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Versatile modes of cellular regulation via cyclic dinucleotides

Abstract

Since the discovery of c-di-GMP almost three decades ago, cyclic dinucleotides (CDNs) have emerged as widely used signaling molecules in most kingdoms of life. The family of second messengers now includes c-di-AMP and distinct versions of mixed cyclic GMP-AMP (cGAMP) compounds. In addition to these nucleotides, a vast number of proteins for the production and turnover of these molecules have been described, as well as effectors that translate the signals into physiological responses. The latter include, but are not limited to, mechanisms for adaptation and survival in prokaryotes, persistence and virulence of bacterial pathogens, and immune responses to viral and bacterial invasion in eukaryotes. In this review, we will focus on recent discoveries and emerging themes that illustrate the ubiquity and versatility of cyclic dinucleotide function at the transcriptional and post-translational levels and, in particular, on insights gained through mechanistic structure-function analyses.

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Figure 1: CDN signaling.
Figure 2: Bacterial CDNs and representative regulatory mechanisms.
Figure 3: Conformational adaptability and mechanism of action of CDNs.
Figure 4: Tripartite transmembrane signaling through HAMP-domaincontaining proteins with active or degenerate GGDEF and EAL domains.
Figure 5: Structures and nucleotide recognition of c-di-GMP-regulated transcription factors.
Figure 6: CDN-dependent regulation of ion transport.
Figure 7: c-di-GMP-dependent regulation of exopolysaccharide secretion in biofilms.
Figure 8: CDN recognition by STING.

References

  1. Ross, P. et al. Regulation of cellulose synthesis in Acetobacter xylinum by cyclic diguanylic acid. Nature 325, 279–281 (1987). Seminal work on the discovery of c-di-GMP as an allosteric regulator of bacterial cellulose synthesis that laid the foundation of CDN signaling research.

    Article  CAS  PubMed  Google Scholar 

  2. Weinhouse, H. et al. c-di-GMP-binding protein, a new factor regulating cellulose synthesis in Acetobacter xylinum. FEBS Lett. 416, 207–211 (1997).

    Article  CAS  PubMed  Google Scholar 

  3. Tal, R. et al. Three cdg operons control cellular turnover of cyclic di-GMP in Acetobacter xylinum: genetic organization and occurrence of conserved domains in isoenzymes. J. Bacteriol. 180, 4416–4425 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Paul, R. et al. Cell cycle-dependent dynamic localization of a bacterial response regulator with a novel di-guanylate cyclase output domain. Genes Dev. 18, 715–727 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Christen, M., Christen, B., Folcher, M., Schauerte, A. & Jenal, U. Identification and characterization of a cyclic di-GMP-specific phosphodiesterase and its allosteric control by GTP. J. Biol. Chem. 280, 30829–30837 (2005).

    Article  CAS  PubMed  Google Scholar 

  6. Simm, R., Morr, M., Kader, A., Nimtz, M. & Römling, U. GGDEF and EAL domains inversely regulate cyclic di-GMP levels and transition from sessility to motility. Mol. Microbiol. 53, 1123–1134 (2004).

    Article  CAS  PubMed  Google Scholar 

  7. Hickman, J.W., Tifrea, D.F. & Harwood, C.S. A chemosensory system that regulates biofilm formation through modulation of cyclic diguanylate levels. Proc. Natl. Acad. Sci. USA 102, 14422–14427 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Hisert, K.B. et al. A glutamate-alanine-leucine (EAL) domain protein of Salmonella controls bacterial survival in mice, antioxidant defence and killing of macrophages: role of cyclic diGMP. Mol. Microbiol. 56, 1234–1245 (2005).

    Article  CAS  PubMed  Google Scholar 

  9. Tischler, A.D. & Camilli, A. Cyclic diguanylate (c-di-GMP) regulates Vibrio cholerae biofilm formation. Mol. Microbiol. 53, 857–869 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Galperin, M.Y., Nikolskaya, A.N. & Koonin, E.V. Novel domains of the prokaryotic two-component signal transduction systems. FEMS Microbiol. Lett. 203, 11–21 (2001). A comprehensive bioinformatics study highlighting the prevalence of c-di-GMP signaling across the bacterial domain, as well as the multi-component, multiple-pathway nature of c-di-GMP signal transduction within highly adaptable species.

