Advertisement

Toxin-Antitoxin Loci in Mycobacterium tuberculosis

  • Ambre Sala
  • Patricia Bordes
  • Gwennaele Fichant
  • Pierre Genevaux
Chapter

Abstract

Chromosomally encoded type II toxin–antitoxin (TA) systems generally consist of two adjacent genes in an operon encoding a stable toxin and a less stable, protease-sensitive cognate antitoxin. While the toxin and the antitoxin form a stable complex under normal growth conditions, the degradation of the antitoxin by stress-proteases under certain conditions leads to activation of the toxin and subsequent growth inhibition. Such stress-responsive TA systems have been associated with various cellular processes, including stabilization of genomic regions, protection against foreign DNA, biofilm formation, persistence, and control of the stress response. Yet, the contribution of chromosomal TA to bacterial virulence is presently unknown. Herein, we investigate the potential role of multiple chromosomally encoded TA systems in virulence, focusing on the tuberculosis agent Mycobacterium tuberculosis, which contains more than 70 TA loci in its genome. We describe what is currently known about the multiple TA families present in this bacterium, with emphasis on the recently discovered atypical stress-responsive toxin–antitoxin-chaperone (TAC) system, a TA system controlled by a SecB-like chaperone.

Keywords

Genomic Island Persister Cell Rickettsia Species Stable Toxin Antitoxin Gene 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

We thank Virginie Calderon and all the members of the Genevaux laboratory for insightful discussions. This work was supported by a French MENRT fellowship to AS and an ATIP-CNRS grant to PG.

