J Appl Biomed 8:179-188, 2010 | DOI: 10.2478/v10136-009-0021-9

Bacterial toxin-antitoxin systems targeting translation

Ramón Díaz-Orejas*, Elizabeth Diago-Navarro, Ana María Hernández Arriaga, Juan López-Villarejo, Marc Lemonnier, Inma Moreno-Córdoba, Concha Nieto, Manuel Espinosa
Departamento de Microbiología Molecular y Biología de las Infecciones, Centro de Investigaciones Biológicas - CSIC, Madrid, Spain

Toxin-antitoxin systems (TAS) emerged more than 25 years ago and have since developed as an important field in molecular microbiology. TAS are autoregulated operons coding a stable toxin and an unstable antitoxin found in the plasmids and chromosomes of Bacteria and Archaea. The conditional activation of their toxins interferes with cell growth/viability and, depending on the context, can influence plasmid maintenance, stress management, bacterial persistence, cell differentiation and, it is likely also bacterial virulence. This review summarizes recent results on the parD system of plasmid R1 and on the chromosomal relBE systems found in Escherichia coli and in Streptococcus pneumoniae with a focus on the RNase activity of their toxins, their regulation and their biomedical applications and implications.

Keywords: toxin-antitoxin systems; plasmid maintenance; cell growth regulation; toxin RNases; protein synthesis inhibition

Received: March 5, 2010; Revised: April 30, 2010; Published: July 31, 2010  Show citation

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Díaz-Orejas R, Diago-Navarro E, Hernández Arriaga AM, López-Villarejo J, Lemonnier M, Moreno-Córdoba I, et al.. Bacterial toxin-antitoxin systems targeting translation. J Appl Biomed. 2010;8(4):179-188. doi: 10.2478/v10136-009-0021-9.
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    References

    1. Bernard P, Couturier M: Cell killing by the F plasmid CcdB protein involves poisoning of DNA-topoisomerase II complexes. J Mol Biol 226:735-745, 1992. Go to original source... Go to PubMed...
    2. Bigger J: Treatment of Staphylococcal infections with penicillin by intermittent sterilisation. Lancet 244:497-500, 1944. Go to original source...
    3. Bravo A, de Torróntegui G, Díaz R: Identification of components of a new stability system of plasmid R1, ParD, that is close to the origin of replication of this plasmid. Mol Gen Genet 210:101-110, 1987. Go to original source... Go to PubMed...
    4. Bravo A, Ortega S, de Torróntegui G, Díaz R: Killing of Escherichia coli cells modulated by components of the stability system ParD of plasmid R1. Mol Gen Genet 215:146-151, 1988. Go to original source... Go to PubMed...
    5. Buts L, Lah J, Dao-Thi MH, Wyns L, Loris R: Toxin-antitoxin modules as bacterial metabolic stress managers. Trends Biochem Sci 30:672-679, 2005. Go to original source... Go to PubMed...
    6. Cherny I, Overgaard M, Borch J, Bram Y, Gerdes K, Gazit E: Structural and thermodynamic characterization of the Escherichia coli RelBE toxin-antitoxin system: indication for a functional role of differential stability. Biochemistry 46:12152-12163, 2007. Go to original source... Go to PubMed...
    7. Christensen SK, Gerdes K: RelE toxins from Bacteria and Archaea cleave mRNAs on translating ribosomes, which are rescued by tmRNA. Mol Microbiol 48:1389-1400, 2003. Go to original source... Go to PubMed...
    8. Christensen SK, Mikkelsen M, Pedersen K, Gerdes K: RelE, a global inhibitor of translation, is activated during nutritional stress. Proc Natl Acad Sci USA 98:14328-14333, 2001. Go to original source... Go to PubMed...
    9. Christensen-Dalsgaard M, Gerdes K: Translation affects YoeB and MazF messenger RNA interferase activities by different mechanisms. Nucleic Acids Res 36:6472-6481, 2008. Go to original source... Go to PubMed...
    10. Condon C: Shutdown decay of mRNA. Mol Microbiol 61:573-583, 2006. Go to original source... Go to PubMed...
    11. Daines, DA, Wu MH, Yuan SY: VapC-1 of nontypeable Haemophilus influenzae is a ribonuclease. J Bacteriol 189:5041-5048, 2007. Go to original source... Go to PubMed...
