Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Antitoxin MqsA helps mediate the bacterial general stress response

Nature Chemical Biology volume 7, pages 359–366 (2011)Cite this article

Subjects

Abstract

Although it is well recognized that bacteria respond to environmental stress through global networks, the mechanism by which stress is relayed to the interior of the cell is poorly understood. Here we show that enigmatic toxin-antitoxin systems are vital in mediating the environmental stress response. Specifically, the antitoxin MqsA represses rpoS, which encodes the master regulator of stress. Repression of rpoS by MqsA reduces the concentration of the internal messenger 3,5-cyclic diguanylic acid, leading to increased motility and decreased biofilm formation. Furthermore, the repression of rpoS by MqsA decreases oxidative stress resistance via catalase activity. Upon oxidative stress, MqsA is rapidly degraded by Lon protease, resulting in induction of rpoS. Hence, we show that external stress alters gene regulation controlled by toxin-antitoxin systems, such that the degradation of antitoxins during stress leads to a switch from the planktonic state (high motility) to the biofilm state (low motility).

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: MqsA binds to wild-type PrpoS but not to mutated PrpoS.
Figure 2: MqsA decreases c-di-GMP and resistance to stress.
Figure 3: MqsA increases motility by regulating rpoS transcription.
Figure 4: MqsA decreases cellulose and curli and biofilm formation.
Figure 5: MqsA is degraded under oxidative stress by Lon, and MqsA decreases RpoS levels.
Figure 6: Schematic of the interaction of antitoxin MqsA with rpoS and its impact on the stress response.

Similar content being viewed by others

References

  1. Gerdes, K., Christensen, S.K. & Løbner-Olesen, A. Prokaryotic toxin-antitoxin stress response loci. Nat. Rev. Microbiol. 3, 371–382 (2005).

    Article  CAS  Google Scholar 

  2. 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).

    Article  CAS  Google Scholar 

  3. Magnuson, R.D. Hypothetical functions of toxin-antitoxin systems. J. Bacteriol. 189, 6089–6092 (2007).

    Article  CAS  Google Scholar 

  4. Shah, D. et al. Persisters: A distinct physiological state of E. coli. BMC Microbiol. 6, 53 (2006).

    Article  Google Scholar 

  5. Pecota, D.C. & Wood, T.K. Exclusion of T4 phage by the hok/sok killer locus from plasmid R1. J. Bacteriol. 178, 2044–2050 (1996).

    Article  CAS  Google Scholar 

  6. Kim, Y., Wang, X., Ma, Q., Zhang, X.-S. & Wood, T.K. Toxin-antitoxin systems in Escherichia coli influence biofilm formation through YjgK (TabA) and fimbriae. J. Bacteriol. 191, 1258–1267 (2009).

    Article  CAS  Google Scholar 

  7. Yamaguchi, Y., Park, J.-H. & Inouye, M. MqsR, a crucial regulator for quorum sensing and biofilm formation, is a GCU-specific mRNA interferase in Escherichia coli. J. Biol. Chem. 284, 28746–28753 (2009).

    Article  CAS  Google Scholar 

  8. Brown, B.L. et al. 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 Pathog. 5, e1000706 (2009).

    Article  Google Scholar 

  9. Aizenman, E., Engelberg-Kulka, H. & Glaser, G. An Escherichia coli chromosomal “addiction module” regulated by 3′,5′-bispyrophosphate: A model for programmed bacterial cell death. Proc. Natl. Acad. Sci. USA 93, 6059–6063 (1996).

    Article  CAS  Google Scholar 

  10. Gotfredsen, M. & Gerdes, K. The Escherichia coli relBE genes belong to a new toxin-antitoxin gene family. Mol. Microbiol. 29, 1065–1076 (1998).

    Article  CAS  Google Scholar 

  11. 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).

    Article  CAS  Google Scholar 

  12. Cherny, I. & Gazit, E. The YefM antitoxin defines a family of natively unfolded proteins: Implications as a novel antibacterial target. J. Biol. Chem. 279, 8252–8261 (2004).

    Article  CAS  Google Scholar 

  13. Motiejūnaite, R., Armalytė, J., Markuckas, A. & Sužiedėlienė, E. Escherichia coli dinJ-yafQ genes act as a toxin-antitoxin module. FEMS Microbiol. Lett. 268, 112–119 (2007).

    Article  Google Scholar 

  14. Schmidt, O. et al. prlF and yhaV encode a new toxin-antitoxin system in Escherichia coli. J. Mol. Biol. 372, 894–905 (2007).

    Article  CAS  Google Scholar 

  15. González Barrios, A.F. et al. Autoinducer 2 controls biofilm formation in Escherichia coli through a novel motility quorum-sensing regulator (MqsR, B3022). J. Bacteriol. 188, 305–316 (2006).

    Article  Google Scholar 

  16. Ren, D., Bedzyk, L.A., Thomas, S.M., Ye, R.W. & Wood, T.K. Gene expression in Escherichia coli biofilms. Appl. Microbiol. Biotechnol. 64, 515–524 (2004).

