1932

Abstract

DNA has been known to be a potent immune stimulus for more than half a century. However, the underlying molecular mechanisms of DNA-triggered immune response have remained elusive until recent years. Cyclic GMP-AMP synthase (cGAS) is a major cytoplasmic DNA sensor in various types of cells that detect either invaded foreign DNA or aberrantly located self-DNA. Upon sensing of DNA, cGAS catalyzes the formation of cyclic GMP-AMP (cGAMP), which in turn activates the ER-localized adaptor protein MITA (also named STING) to elicit the innate immune response. The cGAS-MITA axis not only plays a central role in host defense against pathogen-derived DNA but also acts as a cellular stress response pathway by sensing aberrantly located self-DNA, which is linked to the pathogenesis of various human diseases. In this review, we summarize the spatial and temporal mechanisms of host defense to cytoplasmic DNA mediated by the cGAS-MITA axis and discuss the association of malfunctions of this axis with autoimmune and other diseases.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-immunol-070119-115052
2020-04-26
2024-06-16
Loading full text...

Full text loading...

/deliver/fulltext/immunol/38/1/annurev-immunol-070119-115052.html?itemId=/content/journals/10.1146/annurev-immunol-070119-115052&mimeType=html&fmt=ahah

Literature Cited

  1. 1. 
    Hu MM, Shu HB. 2018. Cytoplasmic mechanisms of recognition and defense of microbial nucleic acids. Annu. Rev. Cell Dev. Biol. 34:357–79
    [Google Scholar]
  2. 2. 
    Akira S, Uematsu S, Takeuchi O 2006. Pathogen recognition and innate immunity. Cell 124:783–801
    [Google Scholar]
  3. 3. 
    Gurunathan S, Klinman DM, Seder RA 2000. DNA vaccines: immunology, application, and optimization. Annu. Rev. Immunol. 18:927–74
    [Google Scholar]
  4. 4. 
    Chen Q, Sun L, Chen ZJ 2016. Regulation and function of the cGAS-STING pathway of cytosolic DNA sensing. Nat. Immunol. 17:1142–49
    [Google Scholar]
  5. 5. 
    Kawai T, Akira S. 2011. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity 34:637–50
    [Google Scholar]
  6. 6. 
    Beutler B, Jiang Z, Georgel P, Crozat K, Croker B et al. 2006. Genetic analysis of host resistance: Toll-like receptor signaling and immunity at large. Annu. Rev. Immunol. 24:353–89
    [Google Scholar]
  7. 7. 
    Ablasser A, Bauernfeind F, Hartmann G, Latz E, Fitzgerald KA, Hornung V 2009. RIG-I-dependent sensing of poly(dA:dT) through the induction of an RNA polymerase III-transcribed RNA intermediate. Nat. Immunol. 10:1065–72
    [Google Scholar]
  8. 8. 
    Sun L, Wu J, Du F, Chen X, Chen ZJ 2013. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science 339:786–91
    [Google Scholar]
  9. 9. 
    Unterholzner L, Keating SE, Baran M, Horan KA, Jensen SB et al. 2010. IFI16 is an innate immune sensor for intracellular DNA. Nat. Immunol. 11:997–1004
    [Google Scholar]
  10. 10. 
    Zhang Z, Yuan B, Bao M, Lu N, Kim T, Liu YJ 2011. The helicase DDX41 senses intracellular DNA mediated by the adaptor STING in dendritic cells. Nat. Immunol. 12:959–65
    [Google Scholar]
  11. 11. 
    Hornung V, Ablasser A, Charrel-Dennis M, Bauernfeind F, Horvath G et al. 2009. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature 458:514–18
    [Google Scholar]
  12. 12. 
    Li Y, Chen R, Zhou Q, Xu Z, Li C et al. 2012. LSm14A is a processing body-associated sensor of viral nucleic acids that initiates cellular antiviral response in the early phase of viral infection. PNAS 109:11770–75
    [Google Scholar]
  13. 13. 
    Ferguson BJ, Mansur DS, Peters NE, Ren H, Smith GL 2012. DNA-PK is a DNA sensor for IRF-3-dependent innate immunity. eLife 1:e00047
    [Google Scholar]
  14. 14. 