    12. de la Cueva-Méndez G, Mills AD, Clay-Farrace L, Díaz-Orejas R, Laskey RA: Regulatable killing of eukaryotic cells by the prokaryotic proteins Kid and Kis. EMBO J 22:246-251, 2003. Go to original source... Go to PubMed...
    13. Diago-Navarro E, Kamphuis MB, Boelens R, Barendregt A, Heck AJ, van den Heuvel RH, Díaz-Orejas R: A mutagenic analysis of the RNase mechanism of the bacterial Kid toxin by mass spectrometry. FEBS J 276:4973-4986 2009a. Go to original source... Go to PubMed...
    14. Diago-Navarro E, Mora L, Buckingham RH, Díaz-Orejas R, Lemonnier M: Novel Escherichia coli RF1 mutants with decreased translation termination activity and increased sensitivity to the cytotoxic effect of the bacterial toxins Kid and RelE. Mol Microbiol 71:66-78, 2009b. Go to original source... Go to PubMed...
    15. Francuski D, Saenger W: Crystal structure of the antitoxin-toxin protein complex RelB-RelE from Methanococcus jannaschii. J Mol Biol 393:898-908, 2009. Go to original source... Go to PubMed...
    16. Garza-Sánchez F, Gin JG, Hayes CS: Amino acid starvation and colicin D treatment induce A-site mRNA cleavage in Escherichia coli. J Mol Biol 378:505-519, 2008. Go to original source... Go to PubMed...
    17. Gerdes K, Christensen SK, Lobner-Olesen A: Prokaryotic toxin-antitoxin stress response loci. Nature Rev Microbiol 3:371-382, 2005. Go to original source... Go to PubMed...
    18. Gerdes K, Rasmussen PB, Molin S: Unique type of plasmid maintenance function: postsegregational killing of plasmid-free cells. Proc Natl Acad Sci USA 83:3116-3120, 1986. Go to original source... Go to PubMed...
    19. Gotfredsen M, Gerdes K: The Escherichia coli relBE genes belong to a new toxin-antitoxin gene family. Mol Microbiol 29:1065-1076, 1998. Go to original source... Go to PubMed...
    20. Gotfredsen M, Gerdes K: Toxin-antitoxin modules may regulate synthesis of macromolecules during nutritional stress. J Bacteriol 182:561-572, 2002. Go to original source... Go to PubMed...
    21. Grady R, Hayes F: Axe-Txe, a broad-spectrum proteic toxin-antitoxin system specified by a multidrug-resistant, clinical isolate of Enterococcus faecium. Mol Microbiol 47:1419-1432, 2003. Go to original source... Go to PubMed...
    22. Gronlund H, Gerdes K: Toxin-antitoxin systems homologous with relBE of Escherichia coli plasmid P307 are ubiquitous in prokaryotes. J Mol Biol 285:1401-1415, 1999. Go to original source... Go to PubMed...
    23. Hargreaves D, Santos-Sierra S, Giraldo R. Sabariegos-Jareño R, de la Cueva-Méndez G, Boelens R, Díaz-Orejas R, Rafferty JB: Structural and functional analysis of the kid toxin protein from E. coli plasmid R1. Structure 10:1425-1433, 2002. Go to original source... Go to PubMed...
    24. Hayes F: Toxins-antitoxins: plasmid maintenance, programmed cell death, and cell cycle arrest. Science 301:1496-1499, 2003. Go to original source... Go to PubMed...
    25. Hiraga S, Jaffe A, Ogura T, Mori H, Takahashi H: F plasmid ccd mechanism in Escherichia coli. J Bacteriol 166:100-104, 1986. Go to original source... Go to PubMed...
    26. Hopper S, Wilbur JS, Vasquez BL, Larson J, Clary S, Mehr IJ, Seifert HS, So M: Isolation of Neisseria gonorrhoeae mutants that show enhanced trafficking across polarized T84 epithelial monolayers. Infection Immun 68:896-905, 2000. Go to original source... Go to PubMed...
