Advertisement

Tearing Down the Wall: Peptidoglycan Metabolism and the WalK/WalR (YycG/YycF) Essential Two-Component System

  • Sarah Dubrac
  • Tarek Msadek
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 631)

Abstract

In order to survive, bacteria have developed a variety of highly sophisticated and sensitive signal transduction pathways with which they adapt their genetic expression to meet the challenges of their ever-changing surroundings. These mechanisms enable bacterial cells to communicate with their environment, their hosts and each other, allowing them adopt specific responses, or develop specialised structures such as biofilms or spores to ensure survival, colonization of their ecological niches and dissemination. As highlighted in this book, the so-called two-component systems (TCSs) are one of the most widespread and efficient strategies used for this purpose, where signal acquisition involves autophosphorylation of a sensor histidine kinase and transduction takes place when the kinase phosphorylates its cognate response regulator protein, leading in turn to specific alteration of gene expression.

In their simplest form, TCSs elegantly combine sensing, transducing and transcription activation modules within two proteins, effectively coupling external signals to genetic adaptation. The high degree of conservation among TCS phosphotransfer domains, their ubiquitous nature and the fact that several are essential for cell viability has made them an attractive target for novel classes of antimicrobial compounds. The WalK/WalR (aka YycG/YycF) two-component system, originally identified in Bacillus subtilis, is very highly conserved and specific to low G+C Gram-positive bacteria, including several pathogens such as Staphylococcus aureus. While this sytem is essential for cell viability, both the nature of its regulon and its physiological role had remained mostly uncharacterized. A number of recent studies have now unveiled a conserved function for this system in different bacteria, defining this signal transduction pathway as a master regulatory system for cell wall metabolism, which we have accordingly renamed WalK/WalR. This review will focus on the cellular function of the WalK/WalR TCS in different bacterial species and the attractive target it constitutes for novel classes of antimicrobial compounds.

