyzed cGAMP synthesis. These results indicate that cGAS is a cytosolic DNA sensor that induces interferons by producing the second messenger cGAMP.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Innate and adaptive immune cells in the tumor microenvironment.

            Most tumor cells express antigens that can mediate recognition by host CD8(+) T cells. Cancers that are detected clinically must have evaded antitumor immune responses to grow progressively. Recent work has suggested two broad categories of tumor escape based on cellular and molecular characteristics of the tumor microenvironment. One major subset shows a T cell-inflamed phenotype consisting of infiltrating T cells, a broad chemokine profile and a type I interferon signature indicative of innate immune activation. These tumors appear to resist immune attack through the dominant inhibitory effects of immune system-suppressive pathways. The other major phenotype lacks this T cell-inflamed phenotype and appears to resist immune attack through immune system exclusion or ignorance. These two major phenotypes of tumor microenvironment may require distinct immunotherapeutic interventions for maximal therapeutic effect.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              STING an Endoplasmic Reticulum Adaptor that Facilitates Innate Immune Signaling

              We report here the identification, following expression cloning, of a molecule, STING (STimulator of INterferon Genes) that regulates innate immune signaling processes. STING, comprising 5 putative transmembrane (TM) regions, predominantly resides in the endoplasmic reticulum (ER) and is able to activate both NF-κB and IRF3 transcription pathways to induce type I IFN and exert a potent anti-viral state following expression. In contrast, loss of STING rendered murine embryonic fibroblasts (STING −/−MEFs) extremely susceptible to negative-stranded virus infection, including vesicular stomatitis virus, VSV. Further, STING ablation abrogated the ability of intracellular B-form DNA, as well as members of the herpes virus family, to induce IFNβ, but did not significantly affect the Toll-like receptor (TLR pathway). Yeast-two hybrid and co-immunprecipitation studies indicated that STING interacts with RIG-I and with Ssr2/TRAPβ, a member of the translocon-associated protein (TRAP) complex required for protein translocation across the ER membrane following translation[1, 2]. RNAi ablation of TRAPβ and translocon adaptor Sec61β was subsequently found to inhibit STING’s ability to stimulate IFNβ. Thus, aside from identifying a novel regulator of innate immune signaling, this data implicates for the first time a potential role for the translocon in innate signaling pathways activated by select viruses as well as intracellular DNA.
                Bookmark

                Author and article information

                Contributors
                gbarber@med.miami.edu
                Journal
                Nat Rev Immunol
                Nat. Rev. Immunol
                Nature Reviews. Immunology
                Nature Publishing Group UK (London )
                1474-1733
                1474-1741
                25 November 2015
                2015
                : 15
                : 12
                : 760-770
                Affiliations
                GRID grid.26790.3a, ISNI 0000 0004 1936 8606, Department of Cell Biology and Sylvester Comprehensive Cancer Center, , University of Miami School of Medicine, ; Miami, 33136 Florida USA
                Article
                BFnri3921
                10.1038/nri3921
                5004891
                26603901
                © Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved. 2015

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                Categories
                Article
                Custom metadata
                © Springer Nature Limited 2015

                Comments

                Comment on this article