    Article  CAS  PubMed  Google Scholar 

  11. Witte, G., Hartung, S., Büttner, K. & Hopfner, K.P. Structural biochemistry of a bacterial checkpoint protein reveals diadenylate cyclase activity regulated by DNA recombination intermediates. Mol. Cell 30, 167–178 (2008). A structure-function study of B. subtilis DNA damage checkpoint protein DisA, which led to the serendipitous discovery of c-di-AMP and its dedicated diadenylate cyclases.

    Article  CAS  PubMed  Google Scholar 

  12. Bai, Y. et al. Cyclic di-AMP impairs potassium uptake mediated by a cyclic di-AMP binding protein in Streptococcus pneumoniae. J. Bacteriol. 196, 614–623 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Huynh, T.N. et al. An HD-domain phosphodiesterase mediates cooperative hydrolysis of c-di-AMP to affect bacterial growth and virulence. Proc. Natl. Acad. Sci. USA 112, E747–E756 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Mehne, F.M. et al. Cyclic di-AMP homeostasis in bacillus subtilis: both lack and high level accumulation of the nucleotide are detrimental for cell growth. J. Biol. Chem. 288, 2004–2017 (2013).

    Article  CAS  PubMed  Google Scholar 

  15. Zhang, L., Li, W. & He, Z.G. DarR, a TetR-like transcriptional factor, is a cyclic di-AMP-responsive repressor in Mycobacterium smegmatis. J. Biol. Chem. 288, 3085–3096 (2013).

    Article  CAS  PubMed  Google Scholar 

  16. Kaplan Zeevi, M. et al. Listeria monocytogenes multidrug resistance transporters and cyclic di-AMP, which contribute to type I interferon induction, play a role in cell wall stress. J. Bacteriol. 195, 5250–5261 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Sureka, K. et al. The cyclic dinucleotide c-di-AMP is an allosteric regulator of metabolic enzyme function. Cell 158, 1389–1401 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Corrigan, R.M. et al. Systematic identification of conserved bacterial c-di-AMP receptor proteins. Proc. Natl. Acad. Sci. USA 110, 9084–9089 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Moscoso, J.A. et al. Binding of cyclic di-AMP to the Staphylococcus aureus Sensor kinase KDPD occurs via the universal stress protein domain and downregulates the expression of the KDP potassium transporter. J. Bacteriol. 198, 98–110 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Davies, B.W., Bogard, R.W., Young, T.S. & Mekalanos, J.J. Coordinated regulation of accessory genetic elements produces cyclic di-nucleotides for V. cholerae virulence. Cell 149, 358–370 (2012). Identification of V. cholerae DncV as a virulence factor and a cyclase for previously undescribed hybrid cGAMP.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Pei, J. & Grishin, N.V. GGDEF domain is homologous to adenylyl cyclase. Proteins 42, 210–216 (2001).

    Article  CAS  PubMed  Google Scholar 

  22. Chan, C. et al. Structural basis of activity and allosteric control of diguanylate cyclase. Proc. Natl. Acad. Sci. USA 101, 17084–17089 (2004). First structural study of a diguanylate cyclase that led to the characterization of the allosteric I-site for feedback regulation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Dahlstrom, K.M., Giglio, K.M., Sondermann, H. & O'Toole, G.A. The inhibitory site of a diguanylate cyclase is a necessary element for interaction and signaling with an effector protein. J. Bacteriol. 198, 1595–1603 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Barends, T.R. et al. Structure and mechanism of a bacterial light-regulated cyclic nucleotide phosphodiesterase. Nature 459, 1015–1018 (2009). A structure-function study revealing the regulation of c-di-GMP specific phosphodiesterases

    Article  CAS  PubMed  Google Scholar 

  25. Bellini, D. et al. Crystal structure of an HD-GYP domain cyclic-di-GMP phosphodiesterase reveals an enzyme with a novel trinuclear catalytic iron centre. Mol. Microbiol. 91, 26–38 (2014).

