1887

Abstract

The stringent response is a conserved bacterial stress response mechanism that allows bacteria to respond to nutritional challenges. It is mediated by the alarmones pppGpp and ppGpp, nucleotides that are synthesized and hydrolyzed by members of the RSH superfamily. Whilst there are key differences in the binding targets for (p)ppGpp between Gram-negative and Gram-positive bacterial species, the transient accumulation of (p)ppGpp caused by nutritional stresses results in a global change in gene expression in all species. The RSH superfamily of enzymes is ubiquitous throughout the bacterial kingdom, and can be split into three main groups: the long-RSH enzymes; the small alarmone synthetases (SAS); and the small alarmone hydrolases (SAH). Despite the prevalence of these enzymes, there are important differences in the way in which they are regulated on a transcriptional and post-translational level. Here we provide an overview of the diverse regulatory mechanisms that are involved in governing this crucial signalling network. Understanding how the RSH superfamily members are regulated gives insights into the varied important biological roles for this signalling pathway across the bacteria.

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2018-03-01
2020-01-20
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References

  1. Cashel M. The control of ribonucleic acid synthesis in Escherichia coli. IV. Relevance of unusual phosphorylated compounds from amino acid-starved stringent strains. J Biol Chem 1969;244:3133–3141[PubMed]
    [Google Scholar]
  2. 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 [CrossRef][PubMed]
    [Google Scholar]
  3. Brown A, Fernández IS, Gordiyenko Y, Ramakrishnan V. Ribosome-dependent activation of stringent control. Nature 2016;534:277–280 [CrossRef][PubMed]
    [Google Scholar]
  4. Loveland AB, Bah E, Madireddy R, Zhang Y, Brilot AF et al. Ribosome•RelA structures reveal the mechanism of stringent response activation. Elife 2016;5: [CrossRef][PubMed]
    [Google Scholar]
  5. Arenz S, Abdelshahid M, Sohmen D, Payoe R, Starosta AL et al. The stringent factor RelA adopts an open conformation on the ribosome to stimulate ppGpp synthesis. Nucleic Acids Res 2016;44:6471–6481 [CrossRef][PubMed]
    [Google Scholar]
  6. Mittenhuber G. Comparative genomics and evolution of genes encoding bacterial (p)ppGpp synthetases/hydrolases (the Rel, RelA and SpoT proteins). J Mol Microbiol Biotechnol 2001;3:585–600[PubMed]
    [Google Scholar]
  7. Aravind L, Koonin EV. The HD domain defines a new superfamily of metal-dependent phosphohydrolases. Trends Biochem Sci 1998;23:469–472 [CrossRef][PubMed]
    [Google Scholar]
  8. das B, Pal RR, Bag S, Bhadra RK. Stringent response in Vibrio cholerae: genetic analysis of spoT gene function and identification of a novel (p)ppGpp synthetase gene. Mol Microbiol 2009;72:380–398 [CrossRef][PubMed]
    [Google Scholar]
  9. Lemos JA, Lin VK, Nascimento MM, Abranches J, Burne RA. Three gene products govern (p)ppGpp production by Streptococcus mutans. Mol Microbiol 2007;65:1568–1581 [CrossRef][PubMed]
    [Google Scholar]
  10. Nanamiya H, Kasai K, Nozawa A, Yun CS, Narisawa T et al. Identification and functional analysis of novel (p)ppGpp synthetase genes in Bacillus subtilis. Mol Microbiol 2008;67:291–304 [CrossRef][PubMed]
    [Google Scholar]
  11. Srivatsan A, Han Y, Peng J, Tehranchi AK, Gibbs R et al. High-precision, whole-genome sequencing of laboratory strains facilitates genetic studies. PLoS Genet 2008;4:e1000139 [CrossRef][PubMed]
    [Google Scholar]
  12. Geiger T, Kästle B, Gratani FL, Goerke C, Wolz C. Two small (p)ppGpp synthases in Staphylococcus aureus mediate tolerance against cell envelope stress conditions. J Bacteriol 2014;196:894–902 [CrossRef][PubMed]
