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Annual Review of Virology

Volume 10, 2023

CBASS to cGAS-STING: The Origins and Mechanisms of Nucleotide Second Messenger Immune Signaling

Abstract

Host defense against viral pathogens is an essential function for all living organisms. In cell-intrinsic innate immunity, dedicated sensor proteins recognize molecular signatures of infection and communicate to downstream adaptor or effector proteins to activate immune defense. Remarkably, recent evidence demonstrates that much of the core machinery of innate immunity is shared across eukaryotic and prokaryotic domains of life. Here, we review a pioneering example of evolutionary conservation in innate immunity: the animal cGAS-STING (cyclic GMP-AMP synthase–stimulator of interferon genes) signaling pathway and its ancestor in bacteria, CBASS (cyclic nucleotide-based antiphage signaling system) antiphage defense. We discuss the unique mechanism by which animal cGLRs (cGAS-like receptors) and bacterial CD-NTases (cGAS/dinucleotide-cyclase in (DncV)-like nucleotidyltransferases) in these pathways link pathogen detection with immune activation using nucleotide second messenger signals. Comparing the biochemical, structural, and mechanistic details of cGAS-STING, cGLR signaling, and CBASS, we highlight emerging questions in the field and examine evolutionary pressures that may have shaped the origins of nucleotide second messenger signaling in antiviral defense.

Keyword(s): antiviral defense, CBASS, cGAS, cGLR, innate immunity, nucleotide second messenger, STING
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/content/journals/10.1146/annurev-virology-111821-115636
2023-09-29
2024-04-28
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Literature Cited

  1. 1.
    Ishikawa H, Barber GN. 2008. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature 455:674–78
     [Google Scholar]
  2. 2.
    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]
  3. 3.
    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]
  4. 4.
    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]
  5. 5.
    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]
  6. 6.
    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]
  7. 7.
    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]
  8. 8.
    Ablasser A, Chen ZJ. 2019. cGAS in action: expanding roles in immunity and inflammation. Science 363:eaat8657
     [Google Scholar]
  9. 9.
    Slavik KM, Morehouse BR, Ragucci AE, Zhou W, Ai X et al. 2021. cGAS-like receptors sense RNA and control 3′2′-cGAMP signalling in Drosophila. Nature 597:109–13
     [Google Scholar]
  10. 10.
    Holleufer A, Winther KG, Gad HH, Ai X, Chen Y et al. 2021. Two cGAS-like receptors induce antiviral immunity in Drosophila. Nature 597:114–18
     [Google Scholar]
  11. 11.
    Li Y, Slavik KM, Morehouse BR, de Oliveira Mann CC, Mears K et al. 2023. cGLRs are a diverse family of pattern recognition receptors in animal innate immunity. bioRxiv 2023.02.22.529553 https://doi.org/10.1101/2023.02.22.529553
    [Crossref]
  12. 12.
    Whiteley AT, Eaglesham JB, de Oliveira Mann CC, Morehouse BR, Lowey B et al. 2019. Bacterial cGAS-like enzymes synthesize diverse nucleotide signals. Nature 567:194–99
     [Google Scholar]
  13. 13.
    Cohen D, Melamed S, Millman A, Shulman G, Oppenheimer-Shaanan Y et al. 2019. Cyclic GMP-AMP signalling protects bacteria against viral infection. Nature 574:691–95
     [Google Scholar]
  14. 14.
    Morehouse BR, Govande AA, Millman A, Keszei AFA, Lowey B et al. 2020. STING cyclic dinucleotide sensing originated in bacteria. Nature 586:429–33
     [Google Scholar]
  15. 15.
    Millman A, Melamed S, Amitai G, Sorek R. 2020. Diversity and classification of cyclic-oligonucleotide-based anti-phage signalling systems. Nat. Microbiol. 5:1608–15
     [Google Scholar]
  16. 16.
    Tesson F, Herve A, Mordret E, Touchon M, d'Humieres C et al. 2022. Systematic and quantitative view of the antiviral arsenal of prokaryotes. Nat. Commun. 13:2561
     [Google Scholar]
  17. 17.
    Lowey B, Whiteley AT, Keszei AFA, Morehouse BR, Mathews IT et al. 2020. CBASS immunity uses CARF-related effectors to sense 3′–5′- and 2′–5′-linked cyclic oligonucleotide signals and protect bacteria from phage infection. Cell 182:38–49
     [Google Scholar]
  18. 18.
    Ye Q, Lau RK, Mathews IT, Birkholz EA, Watrous JD et al. 2020. HORMA domain proteins and a Trip13-like ATPase regulate bacterial cGAS-like enzymes to mediate bacteriophage immunity. Mol. Cell 77:709–22
     [Google Scholar]
  19. 19.