    Article  CAS  PubMed  Google Scholar 

  26. Stelitano, V. et al. C-di-GMP hydrolysis by Pseudomonas aeruginosa HD-GYP phosphodiesterases: analysis of the reaction mechanism and novel roles for pGpG. PLoS One 8, e74920 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Cohen, D. et al. Oligoribonuclease is a central feature of cyclic diguanylate signaling in Pseudomonas aeruginosa. Proc. Natl. Acad. Sci. USA 112, 11359–11364 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Orr, M.W. et al. Oligoribonuclease is the primary degradative enzyme for pGpG in Pseudomonas aeruginosa that is required for cyclic-di-GMP turnover. Proc. Natl. Acad. Sci. USA 112, E5048–E5057 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Galperin, M.Y. A census of membrane-bound and intracellular signal transduction proteins in bacteria: bacterial IQ, extroverts and introverts. BMC Microbiol. 5, 35 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Corrigan, R.M. & Gründling, A. Cyclic di-AMP: another second messenger enters the fray. Nat. Rev. Microbiol. 11, 513–524 (2013).

    Article  CAS  PubMed  Google Scholar 

  31. Rao, F. et al. YybT is a signaling protein that contains a cyclic dinucleotide phosphodiesterase domain and a GGDEF domain with ATPase activity. J. Biol. Chem. 285, 473–482 (2010).

    Article  CAS  PubMed  Google Scholar 

  32. Kranzusch, P.J. et al. Structure-guided reprogramming of human cGAS dinucleotide linkage specificity. Cell 158, 1011–1021 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Zhu, D. et al. Structural biochemistry of a Vibrio cholerae dinucleotide cyclase reveals cyclase activity regulation by folates. Mol. Cell 55, 931–937 (2014).

    Article  CAS  PubMed  Google Scholar 

  34. Hallberg, Z.F. et al. Hybrid promiscuous (Hypr) GGDEF enzymes produce cyclic AMP-GMP (3′, 3′-cGAMP). Proc. Natl. Acad. Sci. USA 113, 1790–1795 (2016). Identification of a subclass of GGDEF-domain-containing dinucleotide cyclases with broad catalytic spectrum and substrate specificity reflecting cellular AMP:GMP ratios.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Navarro, M.V., De, N., Bae, N., Wang, Q. & Sondermann, H. Structural analysis of the GGDEF-EAL domain-containing c-di-GMP receptor FimX. Structure 17, 1104–1116 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Navarro, M.V. et al. Structural basis for c-di-GMP-mediated inside-out signaling controlling periplasmic proteolysis. PLoS Biol. 9, e1000588 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ozaki, S. et al. Activation and polar sequestration of PopA, a c-di-GMP effector protein involved in Caulobacter crescentus cell cycle control. Mol. Microbiol. 94, 580–594 (2014).

    Article  CAS  PubMed  Google Scholar 

  38. Lee, V.T. et al. A cyclic-di-GMP receptor required for bacterial exopolysaccharide production. Mol. Microbiol. 65, 1474–1484 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Amikam, D. & Galperin, M.Y. PilZ domain is part of the bacterial c-di-GMP binding protein. Bioinformatics 22, 3–6 (2006).

    Article  CAS  PubMed  Google Scholar 

  40. Hickman, J.W. & Harwood, C.S. Identification of FleQ from Pseudomonas aeruginosa as a c-di-GMP-responsive transcription factor. Mol. Microbiol. 69, 376–389 (2008). The first work to demonstrate c-di-GMP control at the transcription initiation level through the regulation of biofilm-related genes by direct c-di-GMP binding to P. aeruginosa FleQ.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Krasteva, P.V. et al. Vibrio cholerae VpsT regulates matrix production and motility by directly sensing cyclic di-GMP. Science 327, 866–868 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Srivastava, D., Harris, R.C. & Waters, C.M. Integration of cyclic di-GMP and quorum sensing in the control of vpsT and aphA in Vibrio cholerae. J. Bacteriol. 193, 6331–6341 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Düvel, J. et al. A chemical proteomics approach to identify c-di-GMP binding proteins in Pseudomonas aeruginosa. J. Microbiol. Methods 88, 229–236 (2012).

