The recognition of microbial nucleic acids is a major mechanism by which the immune system detects pathogens. Cyclic GMP-AMP (cGAMP) synthase (cGAS) is a cytosolic DNA sensor that activates innate immune responses through production of the second messenger cGAMP, which activates the adaptor STING. The cGAS–STING pathway not only mediates protective immune defense against infection by a large variety of DNA-containing pathogens but also detects tumor-derived DNA and generates intrinsic antitumor immunity. However, aberrant activation of the cGAS pathway by self DNA can also lead to autoimmune and inflammatory disease. Thus, the cGAS pathway must be properly regulated. Here we review the recent advances in understanding of the cGAS–STING pathway, focusing on the regulatory mechanisms and roles of this pathway in heath and disease.
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Pandey, S., Kawai, T. & Akira, S. Microbial sensing by Toll-like receptors and intracellular nucleic acid sensors. Cold Spring Harb. Perspect. Biol. 7, a016246 (2014).
Broz, P. & Dixit, V.M. Inflammasomes: mechanism of assembly, regulation and signalling. Nat. Rev. Immunol. 16, 407–420 (2016).
Yoneyama, M., Onomoto, K., Jogi, M., Akaboshi, T. & Fujita, T. Viral RNA detection by RIG-I-like receptors. Curr. Opin. Immunol. 32, 48–53 (2015).
Cai, X., Chiu, Y.H. & Chen, Z.J. The cGAS-cGAMP-STING pathway of cytosolic DNA sensing and signaling. Mol. Cell 54, 289–296 (2014).
Land, W.G. Innate Alloimmunity, Part 1: Innate Immunity and Host Defense (Pabst Science Publishers, 2011).
Sun, L., Wu, J., Du, F., Chen, X. & Chen, Z.J. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science 339, 786–791 (2013).
Zhang, X. et al. The cytosolic DNA sensor cGAS forms an oligomeric complex with DNA and undergoes switch-like conformational changes in the activation loop. Cell Rep. 6, 421–430 (2014).
Li, X. et al. Cyclic GMP-AMP synthase is activated by double-stranded DNA-induced oligomerization. Immunity 39, 1019–1031 (2013).
Kranzusch, P.J., Lee, A.S., Berger, J.M. & Doudna, J.A. Structure of human cGAS reveals a conserved family of second-messenger enzymes in innate immunity. Cell Reports 3, 1362–1368 (2013).
Gao, P. et al. Cyclic [G(2′,5′)pA(3′,5′)p] is the metazoan second messenger produced by DNA-activated cyclic GMP-AMP synthase. Cell 153, 1094–1107 (2013).
Civril, F. et al. Structural mechanism of cytosolic DNA sensing by cGAS. Nature 498, 332–337 (2013).
Wu, J. et al. Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA. Science 339, 826–830 (2013).
Zhang, X. et al. Cyclic GMP-AMP containing mixed phosphodiester linkages is an endogenous high-affinity ligand for STING. Mol. Cell 51, 226–235 (2013).
Diner, E.J. et al. The innate immune DNA sensor cGAS produces a noncanonical cyclic dinucleotide that activates human STING. Cell Reports 3, 1355–1361 (2013).
Ablasser, A. et al. cGAS produces a 2′-5′-linked cyclic dinucleotide second messenger that activates STING. Nature 498, 380–384 (2013).
Ishikawa, H. & Barber, G.N. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature 455, 674–678 (2008).
Zhong, B. et al. The adaptor protein MITA links virus-sensing receptors to IRF3 transcription factor activation. Immunity 29, 538–550 (2008).
Saitoh, T. et al. Atg9a controls dsDNA-driven dynamic translocation of STING and the innate immune response. Proc. Natl. Acad. Sci. USA 106, 20842–20846 (2009).
Ishikawa, H., Ma, Z. & Barber, G.N. STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature 461, 788–792 (2009).
Dobbs, N. et al. STING activation by translocation from the ER is associated with infection and autoinflammatory disease. Cell Host Microbe 18, 157–168 (2015).
