1887

Microbiology Society logo

Volume 165, Issue 11

Nucleotide second messengers in Free

Abstract

Antibiotic producing sense and respond to environmental signals by using nucleotide second messengers, including (p)ppGpp, cAMP, c-di-GMP and c-di-AMP. As summarized in this review, these molecules are important message carriers that coordinate the complex morphological transition from filamentous growth to sporulation along with the secondary metabolite production. Here, we provide an overview of the enzymes that make and break these second messengers and suggest candidates for (p)ppGpp and cAMP enzymes to be studied. We highlight the target molecules that bind these signalling molecules and elaborate individual functions that they control in the context of development. Finally, we discuss open questions in the field, which may guide future studies in this exciting research area.

  • Received:
  • Accepted:
  • Published Online:
Keyword(s): (p)ppGpp , c-di-AMP , c-di-GMP , cAMP and Streptomyces
© 2019 The Authors
Loading

Article metrics loading...

/content/journal/micro/10.1099/mic.0.000846
2019-11-01
2024-04-20
Loading full text...

Full text loading...

/deliver/fulltext/micro/165/11/1153.html?itemId=/content/journal/micro/10.1099/mic.0.000846&mimeType=html&fmt=ahah

References

  1. Hengge R. Principles of c-di-GMP signalling in bacteria. Nat Rev Microbiol 2009; 7:263–273 [View Article]
     [Google Scholar]
  2. Gomelsky M. cAMP, c-di-GMP, c-di-AMP and now cGMP: bacteria use them all!. Mol Microbiol 2011; 79:562–565 [View Article]
     [Google Scholar]
  3. Krasteva PV, Sondermann H. Versatile modes of cellular regulation via cyclic dinucleotides. Nat Chem Biol 2017; 13:350–359 [View Article]
     [Google Scholar]
  4. Hengge R, Häussler S, Pruteanu M, Stülke J, Tschowri N et al. Recent advances and current trends in nucleotide second messenger signaling in bacteria. J Mol Biol 2019; 431:908–927 [View Article]
     [Google Scholar]
  5. Davies BW, Bogard RW, Young TS, Mekalanos JJ. Coordinated regulation of accessory genetic elements produces cyclic di-nucleotides for V. cholerae virulence. Cell 2012; 149:358–370 [View Article]
     [Google Scholar]
  6. Whiteley AT, Eaglesham JB, de Oliveira Mann CC, Morehouse BR, Lowey B et al. Bacterial cGAS-like enzymes synthesize diverse nucleotide signals. Nature 2019; 567:194199 [View Article]
     [Google Scholar]
  7. Tschowri N. Cyclic dinucleotide-controlled regulatory pathways in Streptomyces Species. J Bacteriol 2016; 198:47–54 [View Article]
     [Google Scholar]
  8. Flärdh K, Buttner MJ. Streptomyces morphogenetics: dissecting differentiation in a filamentous bacterium. Nat Rev Microbiol 2009; 7:36–49 [View Article]
     [Google Scholar]
  9. Bush MJ, Tschowri N, Schlimpert S, Flärdh K, Buttner MJ. C-Di-Gmp signalling and the regulation of developmental transitions in streptomycetes. Nat Rev Microbiol 2015; 13:749–760 [View Article]
     [Google Scholar]
  10. Elliot MA, Karoonuthaisiri N, Huang J, Bibb MJ, Cohen SN et al. The chaplins: a family of hydrophobic cell-surface proteins involved in aerial mycelium formation in Streptomyces coelicolor . Genes Dev 2003; 17:1727–1740 [View Article]
     [Google Scholar]
  11. Claessen D, Rink R, de Jong W, Siebring J, de Vreugd P et al. A novel class of secreted hydrophobic proteins is involved in aerial hyphae formation in Streptomyces coelicolor by forming amyloid-like fibrils. Genes Dev 2003; 17:1714–1726 [View Article]