Keywords

Bacillus Subtilis Response Regulator Streptococcus Pneumoniae Histidine Kinase Acetyl Phosphate 
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.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Inouye M, Dutta R, eds. Histidine kinases in signal transduction. San Diego: Academic Press; 2003.Google Scholar
  2. 2.
    Hoch JA, Silhavy TJ. Two-component signal transduction. Washington, DC: ASM Press; 1995.Google Scholar
  3. 3.
    Ausmees N, Jacobs-Wagner C. Spatial and temporal control of differentiation and cell cycle progression in Caulobacter crescentus. Annu Rev Microbiol 2003; 57:225–247.PubMedCrossRefGoogle Scholar
  4. 4.
    Skerker JM, Prasol MS, Perchuk BS et al. Two-component signal transduction pathways regulating growth and cell cycle progression in a bacterium: a system-level analysis. PLoS Biol 2005; 3:e334.PubMedCrossRefGoogle Scholar
  5. 5.
    Zahrt TC, Deretic V. An essential two-component signal transduction system in Mycobacterium tuberculosis. J Bacteriol 2000; 182:3832–3838.PubMedCrossRefGoogle Scholar
  6. 6.
    Fol M, Chauhan A, Nair NK et al. Modulation of Mycobacterium tuberculosis proliferation by MtrA, an essential two-component response regulator. Mol Microbiol 2006; 60:643–657.PubMedCrossRefGoogle Scholar
  7. 7.
    Fukuchi K, Kasahara Y, Asai K et al. The essential two-component regulatory system encoded by yycF and yycG modulates expression of the ftsAZ operon in Bacillus subtilis. Microbiology 2000; 146:1573–1583.PubMedGoogle Scholar
  8. 8.
    Fabret C, Hoch JA. A two-component signal transduction system essential for growth of Bacillus subtilis: implications for anti-infective therapy. J Bacteriol 1998; 180:6375–6383.PubMedGoogle Scholar
  9. 9.
    Martin PK, Li T, Sun D et al. Role in cell permeability of an essential two-component system in Staphylococcus aureus. J Bacteriol 1999; 181:3666–3673.PubMedGoogle Scholar
  10. 10.
    Dubrac S, Msadek T. Identification of genes controlled by the essential YycG/YycF two-component system of Staphylococcus aureus. J Bacteriol 2004; 186:1175–1181.PubMedCrossRefGoogle Scholar
  11. 11.
    Throup JP, Koretke KK, Bryant AP et al. A genomic analysis of two-component signal transduction in Streptococcus pneumoniae. Mol Microbiol 2000; 35:566–576.PubMedCrossRefGoogle Scholar
  12. 12.
    Lange R, Wagner C, de Saizieu A et al. Domain organization and molecular characterization of 13 two-component systems identified by genome sequencing of Streptococcus pneumoniae. Gene 1999; 237:223–234.PubMedCrossRefGoogle Scholar
  13. 13.
    Echenique JR, Trombe MC. Competence repression under oxygen limitation through the two-component MicAB signal-transducing system in Streptococcus pneumoniae and involvement of the PAS domain of MicB. J Bacteriol 2001; 183:4599–4608.PubMedCrossRefGoogle Scholar
  14. 14.
    Senadheera MD, Guggenheim B, Spatafora GA et al. A VicRK signal transduction system in Streptococcus mutans affects gtfBCD, gbpB and ftf expression, biofilm formation and genetic competence development. J Bacteriol 2005; 187:4064–4076.PubMedCrossRefGoogle Scholar
  15. 15.
    Liu M, Hanks TS, Zhang J et al. Defects in ex vivo and in vivo growth and sensitivity to osmotic stress of group A Streptococcus caused by interruption of response regulator gene vicR. Microbiology 2006; 152:967–978.PubMedCrossRefGoogle Scholar
  16. 16.
    Kallipolitis BH, Ingmer H. Listeria monocytogenes response regulators important for stress tolerance and pathogenesis. FEMS Microbiol Lett 2001; 204:111–115.PubMedCrossRefGoogle Scholar
  17. 17.
    Hancoek LE, Perego M. Systematic inactivation and phenotypic characterization of two-component signal transduction systems of Enterococcus faecalis V583. J Bacteriol 2004; 186:7951–7958.CrossRefGoogle Scholar
  18. 18.
    Qin Z, Zhang J, Xu B et al. Structure-based discovery of inhibitors of the YycG histidine kinase: new chemical leads to combat Staphylococcus epidermidis infections. BMC Microbiol 2006; 6:96.PubMedCrossRefGoogle Scholar
  19. 19.
