STING: Infection, inflammation and cancer

Nature Reviews Immunology

Volumn 15, Issue 12, 2015, Pages 760-770

  Barber, Glen N ^a  

^a UNIVERSITY OF MIAMI   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

DNA; MEMBRANE PROTEIN; MITOCHONDRIAL DNA; STIMULATOR OF INTERFERON GENES PROTEIN; UNCLASSIFIED DRUG; MPYS PROTEIN, HUMAN;

ADAPTIVE IMMUNITY; AUTOINFLAMMATORY DISEASE; BACTERIAL LOAD; CANCER CONTROL; CARCINOGENESIS; CELL MIGRATION; CYTOSOL; DNA VIRUS; HUMAN; INFECTION; INFLAMMATION; INNATE IMMUNITY; MEDIATOR RELEASE; NEOPLASM; NONHUMAN; PRIORITY JOURNAL; PROTEIN DNA BINDING; PROTEIN FUNCTION; PROTEIN PROCESSING; REGULATORY MECHANISM; RETROVIRIDAE; REVIEW; SIGNAL TRANSDUCTION; TUMOR IMMUNITY; TUMOR MICROENVIRONMENT; VIRUS IMMUNITY; VIRUS LOAD; VIRUS REPLICATION; BACTERIAL INFECTION; BIOLOGICAL MODEL; DNA DAMAGE; IMMUNOLOGY; VIRUS INFECTION;

BACTERIAL INFECTIONS; DNA DAMAGE; HUMANS; IMMUNITY, INNATE; INFLAMMATION; MEMBRANE PROTEINS; MODELS, IMMUNOLOGICAL; NEOPLASMS; SIGNAL TRANSDUCTION; VIRUS DISEASES;

EID: 84948670572     PISSN: 14741733     EISSN: 14741741     Source Type: Journal    
DOI: 10.1038/nri3921     Document Type: Review

References (105)