Tanaka, Y. & Chen, Z.J. STING specifies IRF3 phosphorylation by TBK1 in the cytosolic DNA signaling pathway. Sci. Signal. 5, ra20 (2012).
Fitzgerald, K.A. et al. IKKe and TBK1 are essential components of the IRF3 signaling pathway. Nat. Immunol. 4, 491–496 (2003).
Sharma, S. et al. Triggering the interferon antiviral response through an IKK-related pathway. Science 300, 1148–1151 (2003).
Herzner, A.-M. et al. Sequence-specific activation of the DNA sensor cGAS by Y-form DNA structures as found in primary HIV-1 cDNA. Nat. Immunol. 16, 1025–1033 (2015).
Gehrke, N. et al. Oxidative damage of DNA confers resistance to cytosolic nuclease TREX1 degradation and potentiates STING-dependent immune sensing. Immunity 39, 482–495 (2013).
Seo, G.J. et al. Akt kinase-mediated checkpoint of cGAS DNA sensing pathway. Cell Rep. 13, 440–449 (2015).
Xia, P. et al. Glutamylation of the DNA sensor cGAS regulates its binding and synthase activity in antiviral immunity. Nat. Immunol. 17, 369–378 (2016).
Schoggins, J.W. et al. A diverse range of gene products are effectors of the type I interferon antiviral response. Nature 472, 481–485 (2011).
Ma, F. et al. Positive feedback regulation of type I IFN production by the IFN-inducible DNA sensor cGAS. J. Immunol. 194, 1545–1554 (2015).
Chiu, Y.H., Macmillan, J.B. & Chen, Z.J. RNA polymerase III detects cytosolic DNA and induces type I interferons through the RIG-I pathway. Cell 138, 576–591 (2009).
Xia, T., Konno, H., Ahn, J. & Barber, G.N. Deregulation of STING signaling in colorectal carcinoma constrains DNA damage responses and correlates with tumorigenesis. Cell Rep. 14, 282–297 (2016).
Thomsen, M.K. et al. Lack of immunological DNA sensing in hepatocytes facilitates hepatitis B virus infection. Hepatology 64, 746–759 (2016).
Berg, R.K. et al. T cells detect intracellular DNA but fail to induce type I IFN responses: implications for restriction of HIV replication. PLoS One 9, e84513 (2014).
Li, L. et al. Hydrolysis of 2′3′-cGAMP by ENPP1 and design of nonhydrolyzable analogs. Nat. Chem. Biol. 10, 1043–1048 (2014).
Ablasser, A. et al. Cell intrinsic immunity spreads to bystander cells via the intercellular transfer of cGAMP. Nature 503, 530–534 (2013).
Gentili, M. et al. Transmission of innate immune signaling by packaging of cGAMP in viral particles. Science 349, 1232–1236 (2015).
Bridgeman, A. et al. Viruses transfer the antiviral second messenger cGAMP between cells. Science 349, 1228–1232 (2015).
Gao, P. et al. Structure-function analysis of STING activation by c[G(2′,5′)pA(3′,5′)p] and targeting by antiviral DMXAA. Cell 154, 748–762 (2013).
Yin, Q. et al. Cyclic di-GMP sensing via the innate immune signaling protein STING. Mol. Cell 46, 735–745 (2012).
Shu, C., Yi, G., Watts, T., Kao, C.C. & Li, P. Structure of STING bound to cyclic di-GMP reveals the mechanism of cyclic dinucleotide recognition by the immune system. Nat. Struct. Mol. Biol. 19, 722–724 (2012).
Shang, G. et al. Crystal structures of STING protein reveal basis for recognition of cyclic di-GMP. Nat. Struct. Mol. Biol. 19, 725–727 (2012).
Ouyang, S. et al. Structural analysis of the STING adaptor protein reveals a hydrophobic dimer interface and mode of cyclic di-GMP binding. Immunity 36, 1073–1086 (2012).