    Lopatina A, Tal N, Sorek R. 2020. Abortive infection: bacterial suicide as an antiviral immune strategy. Annu. Rev. Virol. 7:371–84
     [Google Scholar]
  20. 20.
    Akira S, Uematsu S, Takeuchi O. 2006. Pathogen recognition and innate immunity. Cell 124:783–801
     [Google Scholar]
  21. 21.
    Flajnik MF, Kasahara M. 2010. Origin and evolution of the adaptive immune system: genetic events and selective pressures. Nat. Rev. Genet. 11:47–59
     [Google Scholar]
  22. 22.
    Hampton HG, Watson BNJ, Fineran PC. 2020. The arms race between bacteria and their phage foes. Nature 577:327–36
     [Google Scholar]
  23. 23.
    LeRoux M, Laub MT. 2022. Toxin-antitoxin systems as phage defense elements. Annu. Rev. Microbiol. 76:21–43
     [Google Scholar]
  24. 24.
    Niewoehner O, Garcia-Doval C, Rostol JT, Berk C, Schwede F et al. 2017. Type III CRISPR-Cas systems produce cyclic oligoadenylate second messengers. Nature 548:543–48
     [Google Scholar]
  25. 25.
    Kazlauskiene M, Kostiuk G, Venclovas C, Tamulaitis G, Siksnys V. 2017. A cyclic oligonucleotide signaling pathway in type III CRISPR-Cas systems. Science 357:605–9
     [Google Scholar]
  26. 26.
    Tal N, Morehouse BR, Millman A, Stokar-Avihail A, Avraham C et al. 2021. Cyclic CMP and cyclic UMP mediate bacterial immunity against phages. Cell 184:5728–39
     [Google Scholar]
  27. 27.
    Ofir G, Herbst E, Baroz M, Cohen D, Millman A et al. 2021. Antiviral activity of bacterial TIR domains via immune signalling molecules. Nature 600:116–20
     [Google Scholar]
  28. 28.
    Leavitt A, Yirmiya E, Amitai G, Lu A, Garb J et al. 2022. Viruses inhibit TIR gcADPR signalling to overcome bacterial defence. Nature 611:326–31
     [Google Scholar]
  29. 29.
    Kristiansen H, Gad HH, Eskildsen-Larsen S, Despres P, Hartmann R. 2011. The oligoadenylate synthetase family: an ancient protein family with multiple antiviral activities. J. Interferon Cytokine Res. 31:41–47
     [Google Scholar]
  30. 30.
    Stetson DB, Medzhitov R. 2006. Recognition of cytosolic DNA activates an IRF3-dependent innate immune response. Immunity 24:93–103
     [Google Scholar]
  31. 31.
    Eaglesham JB, Kranzusch PJ. 2020. Conserved strategies for pathogen evasion of cGAS-STING immunity. Curr. Opin. Immunol. 66:27–34
     [Google Scholar]
  32. 32.
    Vashi N, Bakhoum SF. 2021. The evolution of STING signaling and its involvement in cancer. Trends Biochem. Sci. 46:446–60
     [Google Scholar]
  33. 33.
    Hutinet G, Lee YJ, de Crecy-Lagard V, Weigele PR. 2021. Hypermodified DNA in viruses of E. coli and Salmonella. EcoSal Plus 9:eESP00282019
     [Google Scholar]
  34. 34.
    Banh DV, Roberts CG, Amador AM, Brady SF, Marraffini LA. 2023. Bacterial cGAS senses a viral RNA to initiate immunity. bioRxiv 2023.03.07.531596. https://doi.org/10.1101/2023.03.07.531596
  35. 35.
    Huiting E, Cao X, Ren J, Athukoralage JS, Luo Z et al. 2023. Bacteriophages inhibit and evade cGAS-like immune function in bacteria. Cell 186:864–76
     [Google Scholar]
  36. 36.
    Gao LA, Wilkinson ME, Strecker J, Makarova KS, Macrae RK et al. 2022. Prokaryotic innate immunity through pattern recognition of conserved viral proteins. Science 377:eabm4096
     [Google Scholar]
  37. 37.
    Zhang T, Tamman H, Coppieters 't Wallant K, Kurata T, LeRoux M et al. 2022. Direct activation of a bacterial innate immune system by a viral capsid protein. Nature 612:132–40
     [Google Scholar]
  38. 38.
    Duncan-Lowey B, Kranzusch PJ. 2022. CBASS phage defense and evolution of antiviral nucleotide signaling. Curr. Opin. Immunol. 74:156–63
     [Google Scholar]
  39. 39.
    Kranzusch PJ. 2019. cGAS and CD-NTase enzymes: structure, mechanism, and evolution. Curr. Opin. Struct. Biol. 59:178–87
     [Google Scholar]
  40. 40.