    Article  CAS  Google Scholar 

  17. Kim, Y. & Wood, T.K. Toxins Hha and CspD and small RNA regulator Hfq are involved in persister cell formation through MqsR in Escherichia coli. Biochem. Biophys. Res. Commun. 391, 209–213 (2010).

    Article  CAS  Google Scholar 

  18. Kim, Y. et al. Escherichia coli toxin/antitoxin pair MqsR/MqsA regulate toxin CspD. Environ. Microbiol. 12, 1105–1121 (2010).

    Article  CAS  Google Scholar 

  19. Pesavento, C. et al. Inverse regulatory coordination of motility and curli-mediated adhesion in Escherichia coli. Genes Dev. 22, 2434–2446 (2008).

    Article  CAS  Google Scholar 

  20. Hengge, R. The two-component network and the general stress sigma factor RpoS (σS) in Escherichia coli. in Bacterial Signal Transduction: Networks and Drug Targets 40–53 (Springer, New York, 2008).

  21. Boehm, A. et al. Second messenger-mediated adjustment of bacterial swimming velocity. Cell 141, 107–116 (2010).

    Article  CAS  Google Scholar 

  22. Pesavento, C. & Hengge, R. Bacterial nucleotide-based second messengers. Curr. Opin. Microbiol. 12, 170–176 (2009).

    Article  CAS  Google Scholar 

  23. Sammartano, L.J., Tuveson, R.W. & Davenport, R. Control of sensitivity to inactivation by H2O2 and broad-spectrum near-UV radiation by the Escherichia coli katF locus. J. Bacteriol. 168, 13–21 (1986).

    Article  CAS  Google Scholar 

  24. Storz, G. & Imlay, J.A. Oxidative stress. Curr. Opin. Microbiol. 2, 188–194 (1999).

    Article  CAS  Google Scholar 

  25. Lacour, S. & Landini, P. σS-dependent gene expression at the onset of stationary phase in Escherichia coli: Function of σS-dependent genes and identification of their promoter sequences. J. Bacteriol. 186, 7186–7195 (2004).

    Article  CAS  Google Scholar 

  26. Baba, T. et al. Construction of Escherichia coli K-12 in-frame, single-gene knockout mutants: the Keio collection. Mol. Syst. Biol. 2, 2006.0008 (2006).

    Article  Google Scholar 

  27. Landini, P. Cross-talk mechanisms in biofilm formation and responses to environmental and physiological stress in Escherichia coli. Res. Microbiol. 160, 259–266 (2009).

    Article  CAS  Google Scholar 

  28. Brown, B.L., Wood, T.K., Peti, W. & Page, R. Structure of the Escherichia coli antitoxin MqsA (YgiT/b3021) bound to its gene promoter reveals extensive domain rearrangements and the specificity of transcriptional regulation. J. Biol. Chem. 286, 2285–2296 (2011).

    Article  CAS  Google Scholar 

  29. Alexeyev, M.F. The pKNOCK series of broad-host-range mobilizable suicide vectors for gene knockout and targeted DNA insertion into the chromosome of gram-negative bacteria. Biotechniques 26, 824–828 (1999).

    Article  CAS  Google Scholar 

  30. Ma, Q. & Wood, T.K. OmpA influences Escherichia coli biofilm formation by repressing cellulose production through the CpxAR two-component system. Environ. Microbiol. 11, 2735–2746 (2009).

    Article  CAS  Google Scholar 

  31. Donegan, N.P., Thompson, E.T., Fu, Z. & Cheung, A.L. Proteolytic regulation of toxin-antitoxin systems by ClpPC in Staphylococcus aureus. J. Bacteriol. 192, 1416–1422 (2010).

    Article  CAS  Google Scholar 

  32. Altuvia, S., Weinstein-Fischer, D., Zhang, A., Postow, L. & Storz, G. A small, stable RNA induced by oxidative stress: Role as a pleiotropic regulator and antimutator. Cell 90, 43–53 (1997).

    Article  CAS  Google Scholar 

  33. Van Melderen, L., Bernard, P. & Couturier, M. Lon-dependent proteolysis of CcdA is the key control for activation of CcdB in plasmid-free segregant bacteria. Mol. Microbiol. 11, 1151–1157 (1994).

    Article  CAS  Google Scholar 

  34. Christensen, S.K., 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).

    Article  CAS  Google Scholar 

  35. Kasari, V., Kurg, K., Margus, T., Tenson, T. & Kaldalu, N. The Escherichia coli mqsR and ygiT genes encode a new toxin-antitoxin pair. J. Bacteriol. 192, 2908–2919 (2010).

    Article  CAS  Google Scholar 

  36. Kolodkin-Gal, I., Verdiger, R., Shlosberg-Fedida, A. & Engelberg-Kulka, H. A differential effect of E. coli toxin-antitoxin systems on cell death in liquid media and biofilm formation. PLoS ONE 4, e6785 (2009).

    Article  Google Scholar 

  37. Zhang, X.-S., García-Contreras, R. & Wood, T.K. YcfR (BhsA) influences Escherichia coli biofilm formation through stress response and surface hydrophobicity. J. Bacteriol. 189, 3051–3062 (2007).