    [Google Scholar]
  13. Sun D, Lee G, Lee JH, Kim HY, Rhee HW et al. A metazoan ortholog of SpoT hydrolyzes ppGpp and functions in starvation responses. Nat Struct Mol Biol 2010;17:1188–1194 [CrossRef][PubMed]
    [Google Scholar]
  14. Potrykus K, Cashel M. (p)ppGpp: still magical?. Annu Rev Microbiol 2008;62:35–51 [CrossRef][PubMed]
    [Google Scholar]
  15. 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 [CrossRef][PubMed]
    [Google Scholar]
  16. Liu K, Bittner AN, Wang JD. Diversity in (p)ppGpp metabolism and effectors. Curr Opin Microbiol 2015;24:72–79 [CrossRef][PubMed]
    [Google Scholar]
  17. Steinchen W, Bange G. The magic dance of the alarmones (p)ppGpp. Mol Microbiol 2016;101:531–544 [CrossRef][PubMed]
    [Google Scholar]
  18. Metzger S, Dror IB, Aizenman E, Schreiber G, Toone M et al. The nucleotide sequence and characterization of the relA gene of Escherichia coli. J Biol Chem 1988;263:15699–15704[PubMed]
    [Google Scholar]
  19. Nakagawa A, Oshima T, Mori H. Identification and characterization of a second, inducible promoter of relA in Escherichia coli. Genes Genet Syst 2006;81:299–310 [CrossRef][PubMed]
    [Google Scholar]
  20. Brown DR, Barton G, Pan Z, Buck M, Wigneshweraraj S. Nitrogen stress response and stringent response are coupled in Escherichia coli. Nat Commun 2014;5:4115 [CrossRef][PubMed]
    [Google Scholar]
  21. Villadsen IS, Michelsen O. Regulation of PRPP and nucleoside tri and tetraphosphate pools in Escherichia coli under conditions of nitrogen starvation. J Bacteriol 1977;130:136–143[PubMed]
    [Google Scholar]
  22. Lin CY, Awano N, Masuda H, Park JH, Inouye M. Transcriptional repressor HipB regulates the multiple promoters in Escherichia coli. J Mol Microbiol Biotechnol 2013;23:440–447 [CrossRef][PubMed]
    [Google Scholar]
  23. Maisonneuve E, Castro-Camargo M, Gerdes K. (p)ppGpp controls bacterial persistence by stochastic induction of toxin-antitoxin activity. Cell 2013;154:1140–1150 [CrossRef][PubMed]
    [Google Scholar]
  24. Wassarman KM, Storz G. 6S RNA regulates E. coli RNA polymerase activity. Cell 2000;101:613–623 [CrossRef][PubMed]
    [Google Scholar]
  25. Cavanagh AT, Chandrangsu P, Wassarman KM. 6S RNA regulation of relA alters ppGpp levels in early stationary phase. Microbiology 2010;156:3791–3800 [CrossRef][PubMed]
    [Google Scholar]
  26. Neusser T, Polen T, Geissen R, Wagner R. Depletion of the non-coding regulatory 6S RNA in E. coli causes a surprising reduction in the expression of the translation machinery. BMC Genomics 2010;11:165 [CrossRef][PubMed]
    [Google Scholar]
  27. Reiss S, Pané-Farré J, Fuchs S, François P, Liebeke M et al. Global analysis of the Staphylococcus aureus response to mupirocin. Antimicrob Agents Chemother 2012;56:787–804 [CrossRef][PubMed]
    [Google Scholar]
  28. Anderson KL, Roberts C, Disz T, Vonstein V, Hwang K et al. Characterization of the Staphylococcus aureus heat shock, cold shock, stringent, and SOS responses and their effects on log-phase mRNA turnover. J Bacteriol 2006;188:6739–6756 [CrossRef][PubMed]
    [Google Scholar]
  29. Lemos JA, Brown TA, Burne RA. Effects of RelA on key virulence properties of planktonic and biofilm populations of Streptococcus mutans. Infect Immun 2004;72:1431–1440 [CrossRef][PubMed]
    [Google Scholar]
  30. Sureka K, Dey S, Datta P, Singh AK, Dasgupta A et al. Polyphosphate kinase is involved in stress-induced mprAB-sigE-rel signalling in mycobacteria. Mol Microbiol 2007;65:261–276 [CrossRef][PubMed]
    [Google Scholar]
  31. Tagami K, Nanamiya H, Kazo Y, Maehashi M, Suzuki S et al. Expression of a small (p)ppGpp synthetase, YwaC, in the (p)ppGpp(0) mutant of Bacillus subtilis triggers YvyD-dependent dimerization of ribosome. Microbiologyopen 2012;1:115–134 [CrossRef][PubMed]