1. Ishikawa, H. & Barber, G. N. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature 455, 674-678 (2008). This is the first report on the discovery of STING as an essential innate immune regulator.
2. Ishikawa, H., Ma, Z. & Barber, G. N. STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature 461, 788-792 (2009).
3. Burdette, D. L. et al. STING is a direct innate immune sensor of cyclic di-GMP. Nature 478, 515-518 (2011). This report demonstrates that CDNs bind to and activate STING.
4. Sauer, J. D. et al. The N-ethyl-N-nitrosourea-induced Goldenticket mouse mutant reveals an essential function of Sting in the in vivo interferon response to Listeria monocytogenes and cyclic dinucleotides. Infect. Immun. 79, 688-694 (2011).
5. Ahn, J. & Barber, G. N. Self-DNA, STING-dependent signaling and the origins of autoinflammatory disease. Curr. Opin. Immunol. 31, 121-126 (2014).
6. Woo, S. R., Corrales, L. & Gajewski, T. F. The STING pathway and the T cell-inflamed tumor microenvironment. Trends Immunol. 36, 250-256 (2015).
7. Barber, G. N. STING-dependent cytosolic DNA sensing pathways. Trends Immunol. 35, 88-93 (2014).
8. Zhong, B. et al. The adaptor protein MITA links virus-sensing receptors to IRF3 transcription factor activation. Immunity 29, 538-550 (2008).
9. Jin, L. et al. MPYS, a novel membrane tetraspanner, is associated with major histocompatibility complex class II and mediates transduction of apoptotic signals. Mol. Cell. Biol. 28, 5014-5026 (2008).
10. Woodward, J. J., Iavarone, A. T. & Portnoy, D. A. c-di-AMP secreted by intracellular Listeria monocytogenes activates a host type I interferon response. Science 328, 1703-1705 (2010). This paper reports that CDNs from bacteria activate innate immune signalling.
11. 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). This study shows that cGAS is a synthase that binds dsDNA to generate STING-activating CDNs.
12. Diner, E. J. et al. The innate immune DNA sensor cGAS produces a noncanonical cyclic dinucleotide that activates human STING. Cell Rep. 3, 1355-1361 (2013).
13. Ablasser, A. et al. cGAS produces a 2-5-linked cyclic dinucleotide second messenger that activates STING. Nature 498, 380-384 (2013).
14. Abe, T. et al. STING recognition of cytoplasmic DNA instigates cellular defense. Mol. Cell 50, 5-15 (2013).
15. 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).
16. 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).
17. 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).
18. Kumar, H., Kawai, T. & Akira, S. Pathogen recognition by the innate immune system. Int. Rev. Immunol. 30, 16-34 (2011).
19. Franchi, L., Munoz-Planillo, R. & Nunez, G. Sensing and reacting to microbes through the inflammasomes. Nat. Immunol. 13, 325-332 (2012).
20. Ahn, J., Gutman, D., Saijo, S. & Barber, G. N. STING manifests self DNA-dependent inflammatory disease. Proc. Natl Acad. Sci. USA 109, 19386-19391 (2012). This report demonstrates that STING activation in phagocytes following engulfment of dead cells is responsible for self-DNA-induced inflammatory disease.
21. Gomes, L. C. & Dikic, I. Autophagy in antimicrobial immunity. Mol. Cell 54, 224-233 (2014).
22. Nyathi, Y., Wilkinson, B. M. & Pool, M. R. Co-translational targeting and translocation of proteins to the endoplasmic reticulum. Biochim. Biophys. Acta 1833, 2392-2402 (2013).
23. Henault, J. et al. Noncanonical autophagy is required for type I interferon secretion in response to DNA-immune complexes. Immunity 37, 986-997 (2012).
24. Liu, S. et al. Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation. Science 347, aaa2630 (2015).
25. Alers, S., Loffler, A. S., Wesselborg, S. & Stork, B. Role of AMPK-mTOR-Ulk1/2 in the regulation of autophagy: cross talk, shortcuts, and feedbacks. Mol. Cell. Biol. 32, 2-11 (2012).
26. Liu, X., Wang, Q., Pan, Y. & Wang, C. Sensing and responding to cytosolic viruses invasions: An orchestra of kaleidoscopic ubiquitinations. Cytokine Growth Factor Rev. 26, 379-387 (2015).
27. Yarbrough, M. L. et al. Primate-specific miR-576-3p sets host defense signalling threshold. Nat. Commun. 5, 4963 (2014).