    Kondo T, Kobayashi J, Saitoh T, Maruyama K, Ishii KJ et al. 2013. DNA damage sensor MRE11 recognizes cytosolic double-stranded DNA and induces type I interferon by regulating STING trafficking. PNAS 110:2969–74
    [Google Scholar]
  15. 15. 
    Takaoka A, Wang Z, Choi MK, Yanai H, Negishi H et al. 2007. DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response. Nature 448:501–5
    [Google Scholar]
  16. 16. 
    Li XD, Wu J, Gao D, Wang H, Sun L, Chen ZJ 2013. Pivotal roles of cGAS-cGAMP signaling in antiviral defense and immune adjuvant effects. Science 341:1390–94
    [Google Scholar]
  17. 17. 
    Zhong B, Yang Y, Li S, Wang YY, Li Y et al. 2008. The adaptor protein MITA links virus-sensing receptors to IRF3 transcription factor activation. Immunity 29:538–50
    [Google Scholar]
  18. 18. 
    Ishikawa H, Ma Z, Barber GN 2009. STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature 461:788–92
    [Google Scholar]
  19. 19. 
    Ablasser A, Chen ZJ. 2019. cGAS in action: expanding roles in immunity and inflammation. Science 363:eaat8657
    [Google Scholar]
  20. 20. 
    Gentili M, Lahaye X, Nadalin F, Nader GPF, Lombardi EP et al. 2019. The N-terminal domain of cGAS determines preferential association with centromeric DNA and innate immune activation in the nucleus. Cell Rep 26:2377–93.e13
    [Google Scholar]
  21. 21. 
    Barnett KC, Coronas-Serna JM, Zhou W, Ernandes MJ, Cao A et al. 2019. Phosphoinositide interactions position cGAS at the plasma membrane to ensure efficient distinction between self- and viral DNA. Cell 176:1432–46.e11
    [Google Scholar]
  22. 22. 
    Tao J, Zhang XW, Jin J, Du XX, Lian T et al. 2017. Nonspecific DNA binding of cGAS N terminus promotes cGAS activation. J. Immunol. 198:3627–36
    [Google Scholar]
  23. 23. 
    Du M, Chen ZJ. 2018. DNA-induced liquid phase condensation of cGAS activates innate immune signaling. Science 361:704–9
    [Google Scholar]
  24. 24. 
    Civril F, Deimling T, de Oliveira Mann CC, Ablasser A, Moldt M et al. 2013. Structural mechanism of cytosolic DNA sensing by cGAS. Nature 498:332–37
    [Google Scholar]
  25. 25. 
    Gao P, Ascano M, Wu Y, Barchet W, Gaffney BL et al. 2013. Cyclic [G(2′,5′)pA(3′,5′)p] is the metazoan second messenger produced by DNA-activated cyclic GMP-AMP synthase. Cell 153:1094–107
    [Google Scholar]
  26. 26. 
    Kranzusch PJ, Lee AS, Berger JM, Doudna JA 2013. Structure of human cGAS reveals a conserved family of second-messenger enzymes in innate immunity. Cell Rep 3:1362–68
    [Google Scholar]
  27. 27. 
    Li X, Shu C, Yi G, Chaton CT, Shelton CL et al. 2013. Cyclic GMP-AMP synthase is activated by double-stranded DNA-induced oligomerization. Immunity 39:1019–31
    [Google Scholar]
  28. 28. 
    Zhang X, Wu J, Du F, Xu H, Sun L et al. 2014. The cytosolic DNA sensor cGAS forms an oligomeric complex with DNA and undergoes switch-like conformational changes in the activation loop. Cell Rep 6:421–30
    [Google Scholar]
  29. 29. 
    Andreeva L, Hiller B, Kostrewa D, Lassig C, de Oliveira Mann CC et al. 2017. cGAS senses long and HMGB/TFAM-bound U-turn DNA by forming protein-DNA ladders. Nature 549:394–98
    [Google Scholar]
  30. 30. 
    Ablasser A, Goldeck M, Cavlar T, Deimling T, Witte G et al. 2013. cGAS produces a 2′-5′-linked cyclic dinucleotide second messenger that activates STING. Nature 498:380–84
    [Google Scholar]
  31. 31. 
