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Volume 163, Issue 7

Endoribonuclease type II toxin–antitoxin systems: functional or selfish? Free

Abstract

Most bacterial genomes have multiple type II toxin–antitoxin systems (TAs) that encode two proteins which are referred to as a toxin and an antitoxin. Toxins inhibit a cellular process, while the interaction of the antitoxin with the toxin attenuates the toxin's activity. Endoribonuclease-encoding TAs cleave RNA in a sequence-dependent fashion, resulting in translational inhibition. To account for their prevalence and retention by bacterial genomes, TAs are credited with clinically significant phenomena, such as bacterial programmed cell death, persistence, biofilms and anti-addiction to plasmids. However, the programmed cell death and persistence hypotheses have been challenged because of conceptual, methodological and/or strain issues. In an alternative view, chromosomal TAs seem to be retained by virtue of addiction at two levels: via a poison–antidote combination (TA proteins) and via transcriptional reprogramming of the downstream core gene (due to integration). Any perturbation in the chromosomal TA operons could cause fitness loss due to polar effects on the downstream genes and hence be detrimental under natural conditions. The endoribonucleases encoding chromosomal TAs are most likely selfish DNA as they are retained by bacterial genomes, even though TAs do not confer a direct advantage via the TA proteins. TAs are likely used by various replicons as ‘genetic arms’ that allow the maintenance of themselves and associated genetic elements. TAs seem to be the ‘selfish arms’ that make the best use of the ‘arms race’ between bacterial genomes and plasmids.

  • Received:
  • Accepted:
  • Published Online:
Keyword(s): Horizontal gene transfer , persistence and stringent response
© 2017 The Authors
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2017-07-01
2024-04-19
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References

  1. Anantharaman V, Aravind L. New connections in the prokaryotic toxin-antitoxin network: relationship with the eukaryotic nonsense-mediated RNA decay system. Genome Biol 2003; 4:R81 [View Article][PubMed]
     [Google Scholar]
  2. Pandey DP, Gerdes K. Toxin-antitoxin loci are highly abundant in free-living but lost from host-associated prokaryotes. Nucleic Acids Res 2005; 33:966–976 [View Article][PubMed]
     [Google Scholar]
  3. Page R, Peti W. Toxin-antitoxin systems in bacterial growth arrest and persistence. Nat Chem Biol 2016; 12:208–214 [View Article][PubMed]
     [Google Scholar]
  4. Gerdes K, Maisonneuve E. Bacterial persistence and toxin-antitoxin loci. Annu Rev Microbiol 2012; 66:103–123 [View Article][PubMed]
     [Google Scholar]
  5. Goeders N, van Melderen L. Toxin-antitoxin systems as multilevel interaction systems. Toxins (Basel) 2014; 6:304–324 [View Article][PubMed]
     [Google Scholar]
  6. Ramisetty BCM, Santhosh RS. Horizontal gene transfer of chromosomal Type II toxin-antitoxin systems of Escherichia coli. FEMS Microbiol Lett 2016; 363:fnv238 [View Article][PubMed]
     [Google Scholar]
  7. Chopra N, Saumitra, Pathak A, Bhatnagar R, Bhatnagar S. Linkage, mobility, and selfishness in the MazF family of bacterial toxins: a snapshot of bacterial evolution. Genome Biol Evol 2013; 5:2268–2284 [View Article][PubMed]
     [Google Scholar]
  8. Leplae R, Geeraerts D, Hallez R, Guglielmini J, Drèze P et al. Diversity of bacterial type II toxin-antitoxin systems: a comprehensive search and functional analysis of novel families. Nucleic Acids Res 2011; 39:5513–5525 [View Article][PubMed]