References

  1. Ahidjo, B. A., Kuhnert, D., McKenzie, J. L., Machowski, E. E., Gordhan, B. G., Arcus, V., et al. (2011). VapC toxins from Mycobacterium tuberculosis are ribonucleases that differentially inhibit growth and are neutralized by cognate VapB antitoxins. PLoS ONE, 6, e21738.PubMedCrossRefGoogle Scholar
  2. Arbing, M. A., Handelman, S. K., Kuzin, A. P., Verdon, G., Wang, C., Su, M., et al. (2010). Crystal structures of Phd-Doc, HigA, and YeeU establish multiple evolutionary links between microbial growth-regulating toxin–antitoxin systems. Structure, 18, 996–1010.PubMedCrossRefGoogle Scholar
  3. Arcus, V. L., McKenzie, J. L., Robson, J., & Cook, G. M. (2011). The PIN-domain ribonucleases and the prokaryotic VapBC toxin–antitoxin array. Protein Engineering, Design & Selection, 24, 33–40.CrossRefGoogle Scholar
  4. Audoly, G., Vincentelli, R., Edouard, S., Georgiades, K., Mediannikov, O., Gimenez, G., et al. (2011). Effect of rickettsial toxin VapC on its eukaryotic host. PLoS ONE, 6, e26528.PubMedCrossRefGoogle Scholar
  5. Barry, C. E., 3rd, Boshoff, H. I., Dartois, V., Dick, T., Ehrt, S., Flynn, J., et al. (2009). The spectrum of latent tuberculosis: rethinking the biology and intervention strategies. Nature Reviews Microbiology, 7, 845–855.PubMedGoogle Scholar
  6. Betts, J. C., Lukey, P. T., Robb, L. C., McAdam, R. A., & Duncan, K. (2002). Evaluation of a nutrient starvation model of Mycobacterium tuberculosis persistence by gene and protein expression profiling. Molecular Microbiology, 43, 717–731.PubMedCrossRefGoogle Scholar
  7. Blower, T. R., Salmond, G. P., & Luisi, B. F. (2011). Balancing at survival’s edge: the structure and adaptive benefits of prokaryotic toxin–antitoxin partners. Current Opinion in Structural Biology, 21, 109–118.PubMedCrossRefGoogle Scholar
  8. Bordes, P., Cirinesi, A. M., Ummels, R., Sala, A., Sakr, S., Bitter, W., et al. (2011). SecB-like chaperone controls a toxin–antitoxin stress-responsive system in Mycobacterium tuberculosis. Proceedings of the National Academy of Sciences of the United States of America, 108, 8438–8443.PubMedCrossRefGoogle Scholar
  9. Brown, B. L., Grigoriu, S., Kim, Y., Arruda, J. M., Davenport, A., Wood, T. K., et al. (2009). Three dimensional structure of the MqsR:MqsA complex: a novel TA pair comprised of a toxin homologous to RelE and an antitoxin with unique properties. PLoS Pathogens, 5, e1000706.PubMedCrossRefGoogle Scholar
  10. Christensen-Dalsgaard, M., & Gerdes, K. (2006). Two higBA loci in the Vibrio cholerae superintegron encode mRNA cleaving enzymes and can stabilize plasmids. Molecular Microbiology, 62, 397–411.PubMedCrossRefGoogle Scholar
  11. Dahl, J. L., Kraus, C. N., Boshoff, H. I., Doan, B., Foley, K., Avarbock, D., et al. (2003). The role of RelMtb-mediated adaptation to stationary phase in long-term persistence of Mycobacterium tuberculosis in mice. Proceedings of the National Academy of Sciences of the United States of America, 100, 10026–10031.PubMedCrossRefGoogle Scholar
  12. de la Paz Santangelo, M., Klepp, L., Nunez-Garcia, J., Blanco, F. C., Soria, M., Garcia-Pelayo, M. C., et al. (2009). Mce3R, a TetR-type transcriptional repressor, controls the expression of a regulon involved in lipid metabolism in Mycobacterium tuberculosis. Microbiology, 155, 2245–2255.PubMedCrossRefGoogle Scholar
  13. Estorninho, M., Smith, H., Thole, J., Harders-Westerveen, J., Kierzek, A., Butler, R. E., et al. (2010). ClgR regulation of chaperone and protease systems is essential for Mycobacterium tuberculosis parasitism of the macrophage. Microbiology, 156, 3445–3455.PubMedCrossRefGoogle Scholar
  14. Fivian-Hughes, A. S., & Davis, E. O. (2010). Analyzing the regulatory role of the HigA antitoxin within Mycobacterium tuberculosis. Journal of Bacteriology, 192, 4348–4356.PubMedCrossRefGoogle Scholar
  15. Georgiades, K., & Raoult, D. (2011). Genomes of the most dangerous epidemic bacteria have a virulence repertoire characterized by fewer genes but more toxin–antitoxin modules. PLoS ONE, 6, e17962.PubMedCrossRefGoogle Scholar
  16. Gerdes, K., Christensen, S. K., & Lobner-Olesen, A. (2005). Prokaryotic toxin–antitoxin stress response loci. Nature Reviews Microbiology, 3, 371–382.PubMedCrossRefGoogle Scholar