    Zhang X, Shi H, Wu J, Zhang X, Sun L et al. 2013. Cyclic GMP-AMP containing mixed phosphodiester linkages is an endogenous high-affinity ligand for STING. Mol. Cell 51:226–35
    [Google Scholar]
  32. 32. 
    Diner EJ, Burdette DL, Wilson SC, Monroe KM, Kellenberger CA et al. 2013. The innate immune DNA sensor cGAS produces a noncanonical cyclic dinucleotide that activates human STING. Cell Rep 3:1355–61
    [Google Scholar]
  33. 33. 
    Liu ZS, Cai H, Xue W, Wang M, Xia T et al. 2019. G3BP1 promotes DNA binding and activation of cGAS. Nat. Immunol. 20:18–28
    [Google Scholar]
  34. 34. 
    Yoh SM, Schneider M, Seifried J, Soonthornvacharin S, Akleh RE et al. 2015. PQBP1 is a proximal sensor of the cGAS-dependent innate response to HIV-1. Cell 161:1293–305
    [Google Scholar]
  35. 35. 
    Lian H, Wei J, Zang R, Ye W, Yang Q et al. 2018. ZCCHC3 is a co-sensor of cGAS for dsDNA recognition in innate immune response. Nat. Commun. 9:3349
    [Google Scholar]
  36. 36. 
    Lian H, Zang R, Wei J, Ye W, Hu MM et al. 2018. The zinc-finger protein ZCCHC3 binds RNA and facilitates viral RNA sensing and activation of the RIG-I-like receptors. Immunity 49:438–48.e5
    [Google Scholar]
  37. 37. 
    Yang H, Wang H, Ren J, Chen Q, Chen ZJ 2017. cGAS is essential for cellular senescence. PNAS 114:E4612–20
    [Google Scholar]
  38. 38. 
    Srikanth S, Woo JS, Wu B, El-Sherbiny YM, Leung J et al. 2019. The Ca2+ sensor STIM1 regulates the type I interferon response by retaining the signaling adaptor STING at the endoplasmic reticulum. Nat. Immunol. 20:152–62
    [Google Scholar]
  39. 39. 
    Shang G, Zhang C, Chen ZJ, Bai XC, Zhang X 2019. Cryo-EM structures of STING reveal its mechanism of activation by cyclic GMP-AMP. Nature 567:389–93
    [Google Scholar]
  40. 40. 
    Zhang C, Shang G, Gui X, Zhang X, Bai XC, Chen ZJ 2019. Structural basis of STING binding with and phosphorylation by TBK1. Nature 567:394–98
    [Google Scholar]
  41. 41. 
    Zhou Q, Lin H, Wang S, Wang S, Ran Y et al. 2014. The ER-associated protein ZDHHC1 is a positive regulator of DNA virus-triggered, MITA/STING-dependent innate immune signaling. Cell Host Microbe 16:450–61
    [Google Scholar]
  42. 42. 
    Dobbs N, Burnaevskiy N, Chen D, Gonugunta VK, Alto NM, Yan N 2015. STING activation by translocation from the ER is associated with infection and autoinflammatory disease. Cell Host Microbe 18:157–68
    [Google Scholar]
  43. 43. 
    Luo WW, Li S, Li C, Lian H, Yang Q et al. 2016. iRhom2 is essential for innate immunity to DNA viruses by mediating trafficking and stability of the adaptor STING. Nat. Immunol. 17:1057–66
    [Google Scholar]
  44. 44. 
    Liu S, Cai X, Wu J, Cong Q, Chen X et al. 2015. Phosphorylation of innate immune adaptor proteins MAVS, STING, and TRIF induces IRF3 activation. Science 347:aaa2630
    [Google Scholar]
  45. 45. 
    Konno H, Konno K, Barber GN 2013. Cyclic dinucleotides trigger ULK1 (ATG1) phosphorylation of STING to prevent sustained innate immune signaling. Cell 155:688–98
    [Google Scholar]
  46. 46. 
    Ablasser A, Schmid-Burgk JL, Hemmerling I, Horvath GL, Schmidt T et al. 2013. Cell intrinsic immunity spreads to bystander cells via the intercellular transfer of cGAMP. Nature 503:530–34
    [Google Scholar]
  47. 47. 
    Bridgeman A, Maelfait J, Davenne T, Partridge T, Peng Y et al. 2015. Viruses transfer the antiviral second messenger cGAMP between cells. Science 349:1228–32
    [Google Scholar]
  48. 48. 