    Article  PubMed  CAS  Google Scholar 

  44. Nesper, J., Reinders, A., Glatter, T., Schmidt, A. & Jenal, U. A novel capture compound for the identification and analysis of cyclic di-GMP binding proteins. J. Proteomics 75, 4874–4878 (2012).

    Article  CAS  PubMed  Google Scholar 

  45. Roelofs, K.G., Wang, J., Sintim, H.O. & Lee, V.T. Differential radial capillary action of ligand assay for high-throughput detection of protein-metabolite interactions. Proc. Natl. Acad. Sci. USA 108, 15528–15533 (2011). A methodological work on a quantitative high-throughput assay for the unbiased discovery and characterization of CDN-binding proteins.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Roelofs, K.G. et al. Systematic identification of cyclic-di-GMP binding proteins in Vibrio cholerae reveals a novel class of cyclic-di-GMP-binding ATPases associated with type II secretion systems. PLoS Pathog. 11, e1005232 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  47. Newell, P.D., Boyd, C.D., Sondermann, H. & O'Toole, G.A. A c-di-GMP effector system controls cell adhesion by inside-out signaling and surface protein cleavage. PLoS Biol. 9, e1000587 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Cooley, R.B. et al. Cyclic di-GMP-regulated periplasmic proteolysis of a Pseudomonas aeruginosa type Vb secretion system substrate. J. Bacteriol. 198, 66–76 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Chatterjee, D. et al. Mechanistic insight into the conserved allosteric regulation of periplasmic proteolysis by the signaling molecule cyclic-di-GMP. eLife 3, e03650 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Giardina, G. et al. Investigating the allosteric regulation of YfiN from Pseudomonas aeruginosa: clues from the structure of the catalytic domain. PLoS One 8, e81324 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Malone, J.G. et al. The YfiBNR signal transduction mechanism reveals novel targets for the evolution of persistent Pseudomonas aeruginosa in cystic fibrosis airways. PLoS Pathog. 8, e1002760 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Srivastava, D., Hsieh, M.L., Khataokar, A., Neiditch, M.B. & Waters, C.M. Cyclic di-GMP inhibits Vibrio cholerae motility by repressing induction of transcription and inducing extracellular polysaccharide production. Mol. Microbiol. 90, 1262–1276 (2013).

    Article  CAS  PubMed  Google Scholar 

  53. Tschowri, N. et al. Tetrameric c-di-GMP mediates effective transcription factor dimerization to control Streptomyces development. Cell 158, 1136–1147 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Chin, K.H. et al. The cAMP receptor-like protein CLP is a novel c-di-GMP receptor linking cell-cell signaling to virulence gene expression in Xanthomonas campestris. J. Mol. Biol. 396, 646–662 (2010).

    Article  CAS  PubMed  Google Scholar 

  55. Li, W. & He, Z.G. LtmA, a novel cyclic di-GMP-responsive activator, broadly regulates the expression of lipid transport and metabolism genes in Mycobacterium smegmatis. Nucleic Acids Res. 40, 11292–11307 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Shikuma, N.J., Fong, J.C. & Yildiz, F.H. Cellular levels and binding of c-di-GMP control subcellular localization and activity of the Vibrio cholerae transcriptional regulator VpsT. PLoS Pathog. 8, e1002719 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Baraquet, C. & Harwood, C.S. Cyclic diguanosine monophosphate represses bacterial flagella synthesis by interacting with the Walker A motif of the enhancer-binding protein FleQ. Proc. Natl. Acad. Sci. USA 110, 18478–18483 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Baraquet, C., Murakami, K., Parsek, M.R. & Harwood, C.S. The FleQ protein from Pseudomonas aeruginosa functions as both a repressor and an activator to control gene expression from the pel operon promoter in response to c-di-GMP. Nucleic Acids Res. 40, 7207–7218 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Matsuyama, B.Y. et al. Mechanistic insights into c-di-GMP-dependent control of the biofilm regulator FleQ from Pseudomonas aeruginosa. Proc. Natl. Acad. Sci. USA 113, E209–E218 (2016).

