The PhoQ/PhoP Regulatory Network of Salmonella enterica

Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 631)


The PhoQ/PhoP two-component regulatory system is a major regulator of virulence in the enteric pathogen Salmonella enterica serovar Typhimurium. It also controls the adaptation to low Mg2+ environments by governing the expression and/or activity of Mg2+ transporters and of enzymes modifying the Mg2+-binding sites on the bacterial cell surface. The regulator PhoP modifies expression of ≈3% of the Salmonella genes in response to the periplasmic Mg2+ concentration detected by the PhoQ protein. Genes that are directly controlled by the PhoP protein often differ in their promoter structures, resulting in distinct expression levels and kinetics in response to the low Mg2+ inducing signal. PhoP regulates a large number of genes indirectly: via other transcription factors and two-component systems that form a panoply of regulatory architectures including transcriptional cascades, feedforward loops and the use of connector proteins that modify the activity of response regulators. These architectures confer distinct expression properties that may be important contributors to Salmonella’s lifestyle.


Response Regulator Pathogenicity Island Feedforward Loop Yersinia Pestis Regulatory Architecture 


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  1. 1.
    Kier LD, Weppelman RM, Ames BN. Regulation of nonspecific acid phosphatase in Salmonella: phoN and phoP genes. J Bacteriol 1979; 138:155–161.PubMedGoogle Scholar
  2. 2.
    Groisman EA, Saier MH Jr, Ochman H. Horizontal transfer of a phosphatase gene as evidence for mosaic structure of the Salmonella genome. EMBO J 1992; 11:1309–1316.PubMedGoogle Scholar
  3. 3.
    Groisman EA, Chiao E, Lipps CJ et al. Salmonella typhimurium phoP virulence gene is a transcriptional regulator. Proc Natl Acad Sci USA 1989; 86:7077–7081.PubMedCrossRefGoogle Scholar
  4. 4.
    Fields PI, Groisman EA, Heffron F. A Salmonella locus that controls resistance to microbicidal proteins from phagocytic cells. Science 1989; 243:1059–1062.PubMedCrossRefGoogle Scholar
  5. 5.
    Miller SI, Kukral AM, Mekalanos JJ. A two-component regulatory system (phoP phoQ) controls Salmonella typhimurium virulence. Proc Natl Acad Sci USA 1989; 86:5054–5058.PubMedCrossRefGoogle Scholar
  6. 6.
    Galan JE, Curtiss R 3rd. Virulence and vaccine potential of phoP mutants of Salmonella typhimurium. Microb Pathog 1989; 6:433–443.PubMedCrossRefGoogle Scholar
  7. 7.
    Groisman EA, Parra CA, Salcedo M et al. Resistance to host antimicrobial peptides is necessary for Salmonella virulence. Proc Natl Acad Sci USA 1992; 89:11939–11943.PubMedCrossRefGoogle Scholar
  8. 8.
    Tu X, Latifi T, Bougdour A et al. The PhoP/PhoQ two-component system stabilizes the alternative sigma factor RpoS in Salmonella enterica. Proc Natl Acad Sci USA 2006; 103:13503–13508.PubMedCrossRefGoogle Scholar
  9. 9.
    Bearson BL, Wilson L, Foster JW. A low pH-inducible, phoPQ-dependent acid tolerance response protects Salmonella typhimurium against inorganic acid stress. J Bacteriol 1998; 180:2409–2417.PubMedGoogle Scholar
  10. 10.
    Soncini FC, García Véscovi E, Solomon F et al. Molecular basis of the magnesium deprivation response in Salmonella typhimurium: identification of PhoP-regulated genes. J Bacteriol 1996; 178:5092–5099.PubMedGoogle Scholar
  11. 11.
    Blanc-Potard A-B, Groisman EA. The Salmonella selC locus contains a pathogenicity island mediating intramacrophage survival. EMBO J 1997; 16:5376–5385.PubMedCrossRefGoogle Scholar
  12. 12.
    Moss JE, Fisher PE, Vick B et al. The regulatory protein PhoP controls susceptibility to the host inflammatory response in Shigella flexneri. Cell Microbiol 2000; 2:443–452.PubMedCrossRefGoogle Scholar
  13. 13.
    Oyston PC, Dorrell N, Williams K et al. The response regulator PhoP is important for survival under conditions of macrophage-induced stress and virulence in Yersinia pestis. Infect Immun 2000; 68:3419–3425.PubMedCrossRefGoogle Scholar
  14. 14.
    Derzelle S, Turlin E, Duchaud E et al. The PhoP-PhoQ two-component regulatory system of Photorhabdus luminescens is essential for virulence in insects. J Bacteriol 2004; 186:1270–1279.PubMedCrossRefGoogle Scholar
  15. 15.
    Flego D, Marits R, Eriksson AR et al. A two-component regulatory system, pehR-pehS, controls endopolygalacturonase production and virulence in the plant pathogen Erwinia carotovora subsp carotovora. Mol Plant Microbe Interact 2000; 13:447–455.PubMedCrossRefGoogle Scholar
  16. 16.