    Gentili M, Kowal J, Tkach M, Satoh T, Lahaye X et al. 2015. Transmission of innate immune signaling by packaging of cGAMP in viral particles. Science 349:1232–36
    [Google Scholar]
  49. 49. 
    Andrade WA, Firon A, Schmidt T, Hornung V, Fitzgerald KA et al. 2016. Group B Streptococcus degrades cyclic-di-AMP to modulate STING-dependent type I interferon production. Cell Host Microbe 20:49–59
    [Google Scholar]
  50. 50. 
    Moretti J, Roy S, Bozec D, Martinez J, Chapman JR et al. 2017. STING senses microbial viability to orchestrate stress-mediated autophagy of the endoplasmic reticulum. Cell 171:809–23.e13
    [Google Scholar]
  51. 51. 
    Seo GJ, Yang A, Tan B, Kim S, Liang Q et al. 2015. Akt kinase-mediated checkpoint of cGAS DNA sensing pathway. Cell Rep 13:440–49
    [Google Scholar]
  52. 52. 
    Gao M, Karin M. 2005. Regulating the regulators: control of protein ubiquitination and ubiquitin-like modifications by extracellular stimuli. Mol. Cell 19:581–93
    [Google Scholar]
  53. 53. 
    Wang Q, Huang L, Hong Z, Lv Z, Mao Z et al. 2017. The E3 ubiquitin ligase RNF185 facilitates the cGAS-mediated innate immune response. PLOS Pathog 13:e1006264
    [Google Scholar]
  54. 54. 
    Chen M, Meng Q, Qin Y, Liang P, Tan P et al. 2016. TRIM14 inhibits cGAS degradation mediated by selective autophagy receptor p62 to promote innate immune responses. Mol. Cell 64:105–19
    [Google Scholar]
  55. 55. 
    Hu MM, Yang Q, Xie XQ, Liao CY, Lin H et al. 2016. Sumoylation promotes the stability of the DNA sensor cGAS and the adaptor STING to regulate the kinetics of response to DNA virus. Immunity 45:555–69
    [Google Scholar]
  56. 56. 
    Hu MM, Liao CY, Yang Q, Xie XQ, Shu HB 2017. Innate immunity to RNA virus is regulated by temporal and reversible sumoylation of RIG-I and MDA5. J. Exp. Med. 214:973–89
    [Google Scholar]
  57. 57. 
    Hu MM, Shu HB. 2017. Multifaceted roles of TRIM38 in innate immune and inflammatory responses. Cell Mol. Immunol. 14:331–38
    [Google Scholar]
  58. 58. 
    Xia P, Ye B, Wang S, Zhu X, Du Y et al. 2016. Glutamylation of the DNA sensor cGAS regulates its binding and synthase activity in antiviral immunity. Nat. Immunol. 17:369–78
    [Google Scholar]
  59. 59. 
    Dai J, Huang YJ, He X, Zhao M, Wang X et al. 2019. Acetylation blocks cGAS activity and inhibits self-DNA-induced autoimmunity. Cell 176:1447–60.e14
    [Google Scholar]
  60. 60. 
    Li Z, Liu G, Sun L, Teng Y, Guo X et al. 2015. PPM1A regulates antiviral signaling by antagonizing TBK1-mediated STING phosphorylation and aggregation. PLOS Pathog 11:e1004783
    [Google Scholar]
  61. 61. 
    Hu MM, He WR, Gao P, Yang Q, He K et al. 2019. Virus-induced accumulation of intracellular bile acids activates the TGR5-β-arrestin-SRC axis to enable innate antiviral immunity. Cell Res 29:193–205
    [Google Scholar]
  62. 62. 
    Shu HB, Wang YY. 2014. Adding to the STING. Immunity 41:871–73
    [Google Scholar]
  63. 63. 
    Wang Q, Liu X, Cui Y, Tang Y, Chen W et al. 2014. The E3 ubiquitin ligase AMFR and INSIG1 bridge the activation of TBK1 kinase by modifying the adaptor STING. Immunity 41:919–33
    [Google Scholar]
  64. 64. 