    Dubrac S, Boneca IG, Poupel O et al. New insights into the WalK/WalR (YycG/YycF) essential signal transduction pathway reveal a major role in controlling cell wall metabolism and biofilm formation in Staphylococcus aureus. J Bacteriol 2007; 189:8257–8269.PubMedCrossRefGoogle Scholar
  20. 20.
    Bisicchia P, Noone D, Lioliou E et al. The essential YycFG two-component system controls cell wall metabolism in Bacillus subtilis. Mol Microbiol 2007; 65:180–200.PubMedCrossRefGoogle Scholar
  21. 21.
    Ng WL, Robertson GT, Kazmierczak KM et al. Constitutive expression of PcsB suppresses the requirement for the essential VicR (YycF) response regulator in Streptococcus pneumoniae R6. Mol Microbiol 2003; 50:1647–1663.PubMedCrossRefGoogle Scholar
  22. 22.
    Ng WL, Kazmierczak KM, Winkler ME. Defective cell wall synthesis in Streptococcus pneumoniae R6 depleted for the essential PcsB putative murein hydrolase or the VicR (YycF) response regulator. Mol Microbiol 2004; 53:1161–1175.PubMedCrossRefGoogle Scholar
  23. 23.
    Dubrac S, Bisicchia P, Devine K et al. A matter of life and death: cell wall homeostasis and the WalKR (YycGF) regulon. (Submitted for publication) 2008Google Scholar
  24. 24.
    Szurmant H, Nelson K, Kim EJ et al. YycH regulates the activity of the essential YycFG two-component system in Bacillus subtilis. J Bacteriol 2005; 187:5419–5426.PubMedCrossRefGoogle Scholar
  25. 25.
    Szurmant H, Mohan MA, Imus PM et al. YycH and YycI interact to regulate the essential YycFG two-component system in Bacillus subtilis. J Bacteriol 2007; 189:3280–3289.PubMedCrossRefGoogle Scholar
  26. 26.
    Szurmant H, Zhao H, Mohan MA et al. The crystal structure of YycH involved in the regulation of the essential YycFG two-component system in Bacillus subtilis reveals a novel tertiary structure. Protein Sci 2006; 15:929–934.PubMedCrossRefGoogle Scholar
  27. 27.
    Santelli E, Liddington RC, Mohan MA et al. The crystal structure of Bacillus subtilis YycI reveals a common fold for two members of an unusual class of sensor histidine kinase regulatory proteins. J Bacteriol 2007; 189:3290–3295.PubMedCrossRefGoogle Scholar
  28. 28.
    Daivasu H, Osaka K, Ishino Y et al. Expansion of the zinc metallo-hydrolase family of the beta-lactamase fold. FEBS Lett 2001; 503:1–6.CrossRefGoogle Scholar
  29. 29.
    Ng WL, Winkler ME. Singular structures and operon organizations of essential two-component systems in species of Streptococcus. Microbiology 2004; 150:3096–3098.PubMedCrossRefGoogle Scholar
  30. 30.
    Wagner C, Saizieu Ad A, Schonfeld HJ et al. Genetic analysis and functional characterization of the Streptococcus pneumoniae vic operon. Infect Immun 2002; 70:6121–6128.PubMedCrossRefGoogle Scholar
  31. 31.
    Senadheera MD, Lee AW, Hung DC et al. The Streptococcus mutans vicX Gene Product Modulates gtfB/C Expression, Biofilm Formation, Genetic Competence and Oxidative Stress Tolerance. J Bacteriol 2007; 189:1451–1458.PubMedCrossRefGoogle Scholar
  32. 32.
    Noone D, Howell A, Collery R et al. YkdA and YvtA, HtrA-like serine proteases in Bacillus subtilis, engage in negative autoregulation and reciprocal cross-regulation of ykdA and yvtA gene expression. J Bacteriol 2001; 183:654–663.PubMedCrossRefGoogle Scholar
  33. 33.
    Clausen T, Southan C, Ehrmann M. The HtrA family of proteases: implications for protein composition and cell fate. Mol Cell 2002; 10:443–455.PubMedCrossRefGoogle Scholar
  34. 34.
    Stack HM, Sleator RD, Bowers M et al. Role for HtrA in stress induction and virulence potential in Listeria monocytogenes. Appl Environ Microbiol 2005; 71:4241–4247.PubMedCrossRefGoogle Scholar
  35. 35.
    Taylor BL, Zhulin IB. PAS domains: internal sensors of oxygen, redox potential and light. Microbiol Mol Biol Rev 1999; 63:479–506.PubMedGoogle Scholar
  36. 36.
    Ulrich LE, Zhulin IB. MiST: a microbial signal transduction database. Nucleic Acids Res 2007; 35:D386–390.PubMedCrossRefGoogle Scholar
  37. 37.
    Clausen VA, Bae W, Throup J et al. Biochemical characterization of the first essential two-component signal transduction system from Staphylococcus aureus and Streptococcus pneumoniae. J Mol Microbiol Biotechnol 2003; 5:252–260.PubMedCrossRefGoogle Scholar