    Article  CAS  PubMed  Google Scholar 

  60. Lauriano, C.M., Ghosh, C., Correa, N.E. & Klose, K.E. The sodium-driven flagellar motor controls exopolysaccharide expression in Vibrio cholerae. J. Bacteriol. 186, 4864–4874 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. den Hengst, C.D. et al. Genes essential for morphological development and antibiotic production in Streptomyces coelicolor are targets of BldD during vegetative growth. Mol. Microbiol. 78, 361–379 (2010).

    Article  CAS  PubMed  Google Scholar 

  62. Vieira-Pires, R.S., Szollosi, A. & Morais-Cabral, J.H. The structure of the KtrAB potassium transporter. Nature 496, 323–328 (2013).

    Article  CAS  PubMed  Google Scholar 

  63. Kim, H. et al. Structural studies of potassium transport protein KtrA regulator of conductance of K+ (RCK) C domain in complex with cyclic diadenosine monophosphate (c-di-AMP). J. Biol. Chem. 290, 16393–16402 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Lolicato, M. et al. Cyclic dinucleotides bind the C-linker of HCN4 to control channel cAMP responsiveness. Nat. Chem. Biol. 10, 457–462 (2014).

    Article  CAS  PubMed  Google Scholar 

  65. Costa, T.R. et al. Secretion systems in Gram-negative bacteria: structural and mechanistic insights. Nat. Rev. Microbiol. 13, 343–359 (2015).

    Article  CAS  PubMed  Google Scholar 

  66. Trampari, E. et al. Bacterial rotary export ATPases are allosterically regulated by the nucleotide second messenger cyclic-di-GMP. J. Biol. Chem. 290, 24470–24483 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Wang, Y.C. et al. Nucleotide binding by the widespread high-affinity cyclic di-GMP receptor MshEN domain. Nat. Commun. 7, 12481 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Whitney, J.C. & Howell, P.L. Synthase-dependent exopolysaccharide secretion in Gram-negative bacteria. Trends Microbiol. 21, 63–72 (2013).

    Article  CAS  PubMed  Google Scholar 

  69. McNamara, J.T., Morgan, J.L. & Zimmer, J. A molecular description of cellulose biosynthesis. Annu. Rev. Biochem. 84, 895–921 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Fang, X. et al. GIL, a new c-di-GMP-binding protein domain involved in regulation of cellulose synthesis in enterobacteria. Mol. Microbiol. 93, 439–452 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Li, Z., Chen, J.H., Hao, Y. & Nair, S.K. Structures of the PelD cyclic diguanylate effector involved in pellicle formation in Pseudomonas aeruginosa PAO1. J. Biol. Chem. 287, 30191–30204 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Whitney, J.C. et al. Structure of the cytoplasmic region of PelD, a degenerate diguanylate cyclase receptor that regulates exopolysaccharide production in Pseudomonas aeruginosa. J. Biol. Chem. 287, 23582–23593 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Steiner, S., Lori, C., Boehm, A. & Jenal, U. Allosteric activation of exopolysaccharide synthesis through cyclic di-GMP-stimulated protein-protein interaction. EMBO J. 32, 354–368 (2013).

    Article  CAS  PubMed  Google Scholar 

  74. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Sun, J., Deng, Z. & Yan, A. Bacterial multidrug efflux pumps: mechanisms, physiology and pharmacological exploitations. Biochem. Biophys. Res. Commun. 453, 254–267 (2014).

    Article  CAS  PubMed  Google Scholar 

  76. Chen, Z.H. & Schaap, P. The prokaryote messenger c-di-GMP triggers stalk cell differentiation in Dictyostelium. Nature 488, 680–683 (2012). The first report of c-di-GMP biosynthesis and signal transduction in eukaryotes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Gentili, M. et al. Transmission of innate immune signaling by packaging of cGAMP in viral particles. Science 349, 1232–1236 (2015).