     [Google Scholar]
  9. Gerdes K, Christensen SK, Løbner-Olesen A. Prokaryotic toxin-antitoxin stress response loci. Nat Rev Microbiol 2005; 3:371–382 [View Article][PubMed]
     [Google Scholar]
  10. Yamaguchi Y, Inouye M. Regulation of growth and death in Escherichia coli by toxin-antitoxin systems. Nat Rev Microbiol 2011; 9:779–790 [View Article][PubMed]
     [Google Scholar]
  11. Gerdes K, Jacobsen JS, Franch T. Plasmid stabilization by post-segregational killing. Genet Eng (N Y) 1997; 19:49–61[PubMed] [CrossRef]
     [Google Scholar]
  12. Gerdes K, Rasmussen PB, Molin S. Unique type of plasmid maintenance function: postsegregational killing of plasmid-free cells. Proc Natl Acad Sci USA 1986; 83:3116–3120 [View Article][PubMed]
     [Google Scholar]
  13. Maisonneuve E, Shakespeare LJ, Jørgensen MG, Gerdes K. Bacterial persistence by RNA endonucleases. Proc Natl Acad Sci USA 2011; 108:13206–13211 [View Article][PubMed]
     [Google Scholar]
  14. Ramisetty BC, Natarajan B, Santhosh RS. mazEF-mediated programmed cell death in bacteria: "what is this?". Crit Rev Microbiol 2015; 41:89–100 [View Article][PubMed]
     [Google Scholar]
  15. Engelberg-Kulka H, Sat B, Reches M, Amitai S, Hazan R. Bacterial programmed cell death systems as targets for antibiotics. Trends Microbiol 2004; 12:66–71 [View Article][PubMed]
     [Google Scholar]
  16. Aizenman E, Engelberg-Kulka H, Glaser G. An Escherichia coli chromosomal "addiction module" regulated by guanosine [corrected] 3',5'-bispyrophosphate: a model for programmed bacterial cell death. Proc Natl Acad Sci USA 1996; 93:6059–6063 [View Article][PubMed]
     [Google Scholar]
  17. Kim Y, Wang X, Ma Q, Zhang XS, Wood TK. Toxin-antitoxin systems in Escherichia coli influence biofilm formation through YjgK (TabA) and fimbriae. J Bacteriol 2009; 191:1258–1267 [View Article][PubMed]
     [Google Scholar]
  18. Wood TK. Insights on Escherichia coli biofilm formation and inhibition from whole-transcriptome profiling. Environ Microbiol 2009; 11:1–15 [View Article][PubMed]
     [Google Scholar]
  19. Wang X, Wood TK. Toxin-antitoxin systems influence biofilm and persister cell formation and the general stress response. Appl Environ Microbiol 2011; 77:5577–5583 [View Article][PubMed]
     [Google Scholar]
  20. Saavedra de Bast M, Mine N, van Melderen L. Chromosomal toxin-antitoxin systems may act as antiaddiction modules. J Bacteriol 2008; 190:4603–4609 [View Article][PubMed]
     [Google Scholar]
  21. Chan WT, Balsa D, Espinosa M. One cannot rule them all: are bacterial toxins-antitoxins druggable?. FEMS Microbiol Rev 2015; 39:522–540 [View Article][PubMed]
     [Google Scholar]
  22. Williams JJ, Hergenrother PJ. Artificial activation of toxin-antitoxin systems as an antibacterial strategy. Trends Microbiol 2012; 20:291–298 [View Article][PubMed]
     [Google Scholar]
  23. Unterholzner SJ, Poppenberger B, Rozhon W. Toxin-antitoxin systems: biology, identification, and application. Mob Genet Elements 2013; 3:e26219 [View Article][PubMed]
     [Google Scholar]
  24. Jensen RB, Gerdes K. Programmed cell death in bacteria: proteic plasmid stabilization systems. Mol Microbiol 1995; 17:205–210 [View Article][PubMed]
     [Google Scholar]
  25. Gerdes K, Bech FW, Jørgensen ST, Løbner-Olesen A, Rasmussen PB et al. Mechanism of postsegregational killing by the hok gene product of the parB system of plasmid R1 and its homology with the relF gene product of the E. coli relB operon. EMBO J 1986; 5:2023–2029[PubMed]