  38. 38.
    Depardieu F, Courvalin P, Msadek T. A six amino acid deletion, partially overlapping the VanSB G2 ATP-binding motif, leads to constitutive glycopeptide resistance in VanB-type Enterococcus faecium. Mol Microbiol 2003; 50:1069–1083.PubMedCrossRefGoogle Scholar
  39. 39.
    Alves R, Savageau MA. Comparative analysis of prototype two-component systems with either bifunctional or monofunctional sensors: differences in molecular structure and physiological function. Mol Microbiol 2003; 48:25–51.PubMedCrossRefGoogle Scholar
  40. 40.
    Howell A, Dubrac S, Andersen KK et al. Genes controlled by the essential YycG/YycF two-component system of Bacillus subtilis revealed through a novel hybrid regulator approach. Mol Microbiol 2003; 49:1639–1655.PubMedCrossRefGoogle Scholar
  41. 41.
    O’Connell-Motherway M, van Sinderen D, Morel-Deville F et al. Six putative two-component regulatory systems isolated from Lactococcus lactis subsp. cremoris MG1363. Microbiology 2000; 146:935–947.PubMedGoogle Scholar
  42. 42.
    Mascher T, Helmann JD, Unden G. Stimulus perception in bacterial signal-transducing histidine kinases. Microbiol Mol Biol Rev 2006; 70:910–938.PubMedCrossRefGoogle Scholar
  43. 43.
    Mizuno T, Tanaka I. Structure of the DNA-binding domain of the OmpR family of response regulators. Molecular Microbiology 1997; 24:665–667.PubMedCrossRefGoogle Scholar
  44. 44.
    Martinez-Hackert E, Stock AM. Structural relationships in the OmpR family of winged-helix transcription factors. J Mol Biol; 1997; 269:301–312.PubMedCrossRefGoogle Scholar
  45. 45.
    Martinez-Hackert E, Stock AM. The DNA-binding domain of OmpR: crystal structures of a winged helix transcription factor. Structure 1997; 5:109–124.PubMedCrossRefGoogle Scholar
  46. 46.
    Blanco AG, Sola M, Gomis-Ruth FX et al. Tandem DNA recognition by PhoB, a two-component signal transduction transcriptional activator. Structure 2002; 10:701–713.PubMedCrossRefGoogle Scholar
  47. 47.
    Makino K, Amemura M, Kawamoto T et al. DNA binding of PhoB and its interaction with RNA polymerase. J Mol Biol 1996; 259:15–26.PubMedCrossRefGoogle Scholar
  48. 48.
    Trinh CH, Liu Y, Phillips SE et al. Structure of the response regulator VicR DNA-binding domain. Acta Crystallogr D Biol Crystallogr 2007; 63:266–269.PubMedCrossRefGoogle Scholar
  49. 49.
    Ng WL, Tsui HC, Winkler ME. Regulation of the pspA virulence factor and essential pcsB murein biosynthetic genes by the phosphorylated VicR (YycF) response regulator in Streptococcus pneumoniae. J Bacteriol 2005; 187:7444–7459.PubMedCrossRefGoogle Scholar
  50. 50.
    Howell A, Dubrac S, Noone D et al. Interactions between the YycFG and PhoPR two-component systems in Bacillus subtilis: the PhoR kinase phosphorylates the noncognate YycF response regulator upon phosphate limitation. Mol Microbiol 2006; 59:1199–1215.PubMedCrossRefGoogle Scholar
  51. 51.
    Lee SF, Delaney GD, Elkhateeb M. A two-component covRS regulatory system regulates expression of fructosyltransferase and a novel extracellular carbohydrate in Streptococcus mutans. Infect Immun 2004; 72:3968–3973.PubMedCrossRefGoogle Scholar
  52. 52.
    Stapleton MR, Horsburgh MJ, Hayhurst EJ et al. Characterization of IsaA and SceD, two putative lytic transglycosylases of Staphylococcus aureus. J Bacteriol 2007; 189:7316–7325.PubMedCrossRefGoogle Scholar
  53. 53.
    Ahn SJ, Burne RA. Effects of oxygen on biofilm formation and the AtlA autolysin of Streptococcus mutans. J Bacteriol 2007; 189:6293–6302.PubMedCrossRefGoogle Scholar
  54. 54.
    Mohedano ML, Overweg K, de la Fuente A et al. Evidence that the essential response regulator YycF in Streptococcus pneumoniae modulates expression of fatty acid biosynthesis genes and alters membrane composition. J Bacteriol 2005; 187:2357–2367.PubMedCrossRefGoogle Scholar
  55. 55.