     [Google Scholar]
  12. Al-Bassam MM, Bibb MJ, Bush MJ, Chandra G, Buttner MJ. Response regulator heterodimer formation controls a key stage in Streptomyces development. PLoS Genet 2014; 10:e1004554 [View Article]
     [Google Scholar]
  13. Bibb MJ, Domonkos A, Chandra G, Buttner MJ. Expression of the chaplin and rodlin hydrophobic sheath proteins in Streptomyces venezuelae is controlled by σ(BldN) and a cognate anti-sigma factor, RsbN. Mol Microbiol 2012; 84:1033–1049 [View Article]
     [Google Scholar]
  14. Tschowri N, Schumacher MA, Schlimpert S, Chinnam NB, Findlay KC et al. Tetrameric c-di-GMP mediates effective transcription factor dimerization to control Streptomyces development. Cell 2014; 158:1136–1147 [View Article]
     [Google Scholar]
  15. Molle V, Palframan WJ, Findlay KC, Buttner MJ. WhiD and WhiB, homologous proteins required for different stages of sporulation in Streptomyces coelicolor A3(2). J Bacteriol 2000; 182:1286–1295 [View Article]
     [Google Scholar]
  16. Bush MJ, Bibb MJ, Chandra G, Findlay KC, Buttner MJ. Genes required for aerial growth, cell division, and chromosome segregation are targets of WhiA before sporulation in Streptomyces venezuelae . MBio 2013; 4:e00684-13 [View Article]
     [Google Scholar]
  17. Liu G, Chater KF, Chandra G, Niu G, Tan H. Molecular regulation of antibiotic biosynthesis in streptomyces . Microbiol Mol Biol Rev 2013; 77:112–143 [View Article]
     [Google Scholar]
  18. Hopwood DA. Streptomyces in Nature and Medicine: The Antibiotic Makers New York: Oxford University Press; 2007
     [Google Scholar]
  19. Brockmann H, Pini H, v. Plotho O. Über Actinomycetenfarbstoffe, I. Mitteil.: actinorhodin, ein roter, antibiotisch wirksamer Farbstoff AUS Actinomyceten. Chem Ber 1950; 83:161–167 [View Article]
     [Google Scholar]
  20. Feitelson JS, Malpartida F, Hopwood DA. Genetic and Biochemical Characterization of the red Gene Cluster of Streptomyces coelicolor A3(2). Microbiology 1985; 131:2431–2441 [View Article]
     [Google Scholar]
  21. Fernández-Moreno MA, Caballero JL, Hopwood DA, Malpartida F. The act cluster contains regulatory and antibiotic export genes, direct targets for translational control by the bldA tRNA gene of Streptomyces . Cell 1991; 66:769–780 [View Article]
     [Google Scholar]
  22. Rudd BA, Hopwood DA. A pigmented mycelial antibiotic in Streptomyces coelicolor: control by a chromosomal gene cluster. Microbiology 1980; 119:333–340 [View Article]
     [Google Scholar]
  23. An G, Vining LC. Intracellular levels of guanosine 5'-diphosphate 3'-diphosphate (ppGpp) and guanosine 5'-triphosphate 3'-diphosphate (pppGpp) in cultures of Streptomyces griseus producing streptomycin. Can J Microbiol 1978; 24:502–511 [View Article]
     [Google Scholar]
  24. St-Onge RJ, Haiser HJ, Yousef MR, Sherwood E, Tschowri N et al. Nucleotide second messenger-mediated regulation of a muralytic enzyme in Streptomyces . Mol Microbiol 2015; 96:779–795 [View Article]
     [Google Scholar]
  25. Hauryliuk V, Atkinson GC, Murakami KS, Tenson T, Gerdes K. Recent functional insights into the role of (p)ppGpp in bacterial physiology. Nat Rev Microbiol 2015; 13:298–309 [View Article]
     [Google Scholar]
  26. Syal K, Joshi H, Chatterji D, Jain V. Novel pppGpp binding site at the C-terminal region of the Rel enzyme from Mycobacterium smegmatis . Febs J 2015; 282:3773–3785 [View Article]