     [Google Scholar]
  26. Cashel M, Gentry DR, Hernandez VJ, Vinella D. The Stringent Response, 2 ed. Washington, DC: American Society for Microbiology Press; 1996
     [Google Scholar]
  27. Barker MM, Gaal T, Josaitis CA, Gourse RL. Mechanism of regulation of transcription initiation by ppGpp. I. Effects of ppGpp on transcription initiation in vivo and in vitro. J Mol Biol 2001; 305:673–688 [View Article][PubMed]
     [Google Scholar]
  28. Diderichsen B, Fiil NP, Lavallé R. Genetics of the relB locus in Escherichia coli. J Bacteriol 1977; 131:30–33[PubMed]
     [Google Scholar]
  29. Mosteller RD. Evidence that glucose starvation-sensitive mutants are altered in the relB locus. J Bacteriol 1978; 133:1034–1037[PubMed]
     [Google Scholar]
  30. Christensen SK, Mikkelsen M, Pedersen K, Gerdes K. RelE, a global inhibitor of translation, is activated during nutritional stress. Proc Natl Acad Sci USA 2001; 98:14328–14333 [View Article][PubMed]
     [Google Scholar]
  31. Bigger J. Treatment of staphylococcal infections with penicillin by intermittent sterilisation. The Lancet 1944; 244:497–500 [View Article]
     [Google Scholar]
  32. McDermott W. Microbial persistence. Yale J Biol Med 1958; 30:257–291[PubMed]
     [Google Scholar]
  33. Moyed HS, Bertrand KP. hipA, a newly recognized gene of Escherichia coli K-12 that affects frequency of persistence after inhibition of murein synthesis. J Bacteriol 1983; 155:768–775[PubMed]
     [Google Scholar]
  34. Korch SB, Henderson TA, Hill TM. Characterization of the hipA7 allele of Escherichia coli and evidence that high persistence is governed by (p)ppGpp synthesis. Mol Microbiol 2003; 50:1199–1213 [View Article][PubMed]
     [Google Scholar]
  35. Kaspy I, Rotem E, Weiss N, Ronin I, Balaban NQ et al. HipA-mediated antibiotic persistence via phosphorylation of the glutamyl-tRNA-synthetase. Nat Commun 2013; 4:3001 [View Article][PubMed]
     [Google Scholar]
  36. Germain E, Castro-Roa D, Zenkin N, Gerdes K. Molecular mechanism of bacterial persistence by HipA. Mol Cell 2013; 52:248–254 [View Article][PubMed]
     [Google Scholar]
  37. Harms A, Maisonneuve E, Gerdes K. Mechanisms of bacterial persistence during stress and antibiotic exposure. Science 2016; 354:aaf4268 [View Article]
     [Google Scholar]
  38. Maisonneuve E, Gerdes K. Molecular mechanisms underlying bacterial persisters. Cell 2014; 157:539–548 [View Article][PubMed]
     [Google Scholar]
  39. Maisonneuve E, Castro-Camargo M, Gerdes K. (p)ppGpp controls bacterial persistence by stochastic induction of toxin-antitoxin activity. Cell 2013; 154:1140–1150 [View Article][PubMed]
     [Google Scholar]
  40. Makarova KS, Grishin NV, Koonin EV. The HicAB cassette, a putative novel, RNA-targeting toxin-antitoxin system in archaea and bacteria. Bioinformatics 2006; 22:2581–2584 [View Article][PubMed]
     [Google Scholar]
  41. Fiedoruk K, Daniluk T, Swiecicka I, Sciepuk M, Leszczynska K. Type II toxin-antitoxin systems are unevenly distributed among Escherichia coli phylogroups. Microbiology 2015; 161:158–167 [View Article][PubMed]
     [Google Scholar]
  42. Magnuson RD. Hypothetical functions of toxin-antitoxin systems. J Bacteriol 2007; 189:6089–6092 [View Article][PubMed]
     [Google Scholar]
  43. van Melderen L, Saavedra de Bast M. Bacterial toxin-antitoxin systems: more than selfish entities?. PLoS Genet 2009; 5:e1000437 [View Article][PubMed]
     [Google Scholar]