    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]
  41. 41.
    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]
  42. 42.
    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]
  43. 43.
    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]
  44. 44.
    Zhou W, Whiteley AT, de Oliveira Mann CC, Morehouse BR, Nowak RP et al. 2018. Structure of the human cGAS-DNA complex reveals enhanced control of immune surveillance. Cell 174:300–11
     [Google Scholar]
  45. 45.
    Kranzusch PJ, Lee ASY, Wilson SC, Solovykh MS, Vance RE et al. 2014. Structure-guided reprogramming of human cGAS dinucleotide linkage specificity. Cell 158:1011–21
     [Google Scholar]
  46. 46.
    Zhu D, Wang L, Shang G, Liu X, Zhu J et al. 2014. Structural biochemistry of a Vibrio cholerae dinucleotide cyclase reveals cyclase activity regulation by folates. Mol. Cell 55:931–37
     [Google Scholar]
  47. 47.
    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]
  48. 48.
    Du M, Chen ZJ. 2018. DNA-induced liquid phase condensation of cGAS activates innate immune signaling. Science 361:704–9
     [Google Scholar]
  49. 49.
    Xie W, Lama L, Adura C, Tomita D, Glickman JF et al. 2019. Human cGAS catalytic domain has an additional DNA-binding interface that enhances enzymatic activity and liquid-phase condensation. PNAS 116:11946–55
     [Google Scholar]
  50. 50.
    Zhou W, Mohr L, Maciejowski J, Kranzusch PJ. 2021. cGAS phase separation inhibits TREX1-mediated DNA degradation and enhances cytosolic DNA sensing. Mol. Cell 81:739–55
     [Google Scholar]
  51. 51.
    Duncan-Lowey B, McNamara-Bordewick NK, Tal N, Sorek R, Kranzusch PJ. 2021. Effector-mediated membrane disruption controls cell death in CBASS antiphage defense. Mol. Cell 81:5039–51
     [Google Scholar]
  52. 52.
    Burroughs AM, Zhang D, Schaffer DE, Iyer LM, Aravind L. 2015. Comparative genomic analyses reveal a vast, novel network of nucleotide-centric systems in biological conflicts, immunity and signaling. Nucleic Acids Res. 43:10633–54
     [Google Scholar]
  53. 53.
    Michalski S, de Oliveira Mann CC, Stafford CA, Witte G, Bartho J et al. 2020. Structural basis for sequestration and autoinhibition of cGAS by chromatin. Nature 587:678–82
     [Google Scholar]
  54. 54.
    Boyer JA, Spangler CJ, Strauss JD, Cesmat AP, Liu P et al. 2020. Structural basis of nucleosome-dependent cGAS inhibition. Science 370:450–54
     [Google Scholar]
  55. 55.
    Cao D, Han X, Fan X, Xu RM, Zhang X. 2020. Structural basis for nucleosome-mediated inhibition of cGAS activity. Cell Res. 30:1088–97
     [Google Scholar]
  56. 56.
    Kujirai T, Zierhut C, Takizawa Y, Kim R, Negishi L et al. 2020. Structural basis for the inhibition of cGAS by nucleosomes. Science 370:455–58
     [Google Scholar]
  57. 57.
    Pathare GR, Decout A, Gluck S, Cavadini S, Makasheva K et al. 2020. Structural mechanism of cGAS inhibition by the nucleosome. Nature 587:668–72
     [Google Scholar]
  58. 58.
    Zhao B, Xu P, Rowlett CM, Jing T, Shinde O et al. 2020. The molecular basis of tight nuclear tethering and inactivation of cGAS. Nature 587:673–77
     [Google Scholar]
  59. 59.
    Guey B, Wischnewski M, Decout A, Makasheva K, Kaynak M et al. 2020. BAF restricts cGAS on nuclear DNA to prevent innate immune activation. Science 369:823–28
     [Google Scholar]
  60. 60.
    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]
  61. 61.
    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–Goutieres syndrome. J. Immunol. 195:1939–43
     [Google Scholar]
  62. 62.
    Seo GJ, Kim C, Shin WJ, Sklan EH, Eoh H, Jung JU. 2018. TRIM56-mediated monoubiquitination of cGAS for cytosolic DNA sensing. Nat. Commun. 9:613
     [Google Scholar]
  63. 63.
    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]
  64. 64.
    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
     [Google Scholar]
  65. 65.
    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]
  66. 66.
    Li T, Huang T, Du M, Chen X, Du F et al. 2021. Phosphorylation and chromatin tethering prevent cGAS activation during mitosis. Science 371:eabc5386
     [Google Scholar]
  67. 67.
    Xu G, Liu C, Zhou S, Li Q, Feng Y et al. 2021. Viral tegument proteins restrict cGAS-DNA phase separation to mediate immune evasion. Mol. Cell 81:2823–37
     [Google Scholar]
  68. 68.