    Article  CAS  PubMed  Google Scholar 

  78. Bridgeman, A. et al. Viruses transfer the antiviral second messenger cGAMP between cells. Science 349, 1228–1232 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Ablasser, A. et al. Cell intrinsic immunity spreads to bystander cells via the intercellular transfer of cGAMP. Nature 503, 530–534 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Chen, Q. et al. Carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer. Nature 533, 493–498 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Li, L. et al. Hydrolysis of 2¢3′-cGAMP by ENPP1 and design of nonhydrolyzable analogs. Nat. Chem. Biol. 10, 1043–1048 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. 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).

    Article  CAS  PubMed  Google Scholar 

  83. Burdette, D.L. et al. STING is a direct innate immune sensor of cyclic di-GMP. Nature 478, 515–518 (2011). Identification of STING as a eukaryotic CDN sensor-effector.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. 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).

    Article  CAS  PubMed  Google Scholar 

  86. Wu, J. et al. Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA. Science 339, 826–830 (2013). Identification of cGAMP as an endogenous CDN product in mammalian cells, as well as its direct role in type I interferon response through direct STING activation.

    Article  CAS  PubMed  Google Scholar 

  87. Ablasser, A. et al. cGAS produces a 2′-5′-linked cyclic dinucleotide second messenger that activates STING. Nature 498, 380–384 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. 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).

    Article  CAS  PubMed  Google Scholar 

  89. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Huang, Y.H., Liu, X.Y., Du, X.X., Jiang, Z.F. & Su, X.D. The structural basis for the sensing and binding of cyclic di-GMP by STING. Nat. Struct. Mol. Biol. 19, 728–730 (2012).

    Article  CAS  PubMed  Google Scholar 

  91. 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).

    Article  CAS  PubMed  Google Scholar 

  92. 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).

    Article  CAS  PubMed  Google Scholar 

  93. Chin, K.H. et al. Novel c-di-GMP recognition modes of the mouse innate immune adaptor protein STING. Acta Crystallogr. D Biol. Crystallogr. 69, 352–366 (2013).

    Article  CAS  PubMed  Google Scholar 

  94. Kranzusch, P.J. et al. Ancient origin of cGAS-STING reveals mechanism of universal 2′,3′ cGAMP signaling. Mol. Cell 59, 891–903 (2015). Structural studies of an anemone STING homolog revealing the likely ancient origins of eukaryotic 2-3cGAMP recognition through the exploitation of a unique conformational intermediate not sampled by 3-3CDNs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Yin, Q. et al. Cyclic di-GMP sensing via the innate immune signaling protein STING. Mol. Cell 46, 735–745 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Zhang, L. et al. NLRC3, a member of the NLR family of proteins, is a negative regulator of innate immune signaling induced by the DNA sensor STING. Immunity 40, 329–341 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Mohite, B.V. & Patil, S.V. A novel biomaterial: bacterial cellulose and its new era applications. Biotechnol. Appl. Biochem. 61, 101–110 (2014).

    Article  CAS  PubMed  Google Scholar 

  99. Opoku-Temeng, C., Zhou, J., Zheng, Y., Su, J. & Sintim, H.O. Cyclic dinucleotide (c-di-GMP, c-di-AMP, and cGAMP) signalings have come of age to be inhibited by small molecules. Chem. Commun. (Camb.) 52, 9327–9342 (2016).

    Article  CAS  Google Scholar 

  100. Gravekamp, C. & Chandra, D. Targeting STING pathways for the treatment of cancer. OncoImmunology 4, e988463 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Acknowledgements

We thank F. Yildiz for critically reading a draft of the review, and N. Reyes, R. Fronzes and R. Cooley for useful discussions. Work in the Sondermann laboratory is supported by US National Institutes of Health grant R01-AI097307 (H.S.). P.V.K. is supported by the Centre National de la Recherche Scientifique (CNRS) and the Institute for Integrative Biology of the Cell (I2BC) and was previously a recipient of a Roux-Cantarini postdoctoral fellowship from the Institut Pasteur.

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Krasteva, P., Sondermann, H. Versatile modes of cellular regulation via cyclic dinucleotides. Nat Chem Biol 13, 350–359 (2017). https://doi.org/10.1038/nchembio.2337

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  • DOI: https://doi.org/10.1038/nchembio.2337

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