  44. Tsilibaris V, Maenhaut-Michel G, Mine N, van Melderen L. What is the benefit to Escherichia coli of having multiple toxin-antitoxin systems in its genome?. J Bacteriol 2007; 189:6101–6108 [View Article][PubMed]
     [Google Scholar]
  45. Engelberg-Kulka H, Glaser G. Addiction modules and programmed cell death and antideath in bacterial cultures. Annu Rev Microbiol 1999; 53:43–70 [View Article][PubMed]
     [Google Scholar]
  46. Hazan R, Sat B, Engelberg-Kulka H. Escherichia coli mazEF-mediated cell death is triggered by various stressful conditions. J Bacteriol 2004; 186:3663–3669 [View Article][PubMed]
     [Google Scholar]
  47. Sat B, Hazan R, Fisher T, Khaner H, Glaser G et al. Programmed cell death in Escherichia coli: some antibiotics can trigger mazEF lethality. J Bacteriol 2001; 183:2041–2045 [View Article][PubMed]
     [Google Scholar]
  48. Amitai S, Yassin Y, Engelberg-Kulka H. MazF-mediated cell death in Escherichia coli: a point of no return. J Bacteriol 2004; 186:8295–8300 [View Article][PubMed]
     [Google Scholar]
  49. Gross M, Marianovsky I, Glaser G. MazG – a regulator of programmed cell death in Escherichia coli. Mol Microbiol 2006; 59:590–601 [View Article][PubMed]
     [Google Scholar]
  50. Ramisetty BC, Raj S, Ghosh D. Escherichia coli MazEF toxin-antitoxin system does not mediate programmed cell death. J Basic Microbiol 2016; 56:1398–1402 [View Article][PubMed]
     [Google Scholar]
  51. Engelberg-Kulka H, Reches M, Narasimhan S, Schoulaker-Schwarz R, Klemes Y et al. rexB of bacteriophage lambda is an anti-cell death gene. Proc Natl Acad Sci USA 1998; 95:15481–15486 [View Article][PubMed]
     [Google Scholar]
  52. Durand PM, Sym S, Michod RE. Programmed cell death and complexity in microbial systems. Curr Biol 2016; 26:R587–R593 [View Article][PubMed]
     [Google Scholar]
  53. Bayles KW. Bacterial programmed cell death: making sense of a paradox. Nat Rev Microbiol 2014; 12:63–69 [View Article][PubMed]
     [Google Scholar]
  54. Moyed HS, Broderick SH. Molecular cloning and expression of hipA, a gene of Escherichia coli K-12 that affects frequency of persistence after inhibition of murein synthesis. J Bacteriol 1986; 166:399–403 [View Article][PubMed]
     [Google Scholar]
  55. Michiels JE, van den Bergh B, Verstraeten N, Michiels J. Molecular mechanisms and clinical implications of bacterial persistence. Drug Resist Updat 2016; 29:76–89 [View Article][PubMed]
     [Google Scholar]
  56. Tripathi A, Dewan PC, Siddique SA, Varadarajan R. MazF-induced growth inhibition and persister generation in Escherichia coli. J Biol Chem 2014; 289:4191–4205 [View Article][PubMed]
     [Google Scholar]
  57. Vázquez-Laslop N, Lee H, Neyfakh AA. Increased persistence in Escherichia coli caused by controlled expression of toxins or other unrelated proteins. J Bacteriol 2006; 188:3494–3497 [View Article][PubMed]
     [Google Scholar]
  58. Kwan BW, Valenta JA, Benedik MJ, Wood TK. Arrested protein synthesis increases persister-like cell formation. Antimicrob Agents Chemother 2013; 57:1468–1473 [View Article][PubMed]
     [Google Scholar]
  59. Chowdhury N, Kwan BW, Wood TK. Persistence increases in the absence of the alarmone guanosine tetraphosphate by reducing cell growth. Sci Rep 2016; 6:20519 [View Article][PubMed]
     [Google Scholar]
  60. Christensen SK, Pedersen K, Hansen FG, Gerdes K. Toxin-antitoxin loci as stress-response-elements: ChpAK/MazF and ChpBK cleave translated RNAs and are counteracted by tmRNA. J Mol Biol 2003; 332:809–819 [View Article][PubMed]
     [Google Scholar]