    [Google Scholar]
  32. Eiamphungporn W, Helmann JD. The Bacillus subtilis σM regulon and its contribution to cell envelope stress responses. Mol Microbiol 2008;67:830–848 [CrossRef][PubMed]
    [Google Scholar]
  33. Cao M, Kobel PA, Morshedi MM, Wu MF, Paddon C et al. Defining the Bacillus subtilis σW regulon: a comparative analysis of promoter consensus search, run-off transcription/macroarray analysis (ROMA), and transcriptional profiling approaches. J Mol Biol 2002;316:443–457 [CrossRef][PubMed]
    [Google Scholar]
  34. Pietiäinen M, Gardemeister M, Mecklin M, Leskelä S, Sarvas M et al. Cationic antimicrobial peptides elicit a complex stress response in Bacillus subtilis that involves ECF-type sigma factors and two-component signal transduction systems. Microbiology 2005;151:1577–1592 [CrossRef][PubMed]
    [Google Scholar]
  35. Thackray PD, Moir A. SigM, an extracytoplasmic function sigma factor of Bacillus subtilis, is activated in response to cell wall antibiotics, ethanol, heat, acid, and superoxide stress. J Bacteriol 2003;185:3491–3498 [CrossRef][PubMed]
    [Google Scholar]
  36. Wiegert T, Homuth G, Versteeg S, Schumann W. Alkaline shock induces the Bacillus subtilis σW regulon. Mol Microbiol 2001;41:59–71 [CrossRef][PubMed]
    [Google Scholar]
  37. Miller HK, Carroll RK, Burda WN, Krute CN, Davenport JE et al. The extracytoplasmic function sigma factor σS protects against both intracellular and extracytoplasmic stresses in Staphylococcus aureus. J Bacteriol 2012;194:4342–4354 [CrossRef][PubMed]
    [Google Scholar]
  38. Pando JM, Pfeltz RF, Cuaron JA, Nagarajan V, Mishra MN et al. Ethanol-induced stress response of Staphylococcus aureus. Can J Microbiol 2017;63:745–757 [CrossRef][PubMed]
    [Google Scholar]
  39. Abranches J, Martinez AR, Kajfasz JK, Chávez V, Garsin DA et al. The molecular alarmone (p)ppGpp mediates stress responses, vancomycin tolerance, and virulence in Enterococcus faecalis. J Bacteriol 2009;191:2248–2256 [CrossRef][PubMed]
    [Google Scholar]
  40. Anderson KL, Roux CM, Olson MW, Luong TT, Lee CY et al. Characterizing the effects of inorganic acid and alkaline shock on the Staphylococcus aureus transcriptome and messenger RNA turnover. FEMS Immunol Med Microbiol 2010;60:208–250 [CrossRef][PubMed]
    [Google Scholar]
  41. Sajish M, Kalayil S, Verma SK, Nandicoori VK, Prakash B. The significance of EXDD and RXKD motif conservation in Rel proteins. J Biol Chem 2009;284:9115–9123 [CrossRef][PubMed]
    [Google Scholar]
  42. Mechold U, Murphy H, Brown L, Cashel M. Intramolecular regulation of the opposing (p)ppGpp catalytic activities of Rel(Seq), the Rel/Spo enzyme from Streptococcus equisimilis. J Bacteriol 2002;184:2878–2888 [CrossRef][PubMed]
    [Google Scholar]
  43. Sajish M, Tiwari D, Rananaware D, Nandicoori VK, Prakash B. A charge reversal differentiates (p)ppGpp synthesis by monofunctional and bifunctional Rel proteins. J Biol Chem 2007;282:34977–34983 [CrossRef][PubMed]
    [Google Scholar]
  44. Mechold U, Potrykus K, Murphy H, Murakami KS, Cashel M. Differential regulation by ppGpp versus pppGpp in Escherichia coli. Nucleic Acids Res 2013;41:6175–6189 [CrossRef][PubMed]
    [Google Scholar]
  45. Wang JD, Sanders GM, Grossman AD. Nutritional control of elongation of DNA replication by (p)ppGpp. Cell 2007;128:865–875 [CrossRef][PubMed]
    [Google Scholar]
  46. Cashel M, Gentry DR, Hernandez VJ, Vinella D. (editors). The Stringent Response Washington, DC: ASM Press; 1996
    [Google Scholar]
  47. Gaca AO, Abranches J, Kajfasz JK, Lemos JA. Global transcriptional analysis of the stringent response in Enterococcus faecalis. Microbiology 2012;158:1994–2004 [CrossRef][PubMed]
    [Google Scholar]