Tsuchiya, Y., Jounai, N., Takeshita, F., Ishii, K.J. & Mizuguchi, K. Ligand-induced ordering of the C-terminal tail primes STING for phosphorylation by TBK1. EBioMedicine 9, 87–96 (2016).
Shi, H., Wu, J., Chen, Z.J. & Chen, C. Molecular basis for the specific recognition of the metazoan cyclic GMP-AMP by the innate immune adaptor protein STING. Proc. Natl. Acad. Sci. USA 112, 8947–8952 (2015).
Kim, S. et al. Anticancer flavonoids are mouse-selective STING agonists. ACS Chem. Biol. 8, 1396–1401 (2013).
Conlon, J. et al. Mouse, but not human STING, binds and signals in response to the vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid. J. Immunol. 190, 5216–5225 (2013).
Cavlar, T., Deimling, T., Ablasser, A., Hopfner, K.P. & Hornung, V. Species-specific detection of the antiviral small-molecule compound CMA by STING. EMBO J. 32, 1440–1450 (2013).
Liu, S. et al. Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation. Science 347, aaa2630 (2015).
Konno, H., Konno, K. & Barber, G.N. Cyclic dinucleotides trigger ULK1 (ATG1) phosphorylation of STING to prevent sustained innate immune signaling. Cell 155, 688–698 (2013).
Zhang, J., Hu, M.M., Wang, Y.Y. & Shu, H.B. TRIM32 protein modulates type I interferon induction and cellular antiviral response by targeting MITA/STING protein for K63-linked ubiquitination. J. Biol. Chem. 287, 28646–28655 (2012).
Tsuchida, T. et al. The ubiquitin ligase TRIM56 regulates innate immune responses to intracellular double-stranded DNA. Immunity 33, 765–776 (2010).
Wang, Q. et al. The E3 ubiquitin ligase AMFR and INSIG1 bridge the activation of TBK1 kinase by modifying the adaptor STING. Immunity 41, 919–933 (2014).
Zhong, B. et al. The ubiquitin ligase RNF5 regulates antiviral responses by mediating degradation of the adaptor protein MITA. Immunity 30, 397–407 (2009).
Wang, Y. et al. TRIM30a Is a negative-feedback regulator of the intracellular DNA and DNA virus-triggered response by targeting STING. PLoS Pathog. 11, e1005012 (2015).
Mukai, K. et al. Activation of STING requires palmitoylation at the Golgi. Nat. Commun. 7, 11932 (2016).
Paludan, S.R. & Bowie, A.G. Immune sensing of DNA. Immunity 38, 870–880 (2013).
Ishii, K.J. et al. TANK-binding kinase-1 delineates innate and adaptive immune responses to DNA vaccines. Nature 451, 725–729 (2008).
Gray, E.E. et al. The AIM2-like receptors are dispensable for the interferon response to intracellular DNA. Immunity 45, 255–266 (2016).
Yoh, S.M. et al. PQBP1 is a proximal sensor of the cGAS-dependent innate response to HIV-1. Cell 161, 1293–1305 (2015).
Liang, Q. et al. Crosstalk between the cGAS DNA sensor and Beclin-1 autophagy protein shapes innate antimicrobial immune responses. Cell Host Microbe 15, 228–238 (2014).
Paijo, J. et al. cGAS senses human cytomegalovirus and induces type I interferon responses in human monocyte-derived cells. PLoS Pathog. 12, e1005546 (2016).
Lio, C.W. et al. cGAS-STING signaling regulates initial innate control of cytomegalovirus infection. J. Virol. 90, 7789–7797 (2016).
Zhang, G. et al. Cytoplasmic isoforms of Kaposi sarcoma herpesvirus LANA recruit and antagonize the innate immune DNA sensor cGAS. Proc. Natl. Acad. Sci. USA 113, E1034–E1043 (2016).
Wu, J.J. et al. Inhibition of cGAS DNA sensing by a herpesvirus virion protein. Cell Host Microbe 18, 333–344 (2015).