    Aguilar PS, Hernandez-Arriaga AM, Cybulski LE et al. Molecular basis of thermosensing: a two-component signal transduction thermometer in Bacillus subtilis. EMBO J 2001; 20:1681–1691.PubMedCrossRefGoogle Scholar
  56. 56.
    Deng DM, Liu MJ, ten Cate JM et al. The VicRK system of Streptococcus mutans responds to oxidative stress. J Dent Res 2007; 86:606–610.PubMedCrossRefGoogle Scholar
  57. 57.
    Ramadurai L, Jayaswal RK. Molecular cloning, sequencing and expression of lytM, a unique autolytic gene of Staphylococcus aureus. J Bacteriol 1997; 179:3625–3631.PubMedGoogle Scholar
  58. 58.
    Sakata N, Mukai T. Production profile of the soluble lytic transglycosylase homologue in Staphylococcus aureus during bacterial proliferation. FEMS Immunol Med Microbiol 2007; 49:288–295.PubMedCrossRefGoogle Scholar
  59. 59.
    Shemesh M, Tam A, Feldman M et al. Differential expression profiles of Streptococcus mutans ftf, gtf and vicR genes in the presence of dietary carbohydrates at early and late exponential growth phases. Carbohydr Res 2006; 341:2090–2097.PubMedCrossRefGoogle Scholar
  60. 60.
    Martin PK, Bao Y, Boyer E et al. Novel locus required for expression of high-level macrolide-lincosamide-streptogramin B resistance in Staphylococcus aureus. J Bacteriol 2002; 184:5810–5813.PubMedCrossRefGoogle Scholar
  61. 61.
    Friedman L, Alder JD, Silverman JA. Genetic changes that correlate with reduced susceptibility to daptomycin in Staphylococcus aureus. Antimicrob Agents Chemother 2006; 50:2137–2145.PubMedCrossRefGoogle Scholar
  62. 62.
    Jansen A, Turck M, Szekat C et al. Role of insertion elements and yycFG in the development of decreased susceptibility to vancomycin in Staphylococcus aureus. Int J Med Microbiol 2007; 297:205–215.PubMedCrossRefGoogle Scholar
  63. 63.
    Mwangi MM, Wu SW, Zhou Y et al. Tracking the in vivo evolution of multidrug resistance in Staphylococcus aureus by whole-genome sequencing. Proc Natl Acad Sci USA 2007; 104:9451–9456.PubMedCrossRefGoogle Scholar
  64. 64.
    Kadioglu A, Echenique J, Manco S et al. The MicAB two-component signaling system is involved in virulence of Streptococcus pneumoniae. Infect Immun 2003; 71:6676–6679.PubMedCrossRefGoogle Scholar
  65. 65.
    Brown JS, Gilliland SM, Holden DW. A Streptococcus pneumoniae pathogenicity island encoding an ABC transporter involved in iron uptake and virulence. Mol Microbiol 2001; 40:572–585.PubMedCrossRefGoogle Scholar
  66. 66.
    Ren B, McCrory MA, Pass C et al. The virulence function of Streptococcus pneumoniae surface protein A involves inhibition of complement activation and impairment of complement receptor-mediated protection. J Immunol 2004; 173:7506–7512.PubMedGoogle Scholar
  67. 67.
    Ren B, Szalai AJ, Hollingshead SK et al. Effects of PspA and antibodies to PspA on activation and deposition of complement on the pneumococcal surface. Infect Immun 2004; 72:114–122.PubMedCrossRefGoogle Scholar
  68. 68.
    Munro C, Michalek SM, Macrina FL. Cariogenicity of Streptococcus mutans V403 glucosyltransferase and fructosyltransferase mutants constructed by allelic exchange. Infect Immun 1991; 59:2316–2323.PubMedGoogle Scholar
  69. 69.
    Yamamoto K, Kitayama T, Minagawa S et al. Antibacterial agents that inhibit histidine protein kinase YycG of Bacillus subtilis. Biosci Biotechnol Biochem 2001; 65:2306–2310.PubMedCrossRefGoogle Scholar
  70. 70.
    Hilliard JJ, Goldschmidt RM, Licata L et al. Multiple mechanisms of action for inhibitors of histidine protein kinases from bacterial two-component systems. Antimicrob Agents Chemother 1999; 43:1693–1699.PubMedGoogle Scholar
  71. 71.
    Furuta E, Yamamoto K, Tatebe D et al. Targeting protein homodimerization: a novel drug discovery system. FEBS Lett 2005; 579:2065–2070.PubMedCrossRefGoogle Scholar
  72. 72.
    Thompson JD, Higgins DG, Gibson TJ. CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice. Nucleic Acids Res 1994; 22:4673–4680.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2008

Authors and Affiliations

  1. 1.Biology of Gram Positive Pathogens, Department of MicrobiologyInstitut PasteurParis Cedex 15France

Personalised recommendations