     [Google Scholar]
  27. Steinchen W, Bange G. The magic dance of the alarmones (p)ppGpp. Mol Microbiol 2016; 101:531–544 [View Article]
     [Google Scholar]
  28. Atkinson GC, Tenson T, Hauryliuk V. The RelA/SpoT homolog (RSH) superfamily: distribution and functional evolution of ppGpp synthetases and hydrolases across the tree of life. PLoS One 2011; 6:e23479 [View Article]
     [Google Scholar]
  29. Chakraburtty R, White J, Takano E, Bibb M. Cloning, characterization and disruption of a (p)ppGpp synthetase gene (relA) of Streptomyces coelicolor A3(2). Mol Microbiol 1996; 19:357–368 [View Article]
     [Google Scholar]
  30. Martínez-Costa OH, Arias P, Romero NM, Parro V, Mellado RP et al. A relA/spoT homologous gene from Streptomyces coelicolor A3(2) controls antibiotic biosynthetic genes. J Biol Chem 1996; 271:10627–10634 [View Article]
     [Google Scholar]
  31. Sun J, Hesketh A, Bibb M. Functional analysis of relA and rshA, two relA/spoT homologues of Streptomyces coelicolor A3(2). J Bacteriol 2001; 183:3488–3498 [View Article]
     [Google Scholar]
  32. Chakraburtty R, Bibb M. The ppGpp synthetase gene (relA) of Streptomyces coelicolor A3(2) plays a conditional role in antibiotic production and morphological differentiation. J Bacteriol 1997; 179:5854–5861 [View Article]
     [Google Scholar]
  33. Ryu YG, Kim ES, Kim DW, Kim SK, Lee KJ. Differential stringent responses of Streptomyces coelicolor M600 to starvation of specific nutrients. J Microbiol Biotechnol 2007; 17:305–312
     [Google Scholar]
  34. Martínez-Costa OH, Fernández-Moreno MA, Malpartida F. The relA/spoT-homologous gene in Streptomyces coelicolor encodes both ribosome-dependent (p)ppGpp-synthesizing and -degrading activities. J Bacteriol 1998; 180:4123–4132
     [Google Scholar]
  35. Hesketh A, Chen WJ, Ryding J, Chang S, Bibb M. The global role of ppGpp synthesis in morphological differentiation and antibiotic production in Streptomyces coelicolor A3(2). Genome Biol 2007; 8:R161 [View Article]
     [Google Scholar]
  36. Kelemen GH, Brian P, Flärdh K, Chamberlin L, Chater KF et al. Developmental regulation of transcription of whiE, a locus specifying the polyketide spore pigment in Streptomyces coelicolor A3 (2). J Bacteriol 1998; 180:2515–2521
     [Google Scholar]
  37. Gatewood ML, Jones GH. (p)ppGpp inhibits polynucleotide phosphorylase from streptomyces but not from Escherichia coli and increases the stability of bulk mRNA in Streptomyces coelicolor . J Bacteriol 2010; 192:4275–4280 [View Article]
     [Google Scholar]
  38. Sivapragasam S, Grove A. Streptomyces coelicolor XdhR is a direct target of (p)ppGpp that controls expression of genes encoding xanthine dehydrogenase to promote purine salvage. Mol Microbiol 2016; 100:701–718 [View Article]
     [Google Scholar]
  39. Sivapragasam S, Grove A. The Link between Purine Metabolism and Production of Antibiotics in Streptomyces . Antibiotics 2019; 8:76 [View Article]
     [Google Scholar]
  40. Yang JK, Epstein W. Purification and characterization of adenylate cyclase from Escherichia coli K12. J Biol Chem 1983; 258:3750–3758
     [Google Scholar]
  41. Krol E, Klaner C, Gnau P, Kaever V, Essen LO et al. Cyclic mononucleotide- and Clr-dependent gene regulation in Sinorhizobium meliloti . Microbiology 2016; 162:1840–1856 [View Article]
     [Google Scholar]