  17. Goulard, C., Langrand, S., Carniel, E., & Chauvaux, S. (2010). The Yersinia pestis chromosome encodes active addiction toxins. Journal of Bacteriology, 192, 3669–3677.PubMedCrossRefGoogle Scholar
  18. Grady, R., & Hayes, F. (2003). Axe-Txe, a broad-spectrum proteic toxin–antitoxin system specified by a multidrug-resistant, clinical isolate of Enterococcus faecium. Molecular Microbiology, 47, 1419–1432.PubMedCrossRefGoogle Scholar
  19. Guo, M., Feng, H., Zhang, J., Wang, W., Wang, Y., Li, Y., et al. (2009). Dissecting transcription regulatory pathways through a new bacterial one-hybrid reporter system. Genome Research, 19, 1301–1308.PubMedCrossRefGoogle Scholar
  20. Gupta, A. (2009). Killing activity and rescue function of genome-wide toxin–antitoxin loci of Mycobacterium tuberculosis. FEMS Microbiology Letters, 290, 45–53.PubMedCrossRefGoogle Scholar
  21. Hazan, R., Sat, B., & Engelberg-Kulka, H. (2004). Escherichia coli mazEF-mediated cell death is triggered by various stressful conditions. Journal of Bacteriology, 186, 3663–3669.PubMedCrossRefGoogle Scholar
  22. Hood, R. D., Singh, P., Hsu, F., Guvener, T., Carl, M. A., Trinidad, R. R., et al. (2010). A type VI secretion system of Pseudomonas aeruginosa targets a toxin to bacteria. Cell Host & Microbe, 7, 25–37.CrossRefGoogle Scholar
  23. Huang, F., & He, Z. G. (2010). Characterization of an interplay between a Mycobacterium tuberculosis MazF homolog, Rv1495 and its sole DNA topoisomerase I. Nucleic Acids Research, 38, 8219–8230.PubMedCrossRefGoogle Scholar
  24. Hurley, J. M., & Woychik, N. A. (2009). Bacterial toxin HigB associates with ribosomes and mediates translation-dependent mRNA cleavage at A-rich sites. Journal of Biological Chemistry, 284, 18605–18613.PubMedCrossRefGoogle Scholar
  25. Jiang, Y., Pogliano, J., Helinski, D. R., & Konieczny, I. (2002). ParE toxin encoded by the broad-host-range plasmid RK2 is an inhibitor of Escherichia coli gyrase. Molecular Microbiology, 44, 971–979.PubMedCrossRefGoogle Scholar
  26. Kamada, K., & Hanaoka, F. (2005). Conformational change in the catalytic site of the ribonuclease YoeB toxin by YefM antitoxin. Molecular Cell, 19, 497–509.PubMedCrossRefGoogle Scholar
  27. Keren, I., Minami, S., Rubin, E., & Lewis, K. (2011). Characterization and transcriptome analysis of Mycobacterium tuberculosis persisters. MBio, 2, 00100–00111.CrossRefGoogle Scholar
  28. Korch, S. B., Contreras, H., & Clark-Curtiss, J. E. (2009). Three Mycobacterium tuberculosis Rel toxin–antitoxin modules inhibit mycobacterial growth and are expressed in infected human macrophages. Journal of Bacteriology, 191, 1618–1630.PubMedCrossRefGoogle Scholar
  29. Kumar, P., Issac, B., Dodson, E. J., Turkenburg, J. P., & Mande, S. C. (2008). Crystal structure of Mycobacterium tuberculosis YefM antitoxin reveals that it is not an intrinsically unstructured protein. Journal of Molecular Biology, 383, 482–493.PubMedCrossRefGoogle Scholar
  30. Lewis, K. (2010). Persister cells. Annual Review of Microbiology, 64, 357–372.PubMedCrossRefGoogle Scholar
  31. Maisonneuve, E., Shakespeare, L. J., Jorgensen, M. G., & Gerdes, K. (2011). Bacterial persistence by RNA endonucleases. Proceedings of the National Academy of Sciences of the United States of America, 108, 13206–13211.PubMedCrossRefGoogle Scholar
  32. Makarova, K. S., Wolf, Y. I., & Koonin, E. V. (2009). Comprehensive comparative-genomic analysis of type 2 toxin–antitoxin systems and related mobile stress response systems in prokaryotes. Biology Direct, 4, 19.PubMedCrossRefGoogle Scholar
  33. McKenzie, J.L., Robson, J., Berney, M., Smith, T.C., Ruthe, A., Gardner, P.P., et al. (2012) A VapBC toxin-antitoxin module is a post-transcriptional regulator of metabolic flux in mycobacteria. Journal of Bacteriology, 194, 2189–21204.PubMedCrossRefGoogle Scholar
  34. Mehra, S., Pahar, B., Dutta, N. K., Conerly, C. N., Philippi-Falkenstein, K., Alvarez, X., et al. (2010). Transcriptional reprogramming in nonhuman primate (rhesus macaque) tuberculosis granulomas. PLoS ONE, 5, e12266.PubMedCrossRefGoogle Scholar
  35. Miallau, L., Faller, M., Chiang, J., Arbing, M., Guo, F., Cascio, D., et al. (2009). Structure and proposed activity of a member of the VapBC family of toxin–antitoxin systems. VapBC-5 from Mycobacterium tuberculosis. Journal of Biological Chemistry, 284, 276–283.PubMedCrossRefGoogle Scholar