    Bhowmik D, Du M, Tian Y, Ma S, Wu J et al. 2021. Cooperative DNA binding mediated by KicGAS/ORF52 oligomerization allows inhibition of DNA-induced phase separation and activation of cGAS. Nucleic Acids Res. 49:9389–403
     [Google Scholar]
  69. 69.
    Meng F, Yu Z, Zhang D, Chen S, Guan H et al. 2021. Induced phase separation of mutant NF2 imprisons the cGAS-STING machinery to abrogate antitumor immunity. Mol. Cell 81:4147–64
     [Google Scholar]
  70. 70.
    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]
  71. 71.
    Liao CY, Lei CQ, Shu HB. 2021. PCBP1 modulates the innate immune response by facilitating the binding of cGAS to DNA. Cell Mol. Immunol. 18:2334–43
     [Google Scholar]
  72. 72.
    Tao X, Song J, Song Y, Zhang Y, Yang J et al. 2022. Ku proteins promote DNA binding and condensation of cyclic GMP-AMP synthase. Cell Rep. 40:111310
     [Google Scholar]
  73. 73.
    Peters NE, Ferguson BJ, Mazzon M, Fahy AS, Krysztofinska E et al. 2013. A mechanism for the inhibition of DNA-PK-mediated DNA sensing by a virus. PLOS Pathog. 9:e1003649
     [Google Scholar]
  74. 74.
    Scutts SR, Ember SW, Ren H, Ye C, Lovejoy CA et al. 2018. DNA-PK is targeted by multiple vaccinia virus proteins to inhibit DNA sensing. Cell Rep. 25:1953–65
     [Google Scholar]
  75. 75.
    Rivera-Calzada A, Arribas-Bosacoma R, Ruiz-Ramos A, Escudero-Bravo P, Boskovic J et al. 2022. Structural basis for the inactivation of cytosolic DNA sensing by the vaccinia virus. Nat. Commun. 13:7062
     [Google Scholar]
  76. 76.
    Ledvina HE, Ye Q, Gu Y, Sullivan AE, Quan Y et al. 2023. An E1–E2 fusion protein primes antiviral immune signalling in bacteria. Nature 616:319–25
     [Google Scholar]
  77. 77.
    Yan Y, Huang F, Yu B, Cheng R, Wu H et al. 2022. Ubiquitin-like cGAS chain formation by a super enzyme activates anti-phage response. bioRxiv 2022.05.25.493364 https://doi.org/10.1101/2022.05.25.493364
    [Crossref]
  78. 78.
    Jenson JM, Li T, Du F, Ea CK, Chen ZJ. 2023. Ubiquitin-like conjugation by bacterial cGAS enhances anti-phage defence. Nature 616:326–31
     [Google Scholar]
  79. 79.
    Blankenchip CL, Nguyen JV, Lau RK, Ye Q, Gu Y, Corbett KD. 2022. Control of bacterial immune signaling by a WYL domain transcription factor. Nucleic Acids Res. 50:5239–50
     [Google Scholar]
  80. 80.
    Govande AA, Duncan-Lowey B, Eaglesham JB, Whiteley AT, Kranzusch PJ. 2021. Molecular basis of CD-NTase nucleotide selection in CBASS anti-phage defense. Cell Rep. 35:109206
     [Google Scholar]
  81. 81.
    Ko TP, Wang YC, Tsai CL, Yang CS, Hou MH, Chen Y. 2021. Crystal structure and functional implication of a bacterial cyclic AMP-AMP-GMP synthetase. Nucleic Acids Res. 49:4725–37
     [Google Scholar]
  82. 82.
    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]
  83. 83.
    Luteijn RD, Zaver SA, Gowen BG, Wyman SK, Garelis NE et al. 2019. SLC19A1 transports immunoreactive cyclic dinucleotides. Nature 573:434–38
     [Google Scholar]
  84. 84.
    Ritchie C, Cordova AF, Hess GT, Bassik MC, Li L. 2019. SLC19A1 is an importer of the immunotransmitter cGAMP. Mol. Cell 75:372–81
     [Google Scholar]
  85. 85.
    Lahey LJ, Mardjuki RE, Wen X, Hess GT, Ritchie C et al. 2020. LRRC8A:C/E heteromeric channels are ubiquitous transporters of cGAMP. Mol. Cell 80:578–91
     [Google Scholar]
  86. 86.
    Gao P, Ascano M, Zillinger T, Wang W, Dai P et al. 2013. Structure-function analysis of STING activation by c[G(2′,5′)pA(3′,5′)p] and targeting by antiviral DMXAA. Cell 154:748–62
     [Google Scholar]
  87. 87.