  42. Danchin A, Pidoux J, Krin E, Thompson CJ, Ullmann A. The adenylate cyclase catalytic domain of Streptomyces coelicolor is carboxy-terminal. FEMS Microbiol Lett 1993; 114:145–151 [View Article]
     [Google Scholar]
  43. Süsstrunk U, Pidoux J, Taubert S, Ullmann A, Thompson CJ. Pleiotropic effects of cAMP on germination, antibiotic biosynthesis and morphological development in Streptomyces coelicolor . Mol Microbiol 1998; 30:33–46 [View Article]
     [Google Scholar]
  44. Gancedo JM. Biological roles of cAMP: variations on a theme in the different kingdoms of life. Biol Rev Camb Philos Soc 2013; 88:645–668 [View Article]
     [Google Scholar]
  45. Hildebrand A, Remmert M, Biegert A, Söding J. Fast and accurate automatic structure prediction with HHpred. Proteins 2009; 77:128–132 [View Article]
     [Google Scholar]
  46. Tews I, Findeisen F, Sinning I, Schultz A, Schultz JE et al. The structure of a pH-sensing mycobacterial adenylyl cyclase holoenzyme. Science 2005; 308:1020–1023 [View Article]
     [Google Scholar]
  47. Francis SH, Blount MA, Corbin JD. Mammalian cyclic nucleotide phosphodiesterases: molecular mechanisms and physiological functions. Physiol Rev 2011; 91:651–690 [View Article]
     [Google Scholar]
  48. Lacombe ML, Podgorski GJ, Franke J, Kessin RH. Molecular cloning and developmental expression of the cyclic nucleotide phosphodiesterase gene of Dictyostelium discoideum . J Biol Chem 1986; 261:16811–16817
     [Google Scholar]
  49. Kimura Y, Yoshimi M, Takata G. Enzymatic and mutational analyses of a class II 3',5'-cyclic nucleotide phosphodiesterase, PdeE, from Myxococcus xanthus . J Bacteriol 2011; 193:2053–2057 [View Article]
     [Google Scholar]
  50. Schulte J, Baumgart M, Bott M. Identification of the cAMP phosphodiesterase cpdA as novel key player in cAMP-dependent regulation in Corynebacterium glutamicum . Mol Microbiol 2017; 103:534–552 [View Article]
     [Google Scholar]
  51. Matange N. Revisiting bacterial cyclic nucleotide phosphodiesterases: cyclic AMP hydrolysis and beyond. FEMS Microbiol Lett 2015; 362:fnv183 [View Article]
     [Google Scholar]
  52. Gao C, Hindra MD, Mulder D, Yin C, Elliot MA. Crp is a global regulator of antibiotic production in streptomyces . MBio 2012; 3:e00407-12 [View Article]
     [Google Scholar]
  53. Green J, Stapleton MR, Smith LJ, Artymiuk PJ, Kahramanoglou C et al. Cyclic-Amp and bacterial cyclic-AMP receptor proteins revisited: adaptation for different ecological niches. Curr Opin Microbiol 2014; 18:1–7 [View Article]
     [Google Scholar]
  54. Devreotes P. Dictyostelium discoideum: a model system for cell-cell interactions in development. Science 1989; 245:1054–1058 [View Article]
     [Google Scholar]
  55. Derouaux A, Halici S, Nothaft H, Neutelings T, Moutzourelis G et al. Deletion of a cyclic AMP receptor protein homologue diminishes germination and affects morphological development of Streptomyces coelicolor . J Bacteriol 2004; 186:1893–1897 [View Article]
     [Google Scholar]
  56. Brückner R, Titgemeyer F. Carbon catabolite repression in bacteria: choice of the carbon source and autoregulatory limitation of sugar utilization. FEMS Microbiol Lett 2002; 209:141–148 [View Article]
     [Google Scholar]
  57. Görke B, Stülke J. Carbon catabolite repression in bacteria: many ways to make the most out of nutrients. Nat Rev Microbiol 2008; 6:613–624 [View Article]
     [Google Scholar]