  48. Corrigan RM, Bowman L, Willis AR, Kaever V, Gründling A. Cross-talk between two nucleotide-signaling pathways in Staphylococcus aureus. J Biol Chem 2015;290:5826–5839 [CrossRef][PubMed]
    [Google Scholar]
  49. Samarrai W, Liu DX, White AM, Studamire B, Edelstein J et al. Differential responses of Bacillus subtilis rRNA promoters to nutritional stress. J Bacteriol 2011;193:723–733 [CrossRef][PubMed]
    [Google Scholar]
  50. Somerville CR, Ahmed A. Mutants of Escherichia coli defective in the degradation of guanosine 5′-triphosphate, 3′-diphosphate (pppGpp). Mol Gen Genet 1979;169:315–323 [CrossRef][PubMed]
    [Google Scholar]
  51. Gaca AO, Kudrin P, Colomer-Winter C, Beljantseva J, Liu K et al. From (p)ppGpp to (pp)pGpp: characterization of regulatory effects of pGpp synthesized by the small alarmone synthetase of Enterococcus faecalis. J Bacteriol 2015;197:2908–2919 [CrossRef][PubMed]
    [Google Scholar]
  52. Ruwe M, Kalinowski J, Persicke M. Identification and functional characterization of small alarmone synthetases in Corynebacterium glutamicum. Front Microbiol 2017;8:1601 [CrossRef][PubMed]
    [Google Scholar]
  53. Shyp V, Tankov S, Ermakov A, Kudrin P, English BP et al. Positive allosteric feedback regulation of the stringent response enzyme RelA by its product. EMBO Rep 2012;13:835–839 [CrossRef][PubMed]
    [Google Scholar]
  54. Steinchen W, Schuhmacher JS, Altegoer F, Fage CD, Srinivasan V et al. Catalytic mechanism and allosteric regulation of an oligomeric (p)ppGpp synthetase by an alarmone. Proc Natl Acad Sci USA 2015;112:13348–13353 [CrossRef][PubMed]
    [Google Scholar]
  55. Beljantseva J, Kudrin P, Andresen L, Shingler V, Atkinson GC et al. Negative allosteric regulation of Enterococcus faecalis small alarmone synthetase RelQ by single-stranded RNA. Proc Natl Acad Sci USA 2017;114:3726–3731 [CrossRef][PubMed]
    [Google Scholar]
  56. Schurr T, Nadir E, Margalit H. Identification and characterization of E.coli ribosomal binding sites by free energy computation. Nucleic Acids Res 1993;21:4019–4023 [CrossRef][PubMed]
    [Google Scholar]
  57. Rao F, See RY, Zhang D, Toh DC, Ji Q et al. YybT is a signaling protein that contains a cyclic dinucleotide phosphodiesterase domain and a GGDEF domain with ATPase activity. J Biol Chem 2010;285:473–482 [CrossRef][PubMed]
    [Google Scholar]
  58. Whiteley AT, Pollock AJ, Portnoy DA. The PAMP c-di-AMP is essential for Listeria monocytogenes growth in rich but not minimal media due to a toxic increase in (p)ppGpp. [corrected]. Cell Host Microbe 2015;17:788–798 [CrossRef][PubMed]
    [Google Scholar]
  59. Hogg T, Mechold U, Malke H, Cashel M, Hilgenfeld R. Conformational antagonism between opposing active sites in a bifunctional RelA/SpoT homolog modulates (p)ppGpp metabolism during the stringent response [corrected]. Cell 2004;117:57–68 [CrossRef][PubMed]
    [Google Scholar]
  60. Yang X, Ishiguro EE. Dimerization of the RelA protein of Escherichia coli. Biochem Cell Biol 2001;79:729–736 [CrossRef][PubMed]
    [Google Scholar]
  61. Gropp M, Strausz Y, Gross M, Glaser G. Regulation of Escherichia coli RelA requires oligomerization of the C-terminal domain. J Bacteriol 2001;183:570–579 [CrossRef][PubMed]
    [Google Scholar]
  62. Avarbock A, Avarbock D, Teh JS, Buckstein M, Wang ZM et al. Functional regulation of the opposing (p)ppGpp synthetase/hydrolase activities of RelMtb from Mycobacterium tuberculosis. Biochemistry 2005;44:9913–9923 [CrossRef][PubMed]
    [Google Scholar]
  63. Murdeshwar MS, Chatterji D. MS_RHII-RSD, a dual-function RNase HII-(p)ppGpp synthetase from Mycobacterium smegmatis. J Bacteriol 2012;194:4003–4014 [CrossRef][PubMed]
    [Google Scholar]
  64. Krishnan S, Petchiappan A, Singh A, Bhatt A, Chatterji D. R-loop induced stress response by second (p)ppGpp synthetase in Mycobacterium smegmatis: functional and domain interdependence. Mol Microbiol 2016;102:168–182 [CrossRef][PubMed]