    Kranzusch PJ, Wilson SC, Lee AS, Berger JM, Doudna JA, Vance RE. 2015. Ancient origin of cGAS-STING reveals mechanism of universal 2′,3′ cGAMP signaling. Mol. Cell 59:891–903
     [Google Scholar]
  88. 88.
    Davies BW, Bogard RW, Young TS, Mekalanos JJ. 2012. Coordinated regulation of accessory genetic elements produces cyclic di-nucleotides for V. cholerae virulence. Cell 149:358–70
     [Google Scholar]
  89. 89.
    Lau RK, Ye Q, Birkholz EA, Berg KR, Patel L et al. 2020. Structure and mechanism of a cyclic trinucleotide-activated bacterial endonuclease mediating bacteriophage immunity. Mol. Cell 77:723–33
     [Google Scholar]
  90. 90.
    Rouillon C, Schneberger N, Chi H, Blumenstock K, Da Vela S et al. 2022. Antiviral signaling by a cyclic nucleotide activated CRISPR protease. Nature 614:7946168–74
     [Google Scholar]
  91. 91.
    McFarland AP, Luo S, Ahmed-Qadri F, Zuck M, Thayer EF et al. 2017. Sensing of bacterial cyclic dinucleotides by the oxidoreductase RECON promotes NF-κB activation and shapes a proinflammatory antibacterial state. Immunity 46:433–45
     [Google Scholar]
  92. 92.
    Fatma S, Chakravarti A, Zeng X, Huang RH. 2021. Molecular mechanisms of the CdnG-Cap5 antiphage defense system employing 3′,2′-cGAMP as the second messenger. Nat. Commun. 12:6381
     [Google Scholar]
  93. 93.
    Maltbaek JH, Cambier S, Snyder JM, Stetson DB. 2022. ABCC1 transporter exports the immunostimulatory cyclic dinucleotide cGAMP. Immunity 55:1799–812
     [Google Scholar]
  94. 94.
    Marcus A, Mao AJ, Lensink-Vasan M, Wang L, Vance RE, Raulet DH. 2018. Tumor-derived cGAMP triggers a STING-mediated interferon response in non-tumor cells to activate the NK cell response. Immunity 49:754–63
     [Google Scholar]
  95. 95.
    Carozza JA, Cordova AF, Brown JA, AlSaif Y, Bohnert V et al. 2022. ENPP1's regulation of extracellular cGAMP is a ubiquitous mechanism of attenuating STING signaling. PNAS 119:e2119189119
     [Google Scholar]
  96. 96.
    Li L, Yin Q, Kuss P, Maliga Z, Millan JL et al. 2014. Hydrolysis of 2′3′-cGAMP by ENPP1 and design of nonhydrolyzable analogs. Nat. Chem. Biol. 10:1043–48
     [Google Scholar]
  97. 97.
    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]
  98. 98.
    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]
  99. 99.
    Segrist E, Dittmar M, Gold B, Cherry S. 2021. Orally acquired cyclic dinucleotides drive dSTING-dependent antiviral immunity in enterocytes. Cell Rep. 37:110150
     [Google Scholar]
  100. 100.
    Eaglesham JB, Pan Y, Kupper TS, Kranzusch PJ. 2019. Viral and metazoan poxins are cGAMP-specific nucleases that restrict cGAS-STING signalling. Nature 566:259–63
     [Google Scholar]
  101. 101.
    Hobbs SJ, Wein T, Lu A, Morehouse BR, Schnabel J et al. 2022. Phage anti-CBASS and anti-Pycsar nucleases subvert bacterial immunity. Nature 605:522–26
     [Google Scholar]
  102. 102.
    Maluquer de Motes C. 2021. Poxvirus cGAMP nucleases: clues and mysteries from a stolen gene. PLOS Pathog. 17:e1009372
     [Google Scholar]
  103. 103.
    Eaglesham JB, McCarty KL, Kranzusch PJ. 2020. Structures of diverse poxin cGAMP nucleases reveal a widespread role for cGAS-STING evasion in host-pathogen conflict. eLife 9:e59753
     [Google Scholar]
  104. 104.
    Hernaez B, Alonso G, Georgana I, El-Jesr M, Martin R et al. 2020. Viral cGAMP nuclease reveals the essential role of DNA sensing in protection against acute lethal virus infection. Sci. Adv. 6:38eabb4565
     [Google Scholar]
  105. 105.
    Burdette DL, Monroe KM, Sotelo-Troha K, Iwig JS, Eckert B et al. 2011. STING is a direct innate immune sensor of cyclic di-GMP. Nature 478:515–18
     [Google Scholar]
  106. 106.
    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]
  107. 107.
    de Oliveira Mann CC, Orzalli MH, King DS, Kagan JC, Lee ASY, Kranzusch PJ. 2019. Modular architecture of the STING C-terminal tail allows interferon and NF-κB signaling adaptation. Cell Rep. 27:1165–75
     [Google Scholar]
  108. 108.