    Zhong B, Zhang L, Lei C, Li Y, Mao AP et al. 2009. The ubiquitin ligase RNF5 regulates antiviral responses by mediating degradation of the adaptor protein MITA. Immunity 30:397–407
    [Google Scholar]
  65. 65. 
    Qin Y, Zhou MT, Hu MM, Hu YH, Zhang J et al. 2014. RNF26 temporally regulates virus-triggered type I interferon induction by two distinct mechanisms. PLOS Pathog 10:e1004358
    [Google Scholar]
  66. 66. 
    Sun H, Zhang Q, Jing YY, Zhang M, Wang HY et al. 2017. USP13 negatively regulates antiviral responses by deubiquitinating STING. Nat. Commun. 8:15534
    [Google Scholar]
  67. 67. 
    Ye L, Zhang Q, Liuyu T, Xu Z, Zhang MX et al. 2019. USP49 negatively regulates cellular antiviral responses via deconjugating K63-linked ubiquitination of MITA. PLOS Pathog 15:e1007680
    [Google Scholar]
  68. 68. 
    Zhang MX, Cai Z, Zhang M, Wang XM, Wang Y et al. 2019. USP20 promotes cellular antiviral responses via deconjugating K48-linked ubiquitination of MITA. J. Immunol. 202:2397–406
    [Google Scholar]
  69. 69. 
    Zhang M, Zhang MX, Zhang Q, Zhu GF, Yuan L et al. 2016. USP18 recruits USP20 to promote innate antiviral response through deubiquitinating STING/MITA. Cell Res 26:1302–19
    [Google Scholar]
  70. 70. 
    Ma Z, Damania B. 2016. The cGAS-STING defense pathway and its counteraction by viruses. Cell Host Microbe 19:150–58
    [Google Scholar]
  71. 71. 
    Zhang G, Chan B, Samarina N, Abere B, Weidner-Glunde M et al. 2016. Cytoplasmic isoforms of Kaposi sarcoma herpesvirus LANA recruit and antagonize the innate immune DNA sensor cGAS. PNAS 113:E1034–43
    [Google Scholar]
  72. 72. 
    Li W, Avey D, Fu B, Wu JJ, Ma S et al. 2016. Kaposi's sarcoma-associated herpesvirus inhibitor of cGAS (KicGAS), encoded by ORF52, is an abundant tegument protein and is required for production of infectious progeny viruses. J. Virol. 90:5329–42
    [Google Scholar]
  73. 73. 
    Huang ZF, Zou HM, Liao BW, Zhang HY, Yang Y et al. 2018. Human cytomegalovirus protein UL31 inhibits DNA sensing of cGAS to mediate immune evasion. Cell Host Microbe 24:69–80.e4
    [Google Scholar]
  74. 74. 
    Fu YZ, Guo Y, Zou HM, Su S, Wang SY et al. 2019. Human cytomegalovirus protein UL42 antagonizes cGAS/MITA-mediated innate antiviral response. PLOS Pathog 15:e1007691
    [Google Scholar]
  75. 75. 
    Biolatti M, Dell'Oste V, Pautasso S, Gugliesi F, von Einem J et al. 2018. Human cytomegalovirus tegument protein pp65 (pUL83) dampens type I interferon production by inactivating the DNA sensor cGAS without affecting STING. J. Virol. 92:e01774–17
    [Google Scholar]
  76. 76. 
    Huang J, You H, Su C, Li Y, Chen S, Zheng C 2018. Herpes simplex virus 1 tegument protein VP22 abrogates cGAS/STING-mediated antiviral innate immunity. J. Virol. 92:e00841–18
    [Google Scholar]
  77. 77. 
    Zhang J, Zhao J, Xu S, Li J, He S et al. 2018. Species-specific deamidation of cGAS by herpes simplex virus UL37 protein facilitates viral replication. Cell Host Microbe 24:234–48.e5
    [Google Scholar]
  78. 78. 
    Su C, Zheng C. 2017. Herpes simplex virus 1 abrogates the cGAS/STING-mediated cytosolic DNA-sensing pathway via its virion host shutoff protein, UL41. J. Virol. 91:e02414–16
    [Google Scholar]
  79. 79. 
    Ma Z, Jacobs SR, West JA, Stopford C, Zhang Z et al. 2015. Modulation of the cGAS-STING DNA sensing pathway by gammaherpesviruses. PNAS 112:E4306–15
    [Google Scholar]
  80. 80. 