  58. Malan TP, Kolb A, Buc H, McClure WR. Mechanism of CRP-cAMP activation of lac operon transcription initiation activation of the P1 promoter. J Mol Biol 1984; 180:881–909 [View Article]
     [Google Scholar]
  59. Saito N, Xu J, Hosaka T, Okamoto S, Aoki H et al. EshA accentuates ppGpp accumulation and is conditionally required for antibiotic production in Streptomyces coelicolor A3(2). J Bacteriol 2006; 188:4952–4961 [View Article]
     [Google Scholar]
  60. Römling U, Galperin MY, Gomelsky M. Cyclic di-GMP: the first 25 years of a universal bacterial second messenger. Microbiol Mol Biol Rev 2013; 77:1–52 [View Article]
     [Google Scholar]
  61. Chan C, Paul R, Samoray D, Amiot NC, Giese B et al. Structural basis of activity and allosteric control of diguanylate cyclase. Proc Natl Acad Sci USA 2004; 101:17084–17089 [View Article]
     [Google Scholar]
  62. Schmidt AJ, Ryjenkov DA, Gomelsky M. The ubiquitous protein domain EAL is a cyclic diguanylate-specific phosphodiesterase: enzymatically active and inactive EAL domains. J Bacteriol 2005; 187:4774–4781 [View Article]
     [Google Scholar]
  63. 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 2005; 280:30829–30837 [View Article]
     [Google Scholar]
  64. Bellini D, Caly DL, McCarthy Y, Bumann M, An SQ 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 2014; 91:26–38 [View Article]
     [Google Scholar]
  65. Tarutina M, Ryjenkov DA, Gomelsky M. An unorthodox bacteriophytochrome from Rhodobacter sphaeroides involved in turnover of the second messenger c-di-GMP. J Biol Chem 2006; 281:34751–34758 [View Article]
     [Google Scholar]
  66. Den Hengst CD, Tran NT, Bibb MJ, Chandra G, Leskiw BK et al. Genes essential for morphological development and antibiotic production in Streptomyces coelicolor are targets of BldD during vegetative growth. Mol Microbiol 2010; 78:361–379 [View Article]
     [Google Scholar]
  67. Tran NT, Den Hengst CD, Gomez-Escribano JP, Buttner MJ. Identification and characterization of CdgB, a diguanylate cyclase involved in developmental processes in Streptomyces coelicolor . J Bacteriol 2011; 193:3100–3108 [View Article]
     [Google Scholar]
  68. Al-Bassam MM, Haist J, Neumann SA, Lindenberg S, Tschowri N. Expression Patterns, Genomic Conservation and Input Into Developmental Regulation of the GGDEF/EAL/HD-GYP Domain Proteins in Streptomyces . Front Microbiol 2018; 9:2524 [View Article]
     [Google Scholar]
  69. Liu X, Zheng G, Wang G, Jiang W, Li L et al. Overexpression of the diguanylate cyclase CdgD blocks developmental transitions and antibiotic biosynthesis in Streptomyces coelicolor . Sci China Life Sci 2019; 9: [View Article]
     [Google Scholar]
  70. Hull TD, Ryu MH, Sullivan MJ, Johnson RC, Klena NT et al. Cyclic Di-GMP phosphodiesterases RmdA and RmdB are involved in regulating colony morphology and development in Streptomyces coelicolor . J Bacteriol 2012; 194:4642–4651 [View Article]
     [Google Scholar]
  71. Jenal U, Reinders A, Lori C. Cyclic di-GMP: second messenger extraordinaire. Nat Rev Microbiol 2017; 15:271–284 [View Article]
     [Google Scholar]
  72. Mouri Y, Konishi K, Fujita A, Tezuka T, Ohnishi Y. Regulation of Sporangium Formation by BldD in the Rare Actinomycete Actinoplanes missouriensis . J Bacteriol 2017; 199: [View Article]
     [Google Scholar]
  73. Xu Z, You D, Tang LY, Zhou Y, Ye BC. Metabolic Engineering Strategies Based on Secondary Messengers (p)ppGpp and c-di-GMP To Increase Erythromycin Yield in Saccharopolyspora erythraea . ACS Synth Biol 2019; 8:332–345 [View Article]