    Wu X, Wu FH, Wang X, Wang L, Siedow JN et al. 2014. Molecular evolutionary and structural analysis of the cytosolic DNA sensor cGAS and STING. Nucleic Acids Res. 42:8243–57
     [Google Scholar]
  109. 109.
    Morehouse BR, Yip MCJ, Keszei AFA, McNamara-Bordewick NK, Shao S, Kranzusch PJ. 2022. Cryo-EM structure of an active bacterial TIR-STING filament complex. Nature 608:803–7
     [Google Scholar]
  110. 110.
    Hogrel G, Guild A, Graham S, Rickman H, Gruschow S et al. 2022. Cyclic nucleotide-induced helical structure activates a TIR immune effector. Nature 608:808–12
     [Google Scholar]
  111. 111.
    Huang YH, Liu XY, Du XX, Jiang ZF, Su XD. 2012. The structural basis for the sensing and binding of cyclic di-GMP by STING. Nat. Struct. Mol. Biol. 19:728–30
     [Google Scholar]
  112. 112.
    Ouyang S, Song X, Wang Y, Ru H, Shaw N et al. 2012. Structural analysis of the STING adaptor protein reveals a hydrophobic dimer interface and mode of cyclic di-GMP binding. Immunity 36:1073–86
     [Google Scholar]
  113. 113.
    Dey B, Dey RJ, Cheung LS, Pokkali S, Guo H et al. 2015. A bacterial cyclic dinucleotide activates the cytosolic surveillance pathway and mediates innate resistance to tuberculosis. Nat. Med. 21:401–6
     [Google Scholar]
  114. 114.
    Sixt BS, Bastidas RJ, Finethy R, Baxter RM, Carpenter VK et al. 2017. The Chlamydia trachomatis inclusion membrane protein CpoS counteracts STING-mediated cellular surveillance and suicide programs. Cell Host Microbe 21:113–21
     [Google Scholar]
  115. 115.
    Woodward JJ, Iavarone AT, Portnoy DA. 2010. c-di-AMP secreted by intracellular Listeria monocytogenes activates a host type I interferon response. Science 328:1703–5
     [Google Scholar]
  116. 116.
    Erttmann SF, Swacha P, Aung KM, Brindefalk B, Jiang H et al. 2022. The gut microbiota prime systemic antiviral immunity via the cGAS-STING-IFN-I axis. Immunity 55:847–61
     [Google Scholar]
  117. 117.
    Lam KC, Araya RE, Huang A, Chen Q, Di Modica M et al. 2021. Microbiota triggers STING-type I IFN-dependent monocyte reprogramming of the tumor microenvironment. Cell 184:5338–56
     [Google Scholar]
  118. 118.
    Ko TP, Wang YC, Yang CS, Hou MH, Chen CJ et al. 2022. Crystal structure and functional implication of bacterial STING. Nat. Commun. 13:26
     [Google Scholar]
  119. 119.
    Severin GB, Ramliden MS, Hawver LA, Wang K, Pell ME et al. 2018. Direct activation of a phospholipase by cyclic GMP-AMP in El Tor Vibrio cholerae. PNAS 115:E6048–55
     [Google Scholar]
  120. 120.
    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]
  121. 121.
    Chu TT, Tu X, Yang K, Wu J, Repa JJ, Yan N. 2021. Tonic prime-boost of STING signalling mediates Niemann-Pick disease type C. Nature 596:570–75
     [Google Scholar]
  122. 122.
    Liu Y, Xu P, Rivara S, Liu C, Ricci J et al. 2022. Clathrin-associated AP-1 controls termination of STING signalling. Nature 610:761–67
     [Google Scholar]
  123. 123.
    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]
  124. 124.
    Zhao B, Du F, Xu P, Shu C, Sankaran B et al. 2019. A conserved PLPLRT/SD motif of STING mediates the recruitment and activation of TBK1. Nature 569:718–22
     [Google Scholar]
  125. 125.
    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]
  126. 126.
    Zhao B, Shu C, Gao X, Sankaran B, Du F et al. 2016. Structural basis for concerted recruitment and activation of IRF-3 by innate immune adaptor proteins. PNAS 113:E3403–12
     [Google Scholar]
  127. 127.
    Chen H, Sun H, You F, Sun W, Zhou X et al. 2011. Activation of STAT6 by STING is critical for antiviral innate immunity. Cell 147:436–46
     [Google Scholar]
  128. 128.
    McWhirter SM, Barbalat R, Monroe KM, Fontana MF, Hyodo M et al. 2009. A host type I interferon response is induced by cytosolic sensing of the bacterial second messenger cyclic-di-GMP. J. Exp. Med. 206:1899–911
     [Google Scholar]
  129. 129.