Ma, Z. et al. Modulation of the cGAS-STING DNA sensing pathway by gammaherpesviruses. Proc. Natl. Acad. Sci. USA 112, E4306–E4315 (2015).
Li, X.D. et al. Pivotal roles of cGAS-cGAMP signaling in antiviral defense and immune adjuvant effects. Science 341, 1390–1394 (2013).
Schoggins, J.W. et al. Pan-viral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity. Nature 505, 691–695 (2014).
Holm, C.K. et al. Virus-cell fusion as a trigger of innate immunity dependent on the adaptor STING. Nat. Immunol. 13, 737–743 (2012).
Rasaiyaah, J. et al. HIV-1 evades innate immune recognition through specific cofactor recruitment. Nature 503, 402–405 (2013).
Lahaye, X. et al. The capsids of HIV-1 and HIV-2 determine immune detection of the viral cDNA by the innate sensor cGAS in dendritic cells. Immunity 39, 1132–1142 (2013).
Gao, D. et al. Cyclic GMP-AMP synthase is an innate immune sensor of HIV and other retroviruses. Science 341, 903–906 (2013).
Zeng, M. et al. MAVS, cGAS, and endogenous retroviruses in T-independent B cell responses. Science 346, 1486–1492 (2014).
Portnoy, D.A., Auerbuch, V. & Glomski, I.J. The cell biology of Listeria monocytogenes infection: the intersection of bacterial pathogenesis and cell-mediated immunity. J. Cell Biol. 158, 409–414 (2002).
Watson, R.O. et al. The cytosolic sensor cGAS detects Mycobacterium tuberculosis DNA to induce type I interferons and activate autophagy. Cell Host Microbe 17, 811–819 (2015).
Wassermann, R. et al. Mycobacterium tuberculosis differentially activates cGAS- and inflammasome-dependent intracellular immune responses through ESX-1. Cell Host Microbe 17, 799–810 (2015).
Collins, A.C. et al. Cyclic GMP-AMP synthase is an innate immune DNA sensor for Mycobacterium tuberculosis. Cell Host Microbe 17, 820–828 (2015).
Hansen, K. et al. Listeria monocytogenes induces IFNb expression through an IFI16-, cGAS- and STING-dependent pathway. EMBO J. 33, 1654–1666 (2014).
Storek, K.M., Gertsvolf, N.A., Ohlson, M.B. & Monack, D.M. cGAS and Ifi204 cooperate to produce type I IFNs in response to Francisella infection. J. Immunol. 194, 3236–3245 (2015).
Zhang, Y. et al. The DNA sensor, cyclic GMP-AMP synthase, is essential for induction of IFN-b during Chlamydia trachomatis infection. J. Immunol. 193, 2394–2404 (2014).
Andrade, W.A. et al. Type I interferon induction by Neisseria gonorrhoeae: dual requirement of cyclic GMP-AMP synthase and Toll-like receptor 4. Cell Rep. 15, 2438–2448 (2016).
Andrade, W.A. et al. Group B streptococcus degrades cyclic-di-AMP to modulate STING-dependent type I interferon production. Cell Host Microbe 20, 49–59 (2016).
Christensen, M.H. et al. HSV-1 ICP27 targets the TBK1-activated STING signalsome to inhibit virus-induced type I IFN expression. EMBO J. 35, 1385–1399 (2016).
Lau, L., Gray, E.E., Brunette, R.L. & Stetson, D.B. DNA tumor virus oncogenes antagonize the cGAS-STING DNA-sensing pathway. Science 350, 568–571 (2015).
Crow, Y.J. Type I interferonopathies: mendelian type I interferon up-regulation. Curr. Opin. Immunol. 32, 7–12 (2015).
Gray, E.E., Treuting, P.M., Woodward, J.J. & Stetson, D.B. Cutting edge: cGAS is required for lethal autoimmune disease in the Trex1-deficient mouse model of Aicardi-Goutières syndrome. J. Immunol. 195, 1939–1943 (2015).
Gao, D. et al. Activation of cyclic GMP-AMP synthase by self-DNA causes autoimmune diseases. Proc. Natl. Acad. Sci. USA 112, E5699–E5705 (2015).
Gall, A. et al. Autoimmunity initiates in nonhematopoietic cells and progresses via lymphocytes in an interferon-dependent autoimmune disease. Immunity 36, 120–131 (2012).
Pokatayev, V. et al. RNase H2 catalytic core Aicardi-Goutières syndrome-related mutant invokes cGAS-STING innate immune-sensing pathway in mice. J. Exp. Med. 213, 329–336 (2016).
Mackenzie, K.J. et al. Ribonuclease H2 mutations induce a cGAS/STING-dependent innate immune response. EMBO J. 35, 831–844 (2016).
Lindahl, T., Barnes, D.E., Yang, Y.G. & Robins, P. Biochemical properties of mammalian TREX1 and its association with DNA replication and inherited inflammatory disease. Biochem. Soc. Trans. 37, 535–538 (2009).
Yang, Y.G., Lindahl, T. & Barnes, D.E. Trex1 exonuclease degrades ssDNA to prevent chronic checkpoint activation and autoimmune disease. Cell 131, 873–886 (2007).
Kawane, K. et al. Requirement of DNase II for definitive erythropoiesis in the mouse fetal liver. Science 292, 1546–1549 (2001).
Yoshida, H., Okabe, Y., Kawane, K., Fukuyama, H. & Nagata, S. Lethal anemia caused by interferon-beta produced in mouse embryos carrying undigested DNA. Nat. Immunol. 6, 49–56 (2005).
Okabe, Y., Kawane, K., Akira, S., Taniguchi, T. & Nagata, S. Toll-like receptor-independent gene induction program activated by mammalian DNA escaped from apoptotic DNA degradation. J. Exp. Med. 202, 1333–1339 (2005).
Liu, Y. et al. Activated STING in a vascular and pulmonary syndrome. N. Engl. J. Med. 371, 507–518 (2014).
Dunn, G.P., Koebel, C.M. & Schreiber, R.D. Interferons, immunity and cancer immunoediting. Nat. Rev. Immunol. 6, 836–848 (2006).
Fuertes, M.B., Woo, S.R., Burnett, B., Fu, Y.X. & Gajewski, T.F. Type I interferon response and innate immune sensing of cancer. Trends Immunol. 34, 67–73 (2013).
Corrales, L. & Gajewski, T.F. Endogenous and pharmacologic targeting of the STING pathway in cancer immunotherapy. Cytokine 77, 245–247 (2016).
Woo, S.R. et al. STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity 41, 830–842 (2014).
Deng, L. et al. STING-dependent cytosolic DNA sensing promotes radiation-induced type I interferon-dependent antitumor immunity in immunogenic tumors. Immunity 41, 843–852 (2014).
Liu, X. et al. CD47 blockade triggers T cell-mediated destruction of immunogenic tumors. Nat. Med. 21, 1209–1215 (2015).
Demaria, O. et al. STING activation of tumor endothelial cells initiates spontaneous and therapeutic antitumor immunity. Proc. Natl. Acad. Sci. USA 112, 15408–15413 (2015).
Corrales, L. et al. Direct activation of STING in the tumor microenvironment leads to potent and systemic tumor regression and immunity. Cell Rep. 11, 1018–1030 (2015).
Huang, L. et al. Cutting edge: DNA sensing via the STING adaptor in myeloid dendritic cells induces potent tolerogenic responses. J. Immunol. 191, 3509–3513 (2013).
Lemos, H. et al. STING promotes the growth of tumors characterized by low antigenicity via IDO activation. Cancer Res. 76, 2076–2081 (2016).
Chen, Q. et al. Carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer. Nature 533, 493–498 (2016).
The authors declare no competing financial interests.
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Chen, Q., Sun, L. & Chen, Z. Regulation and function of the cGAS–STING pathway of cytosolic DNA sensing. Nat Immunol 17, 1142–1149 (2016). https://doi.org/10.1038/ni.3558
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