  36. Mutschler, H., Gebhardt, M., Shoeman, R. L., & Meinhart, A. (2011). A novel mechanism of programmed cell death in bacteria by toxin–antitoxin systems corrupts peptidoglycan synthesis. PLoS Biology, 9, e1001033.PubMedCrossRefGoogle Scholar
  37. Niederweis, M., Danilchanka, O., Huff, J., Hoffmann, C., & Engelhardt, H. (2010). Mycobacterial outer membranes: in search of proteins. Trends in Microbiology, 18, 109–116.PubMedCrossRefGoogle Scholar
  38. Pandey, D. P., & Gerdes, K. (2005). Toxin–antitoxin loci are highly abundant in free-living but lost from host-associated prokaryotes. Nucleic Acids Research, 33, 966–976.PubMedCrossRefGoogle Scholar
  39. Park, J. H., Yamaguchi, Y., & Inouye, M. (2011). Bacillus subtilis MazF-bs (EndoA) is a UACAU-specific mRNA interferase. FEBS Letters, 585, 2526–2532.PubMedCrossRefGoogle Scholar
  40. Pearce, M. J., Mintseris, J., Ferreyra, J., Gygi, S. P., & Darwin, K. H. (2008). Ubiquitin-like protein involved in the proteasome pathway of Mycobacterium tuberculosis. Science, 322, 1104–1107.PubMedCrossRefGoogle Scholar
  41. Poulsen, C., Akhter, Y., Jeon, A. H., Schmitt-Ulms, G., Meyer, H. E., Stefanski, A., et al. (2010). Proteome-wide identification of mycobacterial pupylation targets. Molecular System Biology, 6, 386.Google Scholar
  42. Ramage, H. R., Connolly, L. E., & Cox, J. S. (2009). Comprehensive functional analysis of Mycobacterium tuberculosis toxin–antitoxin systems: implications for pathogenesis, stress responses, and evolution. PLoS Genetics, 5, e1000767.PubMedCrossRefGoogle Scholar
  43. Randall, L. L., & Hardy, S. J. (2002). SecB, one small chaperone in the complex milieu of the cell. Cellular & Molecular Life Sciences, 59, 1617–1623.CrossRefGoogle Scholar
  44. Ribeiro-Guimaraes, M. L., & Pessolani, M. C. (2007). Comparative genomics of mycobacterial proteases. Microbial Pathogenesis, 43, 173–178.PubMedCrossRefGoogle Scholar
  45. Roberts, R. C., & Helinski, D. R. (1992). Definition of a minimal plasmid stabilization system from the broad-host-range plasmid RK2. Journal of Bacteriology, 174, 8119–8132.PubMedGoogle Scholar
  46. Rustad, T. R., Harrell, M. I., Liao, R., & Sherman, D. R. (2008). The enduring hypoxic response of Mycobacterium tuberculosis. PLoS ONE, 3, e1502.PubMedCrossRefGoogle Scholar
  47. Sassetti, C. M., Boyd, D. H., & Rubin, E. J. (2003). Genes required for mycobacterial growth defined by high density mutagenesis. Molecular Microbiology, 48, 77–84.PubMedCrossRefGoogle Scholar
  48. Shah, D., Zhang, Z., Khodursky, A., Kaldalu, N., Kurg, K., & Lewis, K. (2006). Persisters: a distinct physiological state of E. coli. BMC Microbiology, 6, 53.PubMedCrossRefGoogle Scholar
  49. Sharp, J.D., Cruz, J.W., Raman, S., Inouye, M., Husson, R.N. and Woychik, N.A. (2012) Growth and translation inhibition through sequence specific RNA binding by a Mycobacterium tuberculosis VAPC toxin. Journal of Biological Chemistry, 287, 12835–12847.PubMedCrossRefGoogle Scholar
  50. Sherrid, A. M., Rustad, T. R., Cangelosi, G. A., & Sherman, D. R. (2010). Characterization of a Clp protease gene regulator and the reaeration response in Mycobacterium tuberculosis. PLoS ONE, 5, e11622.PubMedCrossRefGoogle Scholar
  51. Singh, R., Barry, C. E., 3rd, & Boshoff, H. I. (2010). The three RelE homologs of Mycobacterium tuberculosis have individual, drug-specific effects on bacterial antibiotic tolerance. Journal of Bacteriology, 192, 1279–1291.PubMedCrossRefGoogle Scholar
  52. Smollett, K. L., Fivian-Hughes, A. S., Smith, J. E., Chang, A., Rao, T., & Davis, E. O. (2009). Experimental determination of translational start sites resolves uncertainties in genomic open reading frame predictions—application to Mycobacterium tuberculosis. Microbiology, 155, 186–197.PubMedCrossRefGoogle Scholar
  53. Stewart, G. R., Wernisch, L., Stabler, R., Mangan, J. A., Hinds, J., Laing, K. G., et al. (2002). Dissection of the heat-shock response in Mycobacterium tuberculosis using mutants and microarrays. Microbiology, 148, 3129–3138.PubMedGoogle Scholar
  54. Stinear, T. P., Seemann, T., Harrison, P. F., Jenkin, G. A., Davies, J. K., Johnson, P. D., et al. (2008). Insights from the complete genome sequence of Mycobacterium marinum on the evolution of Mycobacterium tuberculosis. Genome Research, 18, 729–741.PubMedCrossRefGoogle Scholar