28. Lam, E., Stein, S. & Falck-Pedersen, E. Adenovirus detection by the cGAS/STING/TBK1 DNA sensing cascade. J. Virol. 88, 974-981 (2014).
29. Sunthamala, N. et al. E2 proteins of high risk human papillomaviruses down-modulate STING and IFN-κ transcription in keratinocytes. PLoS ONE 9, e91473 (2014).
30. Ablasser, A. et al. Cell intrinsic immunity spreads to bystander cells via the intercellular transfer of cGAMP. Nature 503, 530-534 (2013).
31. 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).
32. Gao, D. et al. Cyclic GMP-AMP synthase is an innate immune sensor of HIV and other retroviruses. Science 341, 903-906 (2013).
33. 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).
34. 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).
35. Yoh, S. M. et al. PQBP1 is a proximal sensor of the cGAS-dependent innate response to HIV-1. Cell 161, 1293-1305 (2015).
36. Mankan, A. K. et al. Cytosolic RNA:DNA hybrids activate the cGAS-STING axis. EMBO J. 33, 2937-2946 (2014).
37. Yan, N., Regalado-Magdos, A. D., Stiggelbout, B., Lee-Kirsch, M. A. & Lieberman, J. The cytosolic exonuclease TREX1 inhibits the innate immune response to human immunodeficiency virus type 1. Nat. Immunol. 11, 1005-1013 (2010).
38. Booiman, T., Setiawan, L. C. & Kootstra, N. A. Genetic variation in Trex1 affects HIV-1 disease progression. AIDS 28, 2517-2521 (2014).
39. Bridgeman, A. et al. Viruses transfer the antiviral second messenger cGAMP between cells. Science 349, 1228-1232 (2015).
40. Gentili, M. et al. Transmission of innate immune signaling by packaging of cGAMP in viral particles. Science 349, 1232-1236 (2015).
41. Zeng, M. et al. MAVS, cGAS, and endogenous retroviruses in T-independent B cell responses. Science 346, 1486-1492 (2014).
42. Inoue, T. & Tsai, B. How viruses use the endoplasmic reticulum for entry, replication, and assembly. Cold Spring Harb. Perspect. Biol. 5, a013250 (2013).
43. Aguirre, S. et al. DENV inhibits type I IFN production in infected cells by cleaving human STING. PLoS Pathog. 8, e1002934 (2012).
44. Li, X. D. et al. Pivotal roles of cGAS-cGAMP signaling in antiviral defense and immune adjuvant effects. Science 341, 1390-1394 (2013).
45. 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).
46. Maringer, K. & Fernandez-Sesma, A. Message in a bottle: lessons learned from antagonism of STING signalling during RNA virus infection. Cytokine Growth Factor Rev. 25, 669-679 (2014).
47. Kalamvoki, M. & Roizman, B. HSV-1 degrades, stabilizes, requires, or is stung by STING depending on ICP0, the US3 protein kinase, and cell derivation. Proc. Natl Acad. Sci. USA 111, E611-E617 (2014).
48. Zhou, Q. et al. The ER-associated protein ZDHHC1 is a positive regulator of DNA virus-triggered, MITA/STING-dependent innate immune signaling. Cell Host Microbe 16, 450-461 (2014).
49. Luecke, S. & Paludan, S. R. Innate recognition of alphaherpesvirus DNA. Adv. Virus Res. 92, 63-100 (2015).
50. Mitzel, D. N., Lowry, V., Shirali, A. C., Liu, Y. & Stout-Delgado, H. W. Age-enhanced endoplasmic reticulum stress contributes to increased Atg9A inhibition of STING-mediated IFN-β production during Streptococcus pneumoniae infection. J. Immunol. 192, 4273-4283 (2014).
51. Prantner, D., Darville, T. & Nagarajan, U. M. Stimulator of IFN gene is critical for induction of IFN-β during Chlamydia muridarum infection. J. Immunol. 184, 2551-2560 (2010).
52. 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).
53. Watson, R. O., Manzanillo, P. S. & Cox, J. S. Extracellular M. tuberculosis DNA targets bacteria for autophagy by activating the host DNA-sensing pathway. Cell 150, 803-815 (2012).
54. Dey, B. et al. A bacterial cyclic dinucleotide activates the cytosolic surveillance pathway and mediates innate resistance to tuberculosis. Nat. Med. 21, 401-406 (2015).
55. Archer, K. A., Durack, J. & Portnoy, D. A. STING-dependent type I IFN production inhibits cell-mediated immunity to Listeria monocytogenes. PLoS Pathog. 10, e1003861 (2014).
56. Centers for Disease Control and Prevention. Prevalence of doctor-diagnosed arthritis and arthritis-attributable activity limitation-United States, 2010-2012. MMWR Morb. Mortal. Wkly Rep. 62, 869-873 (2013).