    Wu J, Yan N. 2022. No longer a one-trick pony: STING signaling activity beyond interferon. J. Mol. Biol. 434:167257
     [Google Scholar]
  130. 130.
    Goto A, Okado K, Martins N, Cai H, Barbier V et al. 2018. The kinase IKKβ regulates a STING- and NF-κB-dependent antiviral response pathway in Drosophila. Immunity 49:225–34
     [Google Scholar]
  131. 131.
    Liu Y, Gordesky-Gold B, Leney-Greene M, Weinbren NL, Tudor M, Cherry S. 2018. Inflammation-induced, STING-dependent autophagy restricts Zika virus infection in the Drosophila brain. Cell Host Microbe 24:57–68
     [Google Scholar]
  132. 132.
    Martin M, Hiroyasu A, Guzman RM, Roberts SA, Goodman AG. 2018. Analysis of Drosophila STING reveals an evolutionarily conserved antimicrobial function. Cell Rep. 23:3537–50
     [Google Scholar]
  133. 133.
    Cai H, Holleufer A, Simonsen B, Schneider J, Lemoine A et al. 2020. 2′3′-cGAMP triggers a STING- and NF-κB–dependent broad antiviral response in Drosophila. Sci. Signal. 13:660eabc4537
     [Google Scholar]
  134. 134.
    Gui X, Yang H, Li T, Tan X, Shi P et al. 2019. Autophagy induction via STING trafficking is a primordial function of the cGAS pathway. Nature 567:262–66
     [Google Scholar]
  135. 135.
    Margolis SR, Dietzen PA, Hayes BM, Wilson SC, Remick BC et al. 2021. The cyclic dinucleotide 2′3′-cGAMP induces a broad antibacterial and antiviral response in the sea anemone Nematostella vectensis. PNAS 118:e2109022118
     [Google Scholar]
  136. 136.
    Woznica A, Kumar A, Sturge CR, Xing C, King N, Pfeiffer JK. 2021. STING mediates immune responses in the closest living relatives of animals. eLife 10:e70436
     [Google Scholar]
  137. 137.
    Hayden MS, Ghosh S. 2011. NF-κB in immunobiology. Cell Res. 21:223–44
     [Google Scholar]
  138. 138.
    Zhang T, Ma C, Zhang Z, Zhang H, Hu H. 2021. NF-κB signaling in inflammation and cancer. MedComm 2020:2618–53
     [Google Scholar]
  139. 139.
    Schoggins JW. 2019. Interferon-stimulated genes: What do they all do?. Annu. Rev. Virol. 6:567–84
     [Google Scholar]
  140. 140.
    Bernheim A, Millman A, Ofir G, Meitav G, Avraham C et al. 2021. Prokaryotic viperins produce diverse antiviral molecules. Nature 589:120–24
     [Google Scholar]
  141. 141.
    Johnson AG, Wein T, Mayer ML, Duncan-Lowey B, Yirmiya E et al. 2022. Bacterial gasdermins reveal an ancient mechanism of cell death. Science 375:221–25
     [Google Scholar]
  142. 142.
    Bernheim A, Sorek R. 2020. The pan-immune system of bacteria: antiviral defence as a community resource. Nat. Rev. Microbiol. 18:113–19
     [Google Scholar]
  143. 143.
    Gao L, Altae-Tran H, Bohning F, Makarova KS, Segel M et al. 2020. Diverse enzymatic activities mediate antiviral immunity in prokaryotes. Science 369:1077–84
     [Google Scholar]
  144. 144.
    Millman A, Melamed S, Leavitt A, Doron S, Bernheim A et al. 2022. An expanded arsenal of immune systems that protect bacteria from phages. Cell Host Microbe 30:1556–69
     [Google Scholar]
  145. 145.
    Gruschow S, Adamson CS, White MF. 2021. Specificity and sensitivity of an RNA targeting type III CRISPR complex coupled with a NucC endonuclease effector. Nucleic Acids Res. 49:13122–34
     [Google Scholar]
  146. 146.
    Mayo-Munoz D, Smith LM, Garcia-Doval C, Malone LM, Harding KR et al. 2022. Type III CRISPR-Cas provides resistance against nucleus-forming jumbo phages via abortive infection. Mol. Cell 82:4471–86
     [Google Scholar]
  147. 147.
    Essuman K, Summers DW, Sasaki Y, Mao X, Yim AKY et al. 2018. TIR domain proteins are an ancient family of NAD+-consuming enzymes. Curr. Biol. 28:421–30
     [Google Scholar]
  148. 148.
    Horsefield S, Burdett H, Zhang X, Manik MK, Shi Y et al. 2019. NAD+ cleavage activity by animal and plant TIR domains in cell death pathways. Science 365:793–99
     [Google Scholar]
  149. 149.