    Sun C, Schattgen SA, Pisitkun P, Jorgensen JP, Hilterbrand AT et al. 2015. Evasion of innate cytosolic DNA sensing by a gammaherpesvirus facilitates establishment of latent infection. J. Immunol. 194:1819–31
    [Google Scholar]
  81. 81. 
    Fu YZ, Su S, Gao YQ, Wang PP, Huang ZF et al. 2017. Human cytomegalovirus tegument protein UL82 inhibits STING-mediated signaling to evade antiviral immunity. Cell Host Microbe 21:231–43
    [Google Scholar]
  82. 82. 
    Choi HJ, Park A, Kang S, Lee E, Lee TA et al. 2018. Human cytomegalovirus-encoded US9 targets MAVS and STING signaling to evade type I interferon immune responses. Nat. Commun. 9:125
    [Google Scholar]
  83. 83. 
    Deschamps T, Kalamvoki M. 2017. Evasion of the STING DNA-sensing pathway by VP11/12 of herpes simplex virus 1. J. Virol. 91:e00535–17
    [Google Scholar]
  84. 84. 
    Lio CM, McDonald B, Takahashi M, Dhanwani R, Sharma N et al. 2016. cGAS-STING signaling regulates initial innate control of cytomegalovirus infection. J. Virol. 90:7789–97
    [Google Scholar]
  85. 85. 
    Stempel M, Chan B, Juranić Lisnić V, Krmpotić A, Hartung J et al. 2019. The herpesviral antagonist m152 reveals differential activation of STING-dependent IRF and NF-κB signaling and STING's dual role during MCMV infection. EMBO J 38:e100983
    [Google Scholar]
  86. 86. 
    Harding SM, Benci JL, Irianto J, Discher DE, Minn AJ, Greenberg RA 2017. Mitotic progression following DNA damage enables pattern recognition within micronuclei. Nature 548:466–70
    [Google Scholar]
  87. 87. 
    West AP, Khoury-Hanold W, Staron M, Tal MC, Pineda CM et al. 2015. Mitochondrial DNA stress primes the antiviral innate immune response. Nature 520:553–57
    [Google Scholar]
  88. 88. 
    Dang EV, McDonald JG, Russell DW, Cyster JG 2017. Oxysterol restraint of cholesterol synthesis prevents AIM2 inflammasome activation. Cell 171:1057–71.e11
    [Google Scholar]
  89. 89. 
    York AG, Williams KJ, Argus JP, Zhou QD, Brar G et al. 2015. Limiting cholesterol biosynthetic flux spontaneously engages type I IFN signaling. Cell 163:1716–29
    [Google Scholar]
  90. 90. 
    McArthur K, Whitehead LW, Heddleston JM, Li L, Padman BS et al. 2018. BAK/BAX macropores facilitate mitochondrial herniation and mtDNA efflux during apoptosis. Science 359:eaao6047
    [Google Scholar]
  91. 91. 
    White MJ, McArthur K, Metcalf D, Lane RM, Cambier JC et al. 2014. Apoptotic caspases suppress mtDNA-induced STING-mediated type I IFN production. Cell 159:1549–62
    [Google Scholar]
  92. 92. 
    Mackenzie KJ, Carroll P, Martin CA, Murina O, Fluteau A et al. 2017. cGAS surveillance of micronuclei links genome instability to innate immunity. Nature 548:461–65
    [Google Scholar]
  93. 93. 
    Gross DS, Garrard WT. 1988. Nuclease hypersensitive sites in chromatin. Annu. Rev. Biochem. 57:159–97
    [Google Scholar]
  94. 94. 
    Rekvig OP, Mortensen ES. 2012. Immunity and autoimmunity to dsDNA and chromatin—the role of immunogenic DNA-binding proteins and nuclease deficiencies. Autoimmunity 45:588–92
    [Google Scholar]
  95. 95. 
    Yang YG, Lindahl T, Barnes DE 2007. Trex1 exonuclease degrades ssDNA to prevent chronic checkpoint activation and autoimmune disease. Cell 131:873–86
    [Google Scholar]
  96. 96. 
    Stetson DB, Ko JS, Heidmann T, Medzhitov R 2008. Trex1 prevents cell-intrinsic initiation of autoimmunity. Cell 134:587–98
    [Google Scholar]
  97. 97. 