57. Nagata, S. & Kawane, K. Autoinflammation by endogenous DNA. Adv. Immunol. 110, 139-161 (2011).
58. Janko, C. et al. Inflammatory clearance of apoptotic remnants in systemic lupus erythematosus (SLE). Autoimmun. Rev. 8, 9-12 (2008).
59. Martinez Valle, F., Balada, E., Ordi-Ros, J. & Vilardell-Tarres, M. DNase 1 and systemic lupus erythematosus. Autoimmun Rev. 7, 359-363 (2008).
60. Rice, G. I., Rodero, M. P. & Crow, Y. J. Human disease phenotypes associated with mutations in TREX1. J. Clin. Immunol. 35, 235-243 (2015).
61. Gall, A. et al. Autoimmunity initiates in nonhematopoietic cells and progresses via lymphocytes in an interferon-dependent autoimmune disease. Immunity 36, 120-131 (2012). This study shows that STING activation is responsible for TREX1-mediated autoinflamatory disease and plausibly AGS.
62. Ahn, J., Ruiz, P. & Barber, G. N. Intrinsic self-DNA triggers inflammatory disease dependent on STING. J. Immunol. 193, 4634-4642 (2014). This report demonstrates that, in the absence of TREX1, self-DNA in macrophages can activate STING and cause inflammatory diseases, such as AGS.
63. 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).
64. Pereira-Lopes, S. et al. The exonuclease Trex1 restrains macrophage proinflammatory activation. J. Immunol. 191, 6128-6135 (2013).
65. Ablasser, A. et al. TREX1 deficiency triggers cell-autonomous immunity in a cGAS-dependent manner. J. Immunol. 192, 5993-5997 (2014). This study reports that cGAS is involved in STING-dependent autoinflammatory disease that is triggered by TREX1 deficiency.
66. 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).
67. Kukat, C. & Larsson, N. G. mtDNA makes a U-turn for the mitochondrial nucleoid. Trends Cell Biol. 23, 457-463 (2013).
68. West, A. P. et al. Mitochondrial DNA stress primes the antiviral innate immune response. Nature 520, 553-557 (2015).
69. White, M. J. et al. Apoptotic caspases suppress mtDNA-induced STING-mediated type I IFN production. Cell 159, 1549-1562 (2014).
70. Rongvaux, A. et al. Apoptotic caspases prevent the induction of type I interferons by mitochondrial DNA. Cell 159, 1563-1577 (2014). References 69 and 70 show that mitochondrial DNA that has leaked into the cytosol may activate STING-dependent inflammatory responses.
71. Creagh, E. M. Caspase crosstalk: integration of apoptotic and innate immune signalling pathways. Trends Immunol. 35, 631-640 (2014).
72. Perl, A., Hanczko, R. & Doherty, E. Assessment of mitochondrial dysfunction in lymphocytes of patients with systemic lupus erythematosus. Methods Mol. Biol. 900, 61-89 (2012).
73. Nowarski, R., Gagliani, N., Huber, S. & Flavell, R. A. Innate immune cells in inflammation and cancer. Cancer Immunol. Res. 1, 77-84 (2013).
74. Salcedo, R., Cataisson, C., Hasan, U., Yuspa, S. H. & Trinchieri, G. MyD88 and its divergent toll in carcinogenesis. Trends Immunol. 34, 379-389 (2013).
75. Swann, J. B. et al. Demonstration of inflammation-induced cancer and cancer immunoediting during primary tumorigenesis. Proc. Natl Acad. Sci. USA 105, 652-656 (2008).
76. Ahn, J. et al. Inflammation-driven carcinogenesis is mediated through STING. Nat. Commun. 5, 5166 (2014). This study shows that DNA-damaging agents can cause DNA leakage in the cytosol to activate STING-mediated inflammatory events and drive skin cancer.
77. Salcedo, R. et al. MyD88-mediated signaling prevents development of adenocarcinomas of the colon: role of interleukin 18. J. Exp. Med. 207, 1625-1636 (2010).
78. Huber, S. et al. IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine. Nature 491, 259-263 (2012).
79. Irrazabal, T., Belcheva, A., Girardin, S. E., Martin, A. & Philpott, D. J. The multifaceted role of the intestinal microbiota in colon cancer. Mol. Cell 54, 309-320 (2014).
80. Ahn, J., Konno, H. & Barber, G. N. Diverse roles of STING-dependent signaling on the development of cancer. Oncogene 34, 5302-5308 (2015).
81. Zhu, Q. et al. Cutting edge: STING mediates protection against colorectal tumorigenesis by governing the magnitude of intestinal inflammation. J. Immunol. 193, 4779-4782 (2014). References 80 and 81 show a protective role for STING in recognizing DNA damage and facilitating wound repair in the colon.