  55. Tailleux, L., Waddell, S. J., Pelizzola, M., Mortellaro, A., Withers, M., Tanne, A., et al. (2008). Probing host pathogen cross-talk by transcriptional profiling of both Mycobacterium tuberculosis and infected human dendritic cells and macrophages. PLoS ONE, 3, e1403.PubMedCrossRefGoogle Scholar
  56. Tian, Q. B., Ohnishi, M., Tabuchi, A., & Terawaki, Y. (1996). A new plasmid-encoded proteic killer gene system: cloning, sequencing, and analyzing hig locus of plasmid Rts1. Biochemical & Biophysical Research Communications, 220, 280–284.CrossRefGoogle Scholar
  57. Van Melderen, L. (2010). Toxin–antitoxin systems: why so many, what for? Current Opinion in Microbiology, 13, 781–785.PubMedCrossRefGoogle Scholar
  58. Vesper, O., Amitai, S., Belitsky, M., Byrgazov, K., Kaberdina, A. C., Engelberg-Kulka, H., et al. (2011). Selective translation of leaderless mRNAs by specialized ribosomes generated by MazF in Escherichia coli. Cell, 147, 147–157.PubMedCrossRefGoogle Scholar
  59. Voskuil, M. I., Schnappinger, D., Visconti, K. C., Harrell, M. I., Dolganov, G. M., Sherman, D. R., et al. (2003). Inhibition of respiration by nitric oxide induces a Mycobacterium tuberculosis dormancy program. Journal of Experimental Medicine, 198, 705–713.PubMedCrossRefGoogle Scholar
  60. Wang, X., Kim, Y., Hong, S. H., Ma, Q., Brown, B. L., Pu, M., et al. (2011). Antitoxin MqsA helps mediate the bacterial general stress response. Nature Chemical Biology, 7, 359–366.PubMedCrossRefGoogle Scholar
  61. Winther, K. S., & Gerdes, K. (2011). Enteric virulence associated protein VapC inhibits translation by cleavage of initiator tRNA. Proceedings of the National Academy of Sciences of the United States of America, 108, 7403–7407.PubMedCrossRefGoogle Scholar
  62. Wozniak, R. A., & Waldor, M. K. (2009). A toxin–antitoxin system promotes the maintenance of an integrative conjugative element. PLoS Genetics, 5, e1000439.PubMedCrossRefGoogle Scholar
  63. Yamaguchi, Y., & Inouye, M. (2011). Regulation of growth and death in Escherichia coli by toxin–antitoxin systems. Nature Reviews Microbiology, 9, 779–790.PubMedCrossRefGoogle Scholar
  64. Yamaguchi, Y., Park, J. H., & Inouye, M. (2011). Toxin–antitoxin systems in bacteria and archaea. Annual Review of Genetics, 45, 61–79.PubMedCrossRefGoogle Scholar
  65. Yang, M., Gao, C., Wang, Y., Zhang, H., & He, Z. G. (2010). Characterization of the interaction and cross-regulation of three Mycobacterium tuberculosis RelBE modules. PLoS ONE, 5, e10672.PubMedCrossRefGoogle Scholar
  66. Yoshizumi, S., Zhang, Y., Yamaguchi, Y., Chen, L., Kreiswirth, B. N., & Inouye, M. (2009). Staphylococcus aureus YoeB homologues inhibit translation initiation. Journal of Bacteriology, 191, 5868–5872.PubMedCrossRefGoogle Scholar
  67. Zhang, Y., Zhu, L., Zhang, J., & Inouye, M. (2005). Characterization of ChpBK, an mRNA interferase from Escherichia coli. Journal of Biological Chemistry, 280, 26080–26088.PubMedCrossRefGoogle Scholar
  68. Zhu, L., Phadtare, S., Nariya, H., Ouyang, M., Husson, R. N., & Inouye, M. (2008). The mRNA interferases, MazF-mt3 and MazF-mt7 from Mycobacterium tuberculosis target unique pentad sequences in single-stranded RNA. Molecular Microbiology, 69, 559–569.PubMedCrossRefGoogle Scholar
  69. Zhu, L., Sharp, J. D., Kobayashi, H., Woychik, N. A., & Inouye, M. (2010). Noncognate Mycobacterium tuberculosis toxin–antitoxins can physically and functionally interact. Journal of Biological Chemistry, 285, 39732–39738.PubMedCrossRefGoogle Scholar
  70. Zhu, L., Zhang, Y., Teh, J. S., Zhang, J., Connell, N., Rubin, H., et al. (2006). Characterization of mRNA interferases from Mycobacterium tuberculosis. Journal of Biological Chemistry, 281, 18638–18643.PubMedCrossRefGoogle Scholar
  71. Zuber, B., Chami, M., Houssin, C., Dubochet, J., Griffiths, G., & Daffe, M. (2008). Direct visualization of the outer membrane of mycobacteria and corynebacteria in their native state. Journal of Bacteriology, 190, 5672–5680.PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Ambre Sala
    • 1
  • Patricia Bordes
    • 1
  • Gwennaele Fichant
    • 1
  • Pierre Genevaux
    • 1
  1. 1.Laboratoire de Microbiologie et Génétique Moléculaire (LMGM)Centre National de la Recherche Scientifique (CNRS) and Université Paul SabatierToulouseFrance

Personalised recommendations