    Garb J, Lopatina A, Bernheim A, Zaremba M, Siksnys V et al. 2022. Multiple phage resistance systems inhibit infection via SIR2-dependent NAD+ depletion. Nat. Microbiol. 7:1849–56
     [Google Scholar]
  150. 150.
    Rousset F, Yirmiya E, Nesher S, Brandis A, Mehlman T et al. 2023. A conserved family of immune effectors cleaves cellular ATP upon viral infection. bioRxiv 2023.01.24.525353 https://doi.org/10.1101/2023.01.24.525353
    [Crossref]
  151. 151.
    Hee CS, Habazettl J, Schmutz C, Schirmer T, Jenal U, Grzesiek S. 2020. Intercepting second-messenger signaling by rationally designed peptides sequestering c-di-GMP. PNAS 117:17211–20
     [Google Scholar]
  152. 152.
    VanderWal AR, Park J-U, Polevoda B, Nicosia JK, Molina Vargas AM et al. 2023. Csx28 is a membrane pore that enhances CRISPR-Cas13b–dependent antiphage defense. Science 380:6643410–15
     [Google Scholar]
  153. 153.
    Doron S, Melamed S, Ofir G, Leavitt A, Lopatina A et al. 2018. Systematic discovery of antiphage defense systems in the microbial pangenome. Science 359:eaar4120
     [Google Scholar]
  154. 154.
    Makarova KS, Wolf YI, Snir S, Koonin EV. 2011. Defense islands in bacterial and archaeal genomes and prediction of novel defense systems. J. Bacteriol. 193:6039–56
     [Google Scholar]
  155. 155.
    Johnson MC, Laderman E, Huiting E, Zhang C, Davidson A, Bondy-Denomy J. 2022. Core defense hotspots within Pseudomonas aeruginosa are a consistent and rich source of anti-phage defense systems. bioRxiv 2022.11.11.516204. https://doi.org/10.1101/2022.11.11.516204
  156. 156.
    Koonin EV, Makarova KS, Wolf YI. 2017. Evolutionary genomics of defense systems in archaea and bacteria. Annu. Rev. Microbiol. 71:233–61
     [Google Scholar]
  157. 157.
    Martin WF, Garg S, Zimorski V. 2015. Endosymbiotic theories for eukaryote origin. Philos. Trans. R. Soc. B 370:20140330
     [Google Scholar]
  158. 158.
    Wein T, Sorek R. 2022. Bacterial origins of human cell-autonomous innate immune mechanisms. Nat. Rev. Immunol. 22:629–38
     [Google Scholar]
  159. 159.
    Cury J, Mordret E, Trejo VH, Tesson F, Ofir G et al. 2022. Conservation of antiviral systems across domains of life reveals novel immune mechanisms in humans. bioRxiv 2022.12.12.520048 https://doi.org/10.1101/2022.12.12.520048
    [Crossref]
  160. 160.
    Chou S, Daugherty MD, Peterson SB, Biboy J, Yang Y et al. 2015. Transferred interbacterial antagonism genes augment eukaryotic innate immune function. Nature 518:98–101
     [Google Scholar]
  161. 161.
    Dunning Hotopp JC. 2011. Horizontal gene transfer between bacteria and animals. Trends Genet. 27:157–63
     [Google Scholar]
  162. 162.
    de Oliveira Mann CC, Kiefersauer R, Witte G, Hopfner KP. 2016. Structural and biochemical characterization of the cell fate determining nucleotidyltransferase fold protein MAB21L1. Sci. Rep. 6:27498
     [Google Scholar]
  163. 163.
    Horn D, Prescott T, Houge G, Braekke K, Rosendahl K et al. 2015. A Novel Oculo-Skeletal syndrome with intellectual disability caused by a particular MAB21L2 mutation. Eur. J. Med. Genet. 58:387–91
     [Google Scholar]
  164. 164.
    Hovanessian AG, Brown RE, Kerr IM. 1977. Synthesis of low molecular weight inhibitor of protein synthesis with enzyme from interferon-treated cells. Nature 268:537–40
     [Google Scholar]
  165. 165.
    Kerr IM, Brown RE. 1978. pppA2′p5′A2′p5′A: an inhibitor of protein synthesis synthesized with an enzyme fraction from interferon-treated cells. PNAS 75:256–60
     [Google Scholar]
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CBASS to cGAS-STING: The Origins and Mechanisms of Nucleotide Second Messenger Immune Signaling
Annual Review of Virology 10, 423 (2023); https://doi.org/10.1146/annurev-virology-111821-115636
/content/journals/10.1146/annurev-virology-111821-115636
/content/journals/10.1146/annurev-virology-111821-115636
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