    Baum R, Sharma S, Organ JM, Jakobs C, Hornung V et al. 2017. STING contributes to abnormal bone formation induced by deficiency of DNase II in mice. Arthritis Rheumatol 69:460–71
    [Google Scholar]
  98. 98. 
    Baum R, Nundel K, Pawaria S, Sharma S, Busto P et al. 2016. Synergy between hematopoietic and radioresistant stromal cells is required for autoimmune manifestations of DNase II−/−IFNaR−/− mice. J. Immunol. 196:1348–54
    [Google Scholar]
  99. 99. 
    Pawaria S, Moody K, Busto P, Nundel K, Choi CH et al. 2015. Cutting edge: DNase II deficiency prevents activation of autoreactive B cells by double-stranded DNA endogenous ligands. J. Immunol. 194:1403–7
    [Google Scholar]
  100. 100. 
    Lahouassa H, Daddacha W, Hofmann H, Ayinde D, Logue EC et al. 2012. SAMHD1 restricts the replication of human immunodeficiency virus type 1 by depleting the intracellular pool of deoxynucleoside triphosphates. Nat. Immunol. 13:223–28
    [Google Scholar]
  101. 101. 
    Kretschmer S, Wolf C, Konig N, Staroske W, Guck J et al. 2015. SAMHD1 prevents autoimmunity by maintaining genome stability. Ann. Rheum. Dis. 74:e17
    [Google Scholar]
  102. 102. 
    Coquel F, Silva MJ, Techer H, Zadorozhny K, Sharma S et al. 2018. SAMHD1 acts at stalled replication forks to prevent interferon induction. Nature 557:57–61
    [Google Scholar]
  103. 103. 
    Gao D, Li T, Li XD, Chen X, Li QZ et al. 2015. Activation of cyclic GMP-AMP synthase by self-DNA causes autoimmune diseases. PNAS 112:E5699–705
    [Google Scholar]
  104. 104. 
    Crowl JT, Gray EE, Pestal K, Volkman HE, Stetson DB 2017. Intracellular nucleic acid detection in autoimmunity. Annu. Rev. Immunol. 35:313–36
    [Google Scholar]
  105. 105. 
    Aguirre S, Luthra P, Sanchez-Aparicio MT, Maestre AM, Patel J et al. 2017. Dengue virus NS2B protein targets cGAS for degradation and prevents mitochondrial DNA sensing during infection. Nat. Microbiol. 2:17037
    [Google Scholar]
  106. 106. 
    Wiens KE, Ernst JD. 2016. The mechanism for type I interferon induction by Mycobacterium tuberculosis is bacterial strain-dependent. PLOS Pathog 12:e1005809
    [Google Scholar]
  107. 107. 
    You F, Wang P, Yang L, Yang G, Zhao YO et al. 2013. ELF4 is critical for induction of type I interferon and the host antiviral response. Nat. Immunol. 14:1237–46
    [Google Scholar]
  108. 108. 
    Crow YJ. 2015. Type I interferonopathies: Mendelian type I interferon up-regulation. Curr. Opin. Immunol. 32:7–12
    [Google Scholar]
  109. 109. 
    Gray EE, Treuting PM, Woodward JJ, Stetson DB 2015. Cutting edge: cGAS is required for lethal autoimmune disease in the Trex1-deficient mouse model of Aicardi-Goutières syndrome. J. Immunol. 195:1939–43
    [Google Scholar]
  110. 110. 
    Crow YJ, Manel N. 2015. Aicardi-Goutières syndrome and the type I interferonopathies. Nat. Rev. Immunol. 15:429–40
    [Google Scholar]
  111. 111. 
    An J, Durcan L, Karr RM, Briggs TA, Rice GI et al. 2017. Expression of cyclic GMP-AMP synthase in patients with systemic lupus erythematosus. Arthritis Rheumatol 69:800–7
    [Google Scholar]
  112. 112. 
    Namjou B, Kothari PH, Kelly JA, Glenn SB, Ojwang JO et al. 2011. Evaluation of the TREX1 gene in a large multi-ancestral lupus cohort. Genes Immun 12:270–79
    [Google Scholar]
  113. 113. 