    [Google Scholar]
  65. Haseltine WA, Block R. Synthesis of guanosine tetra- and pentaphosphate requires the presence of a codon-specific, uncharged transfer ribonucleic acid in the acceptor site of ribosomes. Proc Natl Acad Sci USA 1973;70:1564–1568 [CrossRef][PubMed]
    [Google Scholar]
  66. Avarbock D, Avarbock A, Rubin H. Differential regulation of opposing RelMtb activities by the aminoacylation state of a tRNA.ribosome.mRNA.RelMtb complex. Biochemistry 2000;39:11640–11648[PubMed][Crossref]
    [Google Scholar]
  67. English BP, Hauryliuk V, Sanamrad A, Tankov S, Dekker NH et al. Single-molecule investigations of the stringent response machinery in living bacterial cells. Proc Natl Acad Sci USA 2011;108:E365E373 [CrossRef][PubMed]
    [Google Scholar]
  68. Wout P, Pu K, Sullivan SM, Reese V, Zhou S et al. The Escherichia coli GTPase CgtAE cofractionates with the 50S ribosomal subunit and interacts with SpoT, a ppGpp synthetase/hydrolase. J Bacteriol 2004;186:5249–5257 [CrossRef][PubMed]
    [Google Scholar]
  69. Jiang M, Sullivan SM, Wout PK, Maddock JR. G-protein control of the ribosome-associated stress response protein SpoT. J Bacteriol 2007;189:6140–6147 [CrossRef][PubMed]
    [Google Scholar]
  70. Persky NS, Ferullo DJ, Cooper DL, Moore HR, Lovett ST. The ObgE/CgtA GTPase influences the stringent response to amino acid starvation in Escherichia coli. Mol Microbiol 2009;73:253–266 [CrossRef][PubMed]
    [Google Scholar]
  71. Seyfzadeh M, Keener J, Nomura M. spoT-dependent accumulation of guanosine tetraphosphate in response to fatty acid starvation in Escherichia coli. Proc Natl Acad Sci USA 1993;90:11004–11008 [CrossRef][PubMed]
    [Google Scholar]
  72. Gong L, Takayama K, Kjelleberg S. Role of spoT-dependent ppGpp accumulation in the survival of light-exposed starved bacteria. Microbiology 2002;148:559–570 [CrossRef][PubMed]
    [Google Scholar]
  73. Butland G, Peregrín-Alvarez JM, Li J, Yang W, Yang X et al. Interaction network containing conserved and essential protein complexes in Escherichia coli. Nature 2005;433:531–537 [CrossRef][PubMed]
    [Google Scholar]
  74. Gully D, Moinier D, Loiseau L, Bouveret E. New partners of acyl carrier protein detected in Escherichia coli by tandem affinity purification. FEBS Lett 2003;548:90–96 [CrossRef][PubMed]
    [Google Scholar]
  75. Battesti A, Bouveret E. Acyl carrier protein/SpoT interaction, the switch linking SpoT-dependent stress response to fatty acid metabolism. Mol Microbiol 2006;62:1048–1063 [CrossRef][PubMed]
    [Google Scholar]
  76. Battesti A, Bouveret E. Bacteria possessing two RelA/SpoT-like proteins have evolved a specific stringent response involving the acyl carrier protein-SpoT interaction. J Bacteriol 2009;191:616–624 [CrossRef][PubMed]
    [Google Scholar]
  77. Pulschen AA, Sastre DE, Machinandiarena F, Crotta Asis A, Albanesi D et al. The stringent response plays a key role in Bacillus subtilis survival of fatty acid starvation. Mol Microbiol 2017;103:698–712 [CrossRef][PubMed]
    [Google Scholar]
  78. Hahn J, Tanner AW, Carabetta VJ, Cristea IM, Dubnau D. ComGA-RelA interaction and persistence in the Bacillus subtilis K-state. Mol Microbiol 2015;97:454–471 [CrossRef][PubMed]
    [Google Scholar]
  79. Pizarro-Cerdá J, Tedin K. The bacterial signal molecule, ppGpp, regulates Salmonella virulence gene expression. Mol Microbiol 2004;52:1827–1844 [CrossRef][PubMed]
    [Google Scholar]
  80. Haralalka S, Nandi S, Bhadra RK. Mutation in the relA gene of Vibrio cholerae affects in vitro and in vivo expression of virulence factors. J Bacteriol 2003;185:4672–4682 [CrossRef][PubMed]
    [Google Scholar]
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