82. Gajewski, T. F., Schreiber, H. & Fu, Y. X. Innate and adaptive immune cells in the tumor microenvironment. Nat. Immunol. 14, 1014-1022 (2013).
83. Woo, S. R. et al. STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity 41, 830-842 (2014). This study shows that antitumour T cell responses require the activation of STING in phagocytes that have engulfed tumour cells.
84. 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). This study shows that radiation-induced tumour cell death stimulates STING-dependent antitumour T cell responses.
85. Klarquist, J. et al. STING-mediated DNA sensing promotes antitumor and autoimmune responses to dying cells. J. Immunol. 193, 6124-6134 (2014).
86. Roberts, Z. J. et al. The chemotherapeutic agent DMXAA potently and specifically activates the TBK1-IRF-3 signaling axis. J. Exp. Med. 204, 1559-1569 (2007).
87. 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). This study demonstrates that the use of STING agonists can exert potent antitumour therapeutic effects.
88. Fu, J. et al. STING agonist formulated cancer vaccines can cure established tumors resistant to PD-1 blockade. Sci. Transl Med. 7, 283ra52 (2015).
89. Wang, Z. & Celis, E. STING activator c-di-GMP enhances the anti-tumor effects of peptide vaccines in melanoma-bearing mice. Cancer Immunol. Immunother. 64, 1057-1066 (2015).
90. Ohkuri, T., Ghosh, A., Kosaka, A., Sarkar, S. N. & Okada, H. Protective role of STING against gliomagenesis: rational use of STING agonist in anti-glioma immunotherapy. Oncoimmunology 4, e999523 (2015).
91. Zitvogel, L., Galluzzi, L., Smyth, M. J. & Kroemer, G. Mechanism of action of conventional and targeted anticancer therapies: reinstating immunosurveillance. Immunity 39, 74-88 (2013).
92. Hartlova, A. et al. DNA damage primes the type I interferon system via the cytosolic DNA sensor STING to promote anti-microbial innate immunity. Immunity 42, 332-343 (2015).
93. Kondo, T. et al. DNA damage sensor MRE11 recognizes cytosolic double-stranded DNA and induces type I interferon by regulating STING trafficking. Proc. Natl Acad. Sci. USA 110, 2969-2974 (2013).
94. Lemos, H., Huang, L., McGaha, T. & Mellor, A. L. STING, nanoparticles, autoimmune disease and cancer: a novel paradigm for immunotherapy? Expert Rev. Clin. Immunol. 11, 155-165 (2015).
95. Zhang, H. et al. Cell-free tumor microparticle vaccines stimulate dendritic cells via cGAS/STING signaling. Cancer Immunol. Res. 3, 196-205 (2015).
96. Dubensky, T. W. Jr., Kanne, D. B. & Leong, M. L. Rationale, progress and development of vaccines utilizing STING-activating cyclic dinucleotide adjuvants. Ther. Adv. Vaccines 1, 131-143 (2013).
97. 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).
98. Jin, L. et al. Identification and characterization of a loss-of-function human MPYS variant. Genes Immun. 12, 263-269 (2011).
99. Prantner, D. et al. 5, 6-Dimethylxanthenone-4-acetic acid (DMXAA) activates stimulator of interferon gene (STING)-dependent innate immune pathways and is regulated by mitochondrial membrane potential. J. Biol. Chem. 287, 39776-39788 (2012).
100. Liu, Y. et al. Activated STING in a vascular and pulmonary syndrome. N. Engl. J. Med. 371, 507-518 (2014). This paper reports that mutations in TMEM173 that cause constitutive activity of STING can induce inflammatory disease.
101. Jeremiah, N. et al. Inherited STING-activating mutation underlies a familial inflammatory syndrome with lupus-like manifestations. J. Clin. Invest. 124, 5516-5520 (2014).
102. Lemos, H. et al. Activation of the STING adaptor attenuates experimental autoimmune encephalitis. J. Immunol. 192, 5571-5578 (2014).
103. Wu, X. et al. Molecular evolutionary and structural analysis of the cytosolic DNA sensor cGAS and STING. Nucleic Acids Res. 42, 8243-8257 (2014).
104. Mozzi, A. et al. OASes and STING: adaptive evolution in concert. Genome Biol. Evol. 7, 1016-1032 (2015).
105. Yi, G. et al. Single nucleotide polymorphisms of human STING can affect innate immune response to cyclic dinucleotides. PLoS ONE 8, e77846 (2013).