    Article  CAS  Google Scholar 

  38. Ito, A., May, T., Kawata, K. & Okabe, S. Significance of rpoS during maturation of Escherichia coli biofilms. Biotechnol. Bioeng. 99, 1462–1471 (2008).

    Article  CAS  Google Scholar 

  39. Domka, J., Lee, J., Bansal, T. & Wood, T.K. Temporal gene-expression in Escherichia coli K-12 biofilms. Environ. Microbiol. 9, 332–346 (2007).

    Article  CAS  Google Scholar 

  40. Ito, A., Taniuchi, A., May, T., Kawata, K. & Okabe, S. Increased antibiotic resistance of Escherichia coli in mature biofilms. Appl. Environ. Microbiol. 75, 4093–4100 (2009).

    Article  CAS  Google Scholar 

  41. Ito, A., May, T., Taniuchi, A., Kawata, K. & Okabe, S. Localized expression profiles of rpoS in Escherichia coli biofilms. Biotechnol. Bioeng. 103, 975–983 (2009).

    Article  CAS  Google Scholar 

  42. Zheng, M. et al. DNA microarray-mediated transcriptional profiling of the Escherichia coli response to hydrogen peroxide. J. Bacteriol. 183, 4562–4570 (2001).

    Article  CAS  Google Scholar 

  43. Zhang, A. et al. The OxyS regulatory RNA represses rpoS translation and binds the Hfq (HF-I) protein. EMBO J. 17, 6061–6068 (1998).

    Article  CAS  Google Scholar 

  44. Gruber, T.M. & Gross, C.A. Multiple sigma subunits and the partitioning of bacterial transcription space. Annu. Rev. Microbiol. 57, 441–466 (2003).

    Article  CAS  Google Scholar 

  45. Pennington, J.M. & Rosenberg, S.M. Spontaneous DNA breakage in single living Escherichia coli cells. Nat. Genet. 39, 797–802 (2007).

    Article  CAS  Google Scholar 

  46. Dörr, T., Lewis, K. & Vulić, M. SOS response induces persistence to fluoroquinolones in Escherichia coli. PLoS Genet. 5, e1000760 (2009).

    Article  Google Scholar 

  47. Datsenko, K.A. & Wanner, B.L. One-step inactivation of chromosomal genes in Escherichia coli K-12 using PCR products. Proc. Natl. Acad. Sci. USA 97, 6640–6645 (2000).

    Article  CAS  Google Scholar 

  48. Ueda, A. & Wood, T.K. Connecting quorum sensing, c-di-GMP, Pel polysaccharide, and biofilm formation in Pseudomonas aeruginosa through tyrosine phosphatase TpbA (PA3885). PLoS Pathog. 5, e1000483 (2009).

    Article  Google Scholar 

  49. Macvanin, M. & Hughes, D. Assays of sensitivity of antibiotic-resistant bacteria to hydrogen peroxide and measurement of catalase activity. in Antibiotic Resistance Protocols: Second Edition, Methods in Molecular Biology Vol. 642 (Gillespie, S.H. & McHugh, T.D., eds), 95–103 (Humana Press, 2010).

  50. Rice, P., Longden, I. & Bleasby, A. EMBOSS: The European Molecular Biology Open Software Suite (2000). Trends Genet. 16, 276–277 (2000).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by grants from the US National Institutes of Health to T.K.W. and W.P. and an F31 fellowship to B.L.B. and by a US National Science Foundation CAREER award to R.P. We are grateful for the Keio and ASKA strains provided by the Genome Analysis Project in Japan.

Author information

Authors and Affiliations

  1. Department of Chemical Engineering, Texas A&M University, College Station, Texas, USA

    Xiaoxue Wang, Younghoon Kim, Seok Hoon Hong, Qun Ma, Mingming Pu & Thomas K Wood

  2. Department of Molecular Pharmacology, Physiology and Biotechnology, Brown University, Providence, Rhode Island, USA

    Breann L Brown & Wolfgang Peti

  3. Department of Entomology, Texas A&M University, College Station, Texas, USA

    Aaron M Tarone

  4. Department of Biology, Texas A&M University, College Station, Texas, USA

    Michael J Benedik & Thomas K Wood

  5. Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island, USA

    Rebecca Page

Authors
  1. Xiaoxue Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Younghoon Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Seok Hoon Hong
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Qun Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Breann L Brown
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mingming Pu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Aaron M Tarone
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Michael J Benedik
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Wolfgang Peti
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Rebecca Page
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Thomas K Wood
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

T.K.W. conceived the project, T.K.W., X.W., R.P., W.P. and M.J.B. designed the experiments. X.W., S.H.H., Q.M., B.L.B., M.P. and Y.K. performed the experiments. M.J.B. and A.M.T. performed the bioinformatics. All authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Thomas K Wood.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Methods, Supplementary Tables 1–4 and Supplementary Figures 1–5 (PDF 1303 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, X., Kim, Y., Hong, S. et al. Antitoxin MqsA helps mediate the bacterial general stress response. Nat Chem Biol 7, 359–366 (2011). https://doi.org/10.1038/nchembio.560

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nchembio.560

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing