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      Beyond DNA sensing: expanding the role of cGAS/STING in immunity and diseases

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          Abstract

          Cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) synthase (cGAS) is a DNA sensor that elicits a robust type I interferon response by recognizing ubiquitous danger-associated molecules. The cGAS/stimulator of interferon genes (cGAS/STING) is activated by endogenous DNA, including DNA released from mitochondria and extranuclear chromatin, as well as exogenous DNA derived from pathogenic microorganisms. cGAS/STING is positioned as a key axis of autoimmunity, the inflammatory response, and cancer progression, suggesting that the cGAS/STING signaling pathway represents an efficient therapeutic target. Based on the accumulated evidence, we present insights into the prevention and treatment of cGAS/STING-related chronic immune and inflammatory diseases. This review presents the current state of clinical and nonclinical development of modulators targeting cGAS/STING, providing useful information on the design of therapeutic strategies.

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

          Zhijian Chen, Lijun Sun, Jiaxi Wu … (2013)
          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.
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            STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors.

            Seng-Ryong Woo, Mercedes Fuertes, Leticia Corrales … (2014)
            Spontaneous T cell responses against tumors occur frequently and have prognostic value in patients. The mechanism of innate immune sensing of immunogenic tumors leading to adaptive T cell responses remains undefined, although type I interferons (IFNs) are implicated in this process. We found that spontaneous CD8(+) T cell priming against tumors was defective in mice lacking stimulator of interferon genes complex (STING), but not other innate signaling pathways, suggesting involvement of a cytosolic DNA sensing pathway. In vitro, IFN-? production and dendritic cell activation were triggered by tumor-cell-derived DNA, via cyclic-GMP-AMP synthase (cGAS), STING, and interferon regulatory factor 3 (IRF3). In the tumor microenvironment in vivo, tumor cell DNA was detected within host antigen-presenting cells, which correlated with STING pathway activation and IFN-? production. Our results demonstrate that a major mechanism for innate immune sensing of cancer occurs via the host STING pathway, with major implications for cancer immunotherapy. Copyright © 2014 Elsevier Inc. All rights reserved.
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              Idiopathic pulmonary fibrosis.

              Luca Richeldi, Harold Collard, Mark G. Jones (2017)
              Idiopathic pulmonary fibrosis is a prototype of chronic, progressive, and fibrotic lung disease. Healthy tissue is replaced by altered extracellular matrix and alveolar architecture is destroyed, which leads to decreased lung compliance, disrupted gas exchange, and ultimately respiratory failure and death. In less than a decade, understanding of the pathogenesis and management of this disease has been transformed, and two disease-modifying therapies have been approved, worldwide. In this Seminar, we summarise the presentation, pathophysiology, diagnosis, and treatment options available for patients with idiopathic pulmonary fibrosis. This disease has improved understanding of the mechanisms of lung fibrosis, and offers hope that similar approaches will transform the management of patients with other progressive fibrotic lung diseases.
              Article 0 comments Cited 711 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Joo Young Lee:
                ORCID: http://orcid.org/0000-0002-6020-3040
                joolee@catholic.ac.kr
                Journal
                Journal ID (nlm-ta): Arch Pharm Res
                Journal ID (iso-abbrev): Arch Pharm Res
                Title: Archives of Pharmacal Research
                Publisher: Pharmaceutical Society of Korea (Seoul )
                ISSN (Print): 0253-6269
                ISSN (Electronic): 1976-3786
                Publication date (Electronic): 24 June 2023
                Publication date PMC-release: 24 June 2023
                Publication date (Print): 2023
                Volume: 46
                Issue: 6
                Pages: 500-534
                Affiliations
                GRID grid.411947.e, ISNI 0000 0004 0470 4224, College of Pharmacy, , The Catholic University of Korea, ; Bucheon, 14662 Republic of Korea
                Author information
                http://orcid.org/0000-0002-6020-3040
                Article
                Publisher ID: 1452
                DOI: 10.1007/s12272-023-01452-3
                PMC ID: 10333371
                PubMed ID: 37354378
                SO-VID: 15c83035-b099-4d5c-bff3-cf8077f59cc0
                Copyright © © The Author(s) 2023
                License:

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                Date received : 23 April 2023
                Date accepted : 13 June 2023
                Funding
                Funded by: National Research Foundation of Korea
                Award ID: NRF‐2019R1A2C2085739
                Award ID: No. 2022M3E5F1017414
                Award Recipient :
                Categories
                Subject: Review
                Custom metadata
                issue-copyright-statement © The Pharmaceutical Society of Korea 2023

                Keywords: cgas,sting,dna, immunity,inflammation,cancer
                Data availability:
                Keywords: cgas, sting, dna, immunity, inflammation, cancer

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