  61. Ramisetty BCM, Ghosh D, Roy Chowdhury M, Santhosh RS. What is the link between stringent response, endoribonuclease encoding Type II toxin-antitoxin systems and persistence?. Front Microbiol 2016; 7: [View Article][PubMed]
     [Google Scholar]
  62. Osbourne DO, Soo VW, Konieczny I, Wood TK. Polyphosphate, cyclic AMP, guanosine tetraphosphate, and c-di-GMP reduce in vitro Lon activity. Bioengineered 2014; 5:264–268 [View Article][PubMed]
     [Google Scholar]
  63. Shan Y, Brown Gandt A, Rowe SE, Deisinger JP, Conlon BP et al. ATP-dependent persister formation in Escherichia coli. MBio 2017; 8:e02267-16 [View Article]
     [Google Scholar]
  64. van Melderen L, Wood TK. Commentary: what is the link between stringent response, endoribonuclease encoding type II toxin-antitoxin systems and persistence?. Front Microbiol 2017; 8:191 [View Article][PubMed]
     [Google Scholar]
  65. Nielsen AK, Gerdes K. Mechanism of post-segregational killing by hok-homologue pnd of plasmid R483: two translational control elements in the pnd mRNA. J Mol Biol 1995; 249:270–282 [View Article][PubMed]
     [Google Scholar]
  66. Thisted T, Sørensen NS, Gerdes K. Mechanism of post-segregational killing: secondary structure analysis of the entire Hok mRNA from plasmid R1 suggests a fold-back structure that prevents translation and antisense RNA binding. J Mol Biol 1995; 247:859–873 [View Article][PubMed]
     [Google Scholar]
  67. Cooper TF, Heinemann JA. Postsegregational killing does not increase plasmid stability but acts to mediate the exclusion of competing plasmids. Proc Natl Acad Sci USA 2000; 97:12643–12648 [View Article][PubMed]
     [Google Scholar]
  68. Cooper TF, Paixão T, Heinemann JA. Within-host competition selects for plasmid-encoded toxin-antitoxin systems. Proc Biol Sci 2010; 277:3149–3155 [View Article][PubMed]
     [Google Scholar]
  69. Iqbal N, Guérout AM, Krin E, Le Roux F, Mazel D. Comprehensive functional analysis of the 18 Vibrio cholerae N16961 toxin-antitoxin systems substantiates their role in stabilizing the superintegron. J Bacteriol 2015; 197:2150–2159 [View Article][PubMed]
     [Google Scholar]
  70. Martins PM, Machado MA, Silva NV, Takita MA, de Souza AA. Type II toxin-antitoxin distribution and adaptive aspects on Xanthomonas genomes: focus on Xanthomonas citri. Front Microbiol 2016; 7:652 [View Article][PubMed]
     [Google Scholar]
  71. Ramisetty BC, Ghosh D, Roy Chowdhury M, Santhosh RS. What is the link between stringent response, endoribonuclease encoding type II toxin-antitoxin systems and persistence?. Front Microbiol 2016; 7:1882 [View Article][PubMed]
     [Google Scholar]
  72. Mine N, Guglielmini J, Wilbaux M, van Melderen L. The decay of the chromosomally encoded ccd0157 toxin-antitoxin system in the Escherichia coli species. Genetics 2009; 181:1557–1566 [View Article][PubMed]
     [Google Scholar]
  73. Christensen SK, Maenhaut-Michel G, Mine N, Gottesman S, Gerdes K et al. Overproduction of the Lon protease triggers inhibition of translation in Escherichia coli: involvement of the yefM-yoeB toxin-antitoxin system. Mol Microbiol 2004; 51:1705–1717 [View Article][PubMed]
     [Google Scholar]
  74. Christensen-Dalsgaard M, Jørgensen MG, Gerdes K. Three new RelE-homologous mRNA interferases of Escherichia coli differentially induced by environmental stresses. Mol Microbiol 2010; 75:333–348 [View Article][PubMed]
     [Google Scholar]
  75. Smith AB, López-Villarejo J, Diago-Navarro E, Mitchenall LA, Barendregt A et al. A common origin for the bacterial toxin-antitoxin systems parD and ccd, suggested by analyses of toxin/target and toxin/antitoxin interactions. PLoS One 2012; 7:e46499 [View Article][PubMed]