    27. Kamada K, Hanaoka F: Conformational change in the catalytic site of the ribonuclease YoeB toxin by YefM antitoxin. Mol Cell 19:497-509, 2005. Go to original source... Go to PubMed...
    28. Kamada K, Hanaoka F, Burley SK: Crystal structure of the MazE/MazF complex: molecular bases of antidote-toxin recognition. Mol Cell 11:875-884, 2003. Go to original source... Go to PubMed...
    29. Kamphuis MB, Bonvin AM, Monti MC, Lemonnier M, Muñoz-Gómez A, van den Heuvel RH, Díaz-Orejas R, Boelens R: Model for RNA binding and the catalytic site of the RNase Kid of the bacterial parD toxin-antitoxin system. J Mol Biol 357:115-126, 2006. Go to original source... Go to PubMed...
    30. Kamphuis MB, Monti MC, van den Heuvel RH, López-Villarejo J, Díaz-Orejas R, Boelens R: Structure and function of bacterial kid-kis and related toxin-antitoxin systems. Protein Pept Lett 14:113-124, 2007a. Go to original source... Go to PubMed...
    31. Kamphuis MB, Monti MC, van den Heuvel RH, Santos-Sierra S, Folkers GE, Lemonnier M, Díaz-Orejas R, Heck AJ, Boelens R: Interactions between the toxin kid of the bacterial parD system and the antitoxins Kis and MazE. Proteins 67:219-231, 2007b. Go to original source... Go to PubMed...
    32. Kedzierska B, Lian LY, Hayes F: Toxin-antitoxin regulation: bimodal interaction of YefM-YoeB with paired DNA palindromes exerts transcriptional autorepression. Nucleic Acids Res 35:325-339, 2007. Go to original source... Go to PubMed...
    33. Korch SB, Contreras H, Clark-Curtiss JE: Three Mycobacterium tuberculosis Rel toxin-antitoxin modules inhibit mycobacterial growth and are expressed in infected human macrophages. J Bacteriol 191:1618-1630, 2009. Go to original source... Go to PubMed...
    34. Kristoffersen P, Jensen GB, Gerdes K, Piskur J: Bacterial toxin-antitoxin gene system as containment control in yeast cells. Appl Environ Microbiol 66:5524-5526, 2000. Go to original source... Go to PubMed...
    35. Kumar P, Issac B, Dodson EJ, Turkenburg JP, Mande SC: Crystal structure of Mycobacterium tuberculosis YefM antitoxin reveals that it is not an intrinsically unstructured protein. J Mol Biol 383:482-493, 2008. Go to original source... Go to PubMed...
    36. Li GY, Zhang Y, Inouye M, Ikura M: Structural mechanism of transcriptional autorepression of the Escherichia coli RelB/RelE antitoxin/toxin module. J Mol Biol 380:107-119, 2008a. Go to original source... Go to PubMed...
    37. Li GY, Zhang Y, Inouye M, Ikura M: Inhibitory mechanism of Escherichia coli RelE-RelB toxin-antitoxin module involves a helix displacement near an mRNA interferase active site. J Biol Chem 284:14628-14636, 2009. Go to original source... Go to PubMed...
    38. Li X, Yagi M, Morita T, Aiba H: Cleavage of mRNAs and role of tmRNA system under amino acid starvation in Escherichia coli. Mol Microbiol 68:462-473, 2008b. Go to original source... Go to PubMed...
    39. Lioy VS, Rey O, Balsa D, Pellicer T, Alonso JC: A toxin-antitoxin module as a target for antimicrobial development. Plasmid 63:31-39, 2010. Go to original source... Go to PubMed...
    40. Makarova KS, Wolf YI, Koonin EV: Comprehensive comparative-genomic analysis of Type 2 toxin-antitoxin systems and related mobile stress response systems in prokaryotes. Biol Direct 4:19, 2009. Go to original source... Go to PubMed...
    41. Masuda Y, Miyakawa K, Nishimura Y, Ohtsubo E: chpA and chpB, Escherichia coli chromosomal homologs of the pem locus responsible for stable maintenance of plasmid R100. J Bacteriol 175:6850-6856, 1993. Go to original source... Go to PubMed...
    42. Monti MC, Hernández-Arriaga AM, Kamphuis MB, López-Villarejo J, Heck AJ, Boelens R, Díaz-Orejas R, van den Heuvel RH: Interactions of Kid-Kis toxin-antitoxin complexes with the parD operator-promoter region of plasmid R1 are piloted by the Kis antitoxin and tuned by the stoichiometry of Kid-Kis oligomers. Nucleic Acids Res 35:1737-1749, 2007. Go to original source... Go to PubMed...
    43. Moritz EM, Hergenrother PJ: Toxin-antitoxin systems are ubiquitous and plasmid-encoded in vancomycin-resistant enterococci. Proc Natl Acad Sci USA 104:311-316, 2007. Go to original source... Go to PubMed...
    44. 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 155:768-775, 1983. Go to original source... Go to PubMed...
    45. Muñoz-Gómez AJ, Santos-Sierra S, Berzal-Herranz A, Lemonnier M, Díaz-Orejas R: Insights into the specificity of RNA cleavage by the Escherichia coli MazF toxin. FEBS Lett 567:316-320, 2004. Go to original source... Go to PubMed...
    46. Muñoz-Gómez AJ, Lemonnier M, Santos-Sierra S, Berzal-Herranz A, Díaz-Orejas R: Rnase/anti-RNase activities of the bacterial parD toxin - antitoxin system. J Bacteriol 187:3151-3157, 2005. Go to original source... Go to PubMed...
    47. Neubauer C, Gao YG, Andersen KR, Dunham CM, Kelley AC, Hentschel J, Gerdes, Ramakrishnan V, Brodersen DE: The structural basis for mRNA recognition and cleavage by the ribosome-dependent endonuclease RelE. Cell 139:1084-1095, 2009. Go to original source... Go to PubMed...
    48. Nieto C, Pellicer T, Balsa D, Christensen SK, Gerdes K, Espinosa M: The chromosomal relBE2 toxin-antitoxin locus of Streptococcus pneumoniae: characterization and use of a bioluminescence resonance energy transfer assay to detect toxin-antitoxin interaction. Mol Microbiol 59:1280-1296, 2006. Go to original source... Go to PubMed...
    49. Nieto C, Cherny I, Khoo SK, de Lacoba MG, Chan WT, Yeo CC, Gazit E, Espinosa M: The yefM-yoeB toxin-antitoxin systems of Escherichia coli and Streptococcus pneumoniae: functional and structural correlation. J Bacteriol 189:1266-1278, 2007. Go to original source... Go to PubMed...
    50. Overgaard M, Borch J, Jorgensen MG, Gerdes K: Messenger RNA interferase RelE controls relBE transcription by conditional cooperativity. Mol Microbiol 69:841-857, 2008. Go to original source... Go to PubMed...
    51. Pandey D, Gerdes K: Toxin- antitoxin loci are highly abundant in free-living but lost from host-associated prokaryotes. Nucleic Acids Res 55:78-89, 2005. Go to original source... Go to PubMed...
    52. Pedersen K, Christensen SK, Gerdes K: Rapid induction and reversal of a bacteriostatic condition by controlled expression of toxins and antitoxins. Mol Microbiol 45:501-510, 2002. Go to original source... Go to PubMed...
    53. Pedersen K, Zavialov AV, Pavlov MY, Elf J, Gerdes K, Ehrenberg M: The bacterial toxin RelE displays codon-specific cleavage of mRNAs in the ribosomal A site. Cell 112:131-140, 2003. Go to original source... Go to PubMed...
    54. Perichon B, Bogaerts P, Lambert T, Frangeul L, Courvalin P, Galimand M: Sequence of conjugative plasmid pIP1206 mediating resistance to aminoglycosides by 16S rRNA methylation and to hydrophilic fluoroquinolones by efflux. Antimicrob Agents Chemother 52:2581-2592, 2008. Go to original source... Go to PubMed...
    55. Pimentel B, Madine MA, de la Cueva-Méndez G: Kid cleaves specific mRNAs at UUACU sites to rescue the copy number of plasmid R1. EMBO J 24:3459-3469, 2005. Go to original source... Go to PubMed...
    56. Potrykus K, Santos S, Lemonnier M, Díaz-Orejas R, Wegrzyn G: Differential effects of Kid toxin on two modes of replication of lambdoid plasmids suggest that this toxin acts before, but not after, the assembly of the replication complex. Microbiology 148:2489-2495, 2002. Go to original source... Go to PubMed...