    Gunther C, Kind B, Reijns MA, Berndt N, Martinez-Bueno M et al. 2015. Defective removal of ribonucleotides from DNA promotes systemic autoimmunity. J. Clin. Investig. 125:413–24
    [Google Scholar]
  114. 114. 
    Vesely MD, Kershaw MH, Schreiber RD, Smyth MJ 2011. Natural innate and adaptive immunity to cancer. Annu. Rev. Immunol. 29:235–71
    [Google Scholar]
  115. 115. 
    Woo SR, Fuertes MB, Corrales L, Spranger S, Furdyna MJ et al. 2014. STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity 41:830–42
    [Google Scholar]
  116. 116. 
    Corrales L, McWhirter SM, Dubensky TW Jr, Gajewski TF 2016. The host STING pathway at the interface of cancer and immunity. J. Clin. Investig. 126:2404–11
    [Google Scholar]
  117. 117. 
    Corrales L, Glickman LH, McWhirter SM, Kanne DB, Sivick KE et al. 2015. Direct activation of STING in the tumor microenvironment leads to potent and systemic tumor regression and immunity. Cell Rep 11:1018–30
    [Google Scholar]
  118. 118. 
    Wang H, Hu S, Chen X, Shi H, Chen C et al. 2017. cGAS is essential for the antitumor effect of immune checkpoint blockade. PNAS 114:1637–42
    [Google Scholar]
  119. 119. 
    Xia T, Konno H, Ahn J, Barber GN 2016. Deregulation of STING signaling in colorectal carcinoma constrains DNA damage responses and correlates with tumorigenesis. Cell Rep 14:282–97
    [Google Scholar]
  120. 120. 
    Ramanjulu JM, Pesiridis GS, Yang J, Concha N, Singhaus R et al. 2018. Design of amidobenzimidazole STING receptor agonists with systemic activity. Nature 564:439–43
    [Google Scholar]
  121. 121. 
    Chen Q, Boire A, Jin X, Valiente M, Er EE et al. 2016. Carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer. Nature 533:493–98
    [Google Scholar]
  122. 122. 
    Liu H, Zhang H, Wu X, Ma D, Wu J et al. 2018. Nuclear cGAS suppresses DNA repair and promotes tumorigenesis. Nature 563:131–36
    [Google Scholar]
  123. 123. 
    King KR, Aguirre AD, Ye YX, Sun Y, Roh JD et al. 2017. IRF3 and type I interferons fuel a fatal response to myocardial infarction. Nat. Med. 23:1481–87
    [Google Scholar]
  124. 124. 
    Cao DJ, Schiattarella GG, Villalobos E, Jiang N, May HI et al. 2018. Cytosolic DNA sensing promotes macrophage transformation and governs myocardial ischemic injury. Circulation 137:2613–34
    [Google Scholar]
  125. 125. 
    Sliter DA, Martinez J, Hao L, Chen X, Sun N et al. 2018. Parkin and PINK1 mitigate STING-induced inflammation. Nature 561:258–62
    [Google Scholar]
  126. 126. 
    Martin I, Dawson VL, Dawson TM 2011. Recent advances in the genetics of Parkinson's disease. Annu. Rev. Genom. Hum. Genet. 12:301–25
    [Google Scholar]
  127. 127. 
    Springer W, Kahle PJ. 2011. Regulation of PINK1-Parkin-mediated mitophagy. Autophagy 7:266–78
    [Google Scholar]
  128. 128. 
    Bai J, Liu F. 2019. The cGAS-cGAMP-STING pathway: a molecular link between immunity and metabolism. Diabetes 68:1099–108
    [Google Scholar]
  129. 129. 
    Holm CK, Jensen SB, Jakobsen MR, Cheshenko N, Horan KA et al. 2012. Virus-cell fusion as a trigger of innate immunity dependent on the adaptor STING. Nat. Immunol. 13:737–43
    [Google Scholar]
  130. 130. 
    Zhang W, Wang G, Xu ZG, Tu H, Hu F et al. 2019. Lactate is a natural suppressor of RLR signaling by targeting MAVS. Cell 178:176–89.e15
    [Google Scholar]
/content/journals/10.1146/annurev-immunol-070119-115052
Loading
/content/journals/10.1146/annurev-immunol-070119-115052
Loading

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error