     [Google Scholar]
  76. Kasari V, Mets T, Tenson T, Kaldalu N. Transcriptional cross-activation between toxin-antitoxin systems of Escherichia coli. BMC Microbiol 2013; 13:45 [View Article][PubMed]
     [Google Scholar]
  77. Zhou J, Rudd KE. EcoGene 3.0. Nucleic Acids Res 2013; 41:D613–D624 [View Article]
     [Google Scholar]
  78. Ray WK, Larson TJ. Application of AgaR repressor and dominant repressor variants for verification of a gene cluster involved in N-acetylgalactosamine metabolism in Escherichia coli K-12. Mol Microbiol 2004; 51:813–826 [View Article][PubMed]
     [Google Scholar]
  79. Brinkkötter A, Klöss H, Alpert C, Lengeler JW. Pathways for the utilization of N-acetyl-galactosamine and galactosamine in Escherichia coli. Mol Microbiol 2000; 37:125–135 [View Article][PubMed]
     [Google Scholar]
  80. Leyn SA, Gao F, Yang C, Rodionov DA. N-acetylgalactosamine utilization pathway and regulon in proteobacteria: genomic reconstruction and experimental characterization in Shewanella. J Biol Chem 2012; 287:28047–28056 [View Article][PubMed]
     [Google Scholar]
  81. Hu Y, Benedik MJ, Wood TK. Antitoxin DinJ influences the general stress response through transcript stabilizer CspE. Environ Microbiol 2012; 14:669–679 [View Article][PubMed]
     [Google Scholar]
  82. Kim Y, Wang X, Zhang XS, Grigoriu S, Page R et al. Escherichia coli toxin/antitoxin pair MqsR/MqsA regulate toxin CspD. Environ Microbiol 2010; 12:1105–1121 [View Article][PubMed]
     [Google Scholar]
  83. Soo VW, Wood TK. Antitoxin MqsA represses curli formation through the master biofilm regulator CsgD. Sci Rep 2013; 3:3186 [View Article][PubMed]
     [Google Scholar]
  84. Yeo CC, Abu Bakar F, Chan WT, Espinosa M, Harikrishna JA. Heterologous expression of toxins from bacterial toxin-antitoxin systems in eukaryotic cells: strategies and applications. Toxins (Basel) 2016; 8:49 [View Article][PubMed]
     [Google Scholar]
  85. Yamamoto TA, Gerdes K, Tunnacliffe A. Bacterial toxin RelE induces apoptosis in human cells. FEBS Lett 2002; 519:191–194 [View Article][PubMed]
     [Google Scholar]
  86. Christensen-Dalsgaard M, Gerdes K. Two higBA loci in the Vibrio cholerae superintegron encode mRNA cleaving enzymes and can stabilize plasmids. Mol Microbiol 2006; 62:397–411 [View Article][PubMed]
     [Google Scholar]
  87. Iqbal N, Guérout AM, Krin E, Le Roux F, Mazel D. Comprehensive functional analysis of the 18 Vibrio cholerae N16961 toxin-antitoxin systems substantiates their role in stabilizing the superintegron. J Bacteriol 2015; 197:2150–2159 [View Article][PubMed]
     [Google Scholar]
  88. Szekeres S, Dauti M, Wilde C, Mazel D, Rowe-Magnus DA. Chromosomal toxin-antitoxin loci can diminish large-scale genome reductions in the absence of selection. Mol Microbiol 2007; 63:1588–1605 [View Article][PubMed]
     [Google Scholar]
  89. Kobayashi I. Behavior of restriction-modification systems as selfish mobile elements and their impact on genome evolution. Nucleic Acids Res 2001; 29:3742–3756 [View Article][PubMed]
     [Google Scholar]
  90. Kobayashi I. Selfishness and death: raison d'être of restriction, recombination and mitochondria. Trends Genet 1998; 14:368–374 [View Article][PubMed]
     [Google Scholar]
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Endoribonuclease type II toxin–antitoxin systems: functional or selfish?
Microbiology 163, 931 (2017); https://doi.org/10.1099/mic.0.000487
/content/journal/micro/10.1099/mic.0.000487
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