     [Google Scholar]
  74. Chou SH, Galperin MY. Diversity of cyclic di-GMP-Binding proteins and mechanisms. J Bacteriol 2016; 198:32–46 [View Article]
     [Google Scholar]
  75. Schumacher MA, Zeng W, Findlay KC, Buttner MJ, Brennan RG et al. The Streptomyces master regulator BldD binds c-di-GMP sequentially to create a functional BldD2-(c-di-GMP)4 complex. Nucleic Acids Res 2017; 45:6923–6933 [View Article]
     [Google Scholar]
  76. Witte G, Hartung S, Büttner K, Hopfner KP. Structural biochemistry of a bacterial checkpoint protein reveals diadenylate cyclase activity regulated by DNA recombination intermediates. Mol Cell 2008; 30:167–178 [View Article]
     [Google Scholar]
  77. Corrigan RM, Gründling A. Cyclic di-AMP: another second messenger enters the Fray. Nat Rev Microbiol 2013; 11:513–524 [View Article]
     [Google Scholar]
  78. St-Onge RJ, Elliot MA. Regulation of a muralytic enzyme-encoding gene by two non-coding RNAs. RNA Biol 2017; 14:1592–1605 [View Article]
     [Google Scholar]
  79. Huynh TN, Woodward JJ. Too much of a good thing: regulated depletion of c-di-AMP in the bacterial cytoplasm. Curr Opin Microbiol 2016; 30:22–29 [View Article]
     [Google Scholar]
  80. Commichau FM, Heidemann JL, Ficner R, Stulke J. Making and breaking of an essential poison: the cyclases and phosphodiesterases that produce and degrade the essential second messenger cyclic di-AMP in bacteria. Journal of bacteriology 2019; 201:
     [Google Scholar]
  81. Fahmi T, Port G, Cho K. c-Di-Amp: an essential molecule in the signaling pathways that regulate the viability and virulence of Gram-positive bacteria. Genes 2017; 8:197 [View Article]
     [Google Scholar]
  82. Commichau FM, Gibhardt J, Halbedel S, Gundlach J, Stülke J. A delicate connection: c-di-AMP affects cell integrity by controlling osmolyte transport. Trends Microbiol 2018; 26:175–185 [View Article]
     [Google Scholar]
  83. Bremer E, Krämer R. Responses of microorganisms to osmotic stress. Annu Rev Microbiol 2019; 73: [View Article]
     [Google Scholar]
  84. Serganov A, Nudler E. A decade of riboswitches. Cell 2013; 152:17–24 [View Article]
     [Google Scholar]
  85. Nelson JW, Sudarsan N, Furukawa K, Weinberg Z, Wang JX et al. Riboswitches in eubacteria sense the second messenger c-di-AMP. Nat Chem Biol 2013; 9:834–839 [View Article]
     [Google Scholar]
  86. Haiser HJ, Yousef MR, Elliot MA. Cell wall hydrolases affect germination, vegetative growth, and sporulation in Streptomyces coelicolor . J Bacteriol 2009; 191:6501–6512 [View Article]
     [Google Scholar]
  87. Telkov MV, Demina GR, Voloshin SA, Salina EG, Dudik TV et al. Proteins of the Rpf (resuscitation promoting factor) family are peptidoglycan hydrolases. Biochemistry 2006; 71:414–422 [View Article]
     [Google Scholar]
  88. Keep NH, Ward JM, Cohen-Gonsaud M, Henderson B. Wake up! peptidoglycan lysis and bacterial non-growth states. Trends Microbiol 2006; 14:271–276 [View Article]
     [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/micro/10.1099/mic.0.000846
Loading
Nucleotide second messengers in Streptomyces
Microbiology 165, 1153 (2019); https://doi.org/10.1099/mic.0.000846
/content/journal/micro/10.1099/mic.0.000846
/content/journal/micro/10.1099/mic.0.000846
Loading

Data & Media loading...

Most cited Most Cited RSS feed

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