    57. Ruiz-Echevarría MJ, de la Cueva G, Díaz-Orejas: Translational coupling and limited degradation of a polycistronic messenger modulate differential gene expression in the parD stability system of plasmid R1. Mol Gen Genet 248:599-609, 1995a. Go to original source... Go to PubMed...
    58. Ruiz-Echevarría MJ, de la Torre MA, Díaz-Orejas R: A mutation that decreases the efficiency of plasmid R1 replication leads to the activation of parD, a killer stability system of the plasmid. FEMS Microbiol Lett 130:129-135, 1995b. Go to original source... Go to PubMed...
    59. Santos-Sierra S, Giraldo R, Díaz-Orejas R: Functional interactions between homologous conditional killer systems of plasmid and chromosomal origin. FEMS Microbiol Lett 152:51-56, 1997. Go to original source... Go to PubMed...
    60. Santos-Sierra S, Giraldo R, Díaz-Orejas R: Functional interactions between chpB and parD, two homologous conditional killer systems found in the Escherichia coli chromosome and in plasmid R1. FEMS Microbiol Lett 168:51-58, 1998. Go to original source... Go to PubMed...
    61. Schumacher MA, Piro KM, Xu W, Hansen S, Lewis K, Brennan RG: Molecular mechanisms of HipA-mediated multidrug tolerance and its neutralization by HipB. Science 323:396-401, 2009. Go to original source... Go to PubMed...
    62. Slanchev K, Stebler J, de la Cueva-Méndez G, Raz E: Development without germ cells: the role of the germ line in zebrafish sex differentiation. Proc Natl Acad Sci USA 102:4074-4079, 2005. Go to original source... Go to PubMed...
    63. Takagi H, Kakuta Y, Okada T, Yao M, Tanaka I, Kimura M: Crystal structure of archaeal toxin-antitoxin RelE-RelB complex with implications for toxin activity and antitoxin effects. Nat Struct Mol Biol 12:327-331, 2005. Go to original source... Go to PubMed...
    64. 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 189:6101-6108, 2007. Go to original source... Go to PubMed...
    65. Tsuchimoto S, Ohtsubo H, Ohtsubo E: Two genes, pemK and pemI, responsible for stable maintenance of resistance plasmid R100. J Bacteriol 170:1461-1466, 1988. Go to original source... Go to PubMed...
    66. Tsuchimoto S, Nishimura Y, Ohtsubo E: The stable maintenance system pem of plasmid R100: degradation of PemI protein may allow PemK protein to inhibit cell growth. J Bacteriol 174:4205-4211, 1992. Go to original source... Go to PubMed...
    67. Van Melderen L, Saavedra De Bast M: Bacterial toxin-antitoxin systems: more than selfish entities? PLoS Genet 5:e1000437, 2009. Go to original source... Go to PubMed...
    68. Yamamoto TA, Gerdes K, Tunnacliffe A: Bacterial toxin RelE induces apoptosis in human cells. FEBS Lett 519:191-194, 2002. Go to original source... Go to PubMed...
    69. Yoshizumi S, Zhang Y, Yamaguchi Y, Chen L, Kreiswirth BN, Inouye M: Staphylococcus aureus YoeB homologues inhibit translation initiation. J Bacteriol 191:5868-5872, 2009. Go to original source... Go to PubMed...
    70. Zhang J, Zhang Y, Zhu L, Suzuki M, Inouye M: Interference of mRNA function by sequence-specific endoribonuclease PemK. J Biol Chem 279:20678-20684, 2004. Go to original source... Go to PubMed...
    71. Zhang Y, Inouye M: The inhibitory mechanism of protein synthesis by YoeB, an Escherichia coli toxin. J Biol Chem 284:6627-6638, 2009. Go to original source... Go to PubMed...
    72. Zhang Y, Zhang J, Hoeflich KP, Ikura M, Qing G, Inouye M: MazF cleaves cellular mRNAs specifically at ACA to block protein synthesis in Escherichia coli. Mol Cell 12:913-923, 2003. Go to original source... Go to PubMed...

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