    Shin D, Groisman EA. Signal-dependent binding of the response regulators PhoP and PmrA to their target promoters in vivo. J Biol Chem 2005; 280:4089–4094.PubMedCrossRefGoogle Scholar
  17. 17.
    Chamnongpol S, Groisman EA. Acetyl phosphate-dependent activation of a mutant PhoP response regulator that functions independently of its cognate sensor kinase. J Mol Biol 2000; 300:291–305.PubMedCrossRefGoogle Scholar
  18. 18.
    Castelli ME, Garcia Vescovi E, Soncini FC. The phosphatase activity is the target for Mg2+ regulation of the sensor protein PhoQ in Salmonella. J Biol Chem 2000; 275:22948–22954.PubMedCrossRefGoogle Scholar
  19. 19.
    García Véscovi E, Soncini FC, Groisman EA. Mg2+ as an extracellular signal: environmental regulation of Salmonella virulence. Cell 1996; 84:165–174.PubMedCrossRefGoogle Scholar
  20. 20.
    Chamnongpol S, Cromie M, Groisman EA. Mg2+ sensing by the Mg2+ sensor PhoQ of Salmonella enterica. J Mol Biol 2003; 325:795–807.PubMedCrossRefGoogle Scholar
  21. 21.
    García Véscovi E, Ayala M, Di Cera E et al. Characterization of the bacterial sensor protein PhoQ. Evidence for distinct binding sites for Mg2+ and Ca2+. J Mol Biol 1997; 272:1440–1443.Google Scholar
  22. 22.
    Cho US, Bader MW, Amaya MF et al. Metal bridges between the PhoQ sensor domain and the membrane regulate transmembrane signaling. J Mol Biol 2006; 356:1193–1206.PubMedCrossRefGoogle Scholar
  23. 23.
    Shin D, Lee EJ, Huang H et al. A positive feedback loop promotes transcription surge that jump-starts Salmonella virulence circuit. Science 2006; 314:1607–1609.PubMedCrossRefGoogle Scholar
  24. 24.
    Bader MW, Sanowar S, Daley ME et al. Recognition of antimicrobial peptides by a bacterial sensor kinase. Cell 2005; 122:461–472.PubMedCrossRefGoogle Scholar
  25. 25.
    Prost LR, Daley ME, Le Sage V et al. Activation of the bacterial sensor kinase PhoQ by acidic pH. Mol Cell 2007; 26:165–174.PubMedCrossRefGoogle Scholar
  26. 26.
    Groisman EA, Mouslim C. Sensing by bacterial regulatory systems in host and nonhost environments. Nat Rev Microbiol 2006; 4:705–709.PubMedCrossRefGoogle Scholar
  27. 27.
    Gunn JS, Hohmann EL, Miller SI. Transcriptional regulation of Salmonella virulence: a PhoQ periplasmic domain mutation results in increased net phosphotransfer to PhoP. J Bacteriol 1996; 178:6369–6373.PubMedGoogle Scholar
  28. 28.
    Miller SI, Mekalanos JJ. Constitutive expression of the phoP regulon attenuates Salmonella virulence and survival within macrophages J Bacteriol 1990; 172:2485–2490.PubMedGoogle Scholar
  29. 29.
    Zwir I, Shin D, Kato A et al. Dissecting the PhoP regulatory network of Escherichia coli and Salmonella enterica. Proc Natl Acad Sci USA 2005; 102:2862–2867PubMedCrossRefGoogle Scholar
  30. 30.
    Guina T, Yi EC, Wang H et al. A PhoP-regulated outer membrane protease of Salmonella enterica serovar Typhimurium promotes resistance to alpha-helical antimicrobial peptides. J Bacteriol 2000; 182:4077–4086.PubMedCrossRefGoogle Scholar
  31. 31.
    Heithoff DM, Conner CP, Hanna PC et al. Bacterial infection as assessed by in vivo gene expression. Proc Natl Acad Sci USA 1997; 94:934–939.PubMedCrossRefGoogle Scholar
  32. 32.
    Valdivia RH, Falkow S. Fluorescence-based isolation of bacterial genes expressed within host cells. Science 1997; 277:2007–2011.PubMedCrossRefGoogle Scholar
  33. 33.
    Behlau I, Miller SI. A PhoP-repressed gene promotes Salmonella typhimurium invasion of epithelial cells. J Bacteriol 1993; 175:4475–4484.PubMedGoogle Scholar
  34. 34.
    Belden WJ, Miller SI. Further characterization of the PhoP regulon: identification of new PhoP-activated virulence loci. Infect Immun 1994; 62:5095–5101.PubMedGoogle Scholar
  35. 35.
    Groisman EA, Kayser J, Soncini FC. Regulation of polymyxin resistance and adaptation to low-Mg2+ environments. J Bacteriol 1997; 179:7040–7045.PubMedGoogle Scholar
  36. 36.
    Guo L, Lim KB, Poduje CM et al. Lipid A acylation and bacterial resistance against vertebrate antimicrobial peptides. Cell 1998; 95:189–198.PubMedCrossRefGoogle Scholar
  37. 37.
    Hilbert F, García del Portillo F, Groisman EA. A periplasmic D-alanyl-D-alanine dipeptidase in the gram-negative bacterium Salmonella enterica. J Bacteriol 1999; 181:2158–2165.PubMedGoogle Scholar
  38. 38.
    Gunn JS, Belden WJ, Miller SI. Identification of phoP-phoQ activated genes within a duplicated region of the Salmonella typhimurium chromosome. Microb Pathog 1998; 25:77–90.PubMedCrossRefGoogle Scholar
  39. 39.
    Groisman EA. The pleiotropic two-component regulatory system PhoP-PhoQ. J Bacteriol 2001; 183:1835–1842.PubMedCrossRefGoogle Scholar
  40. 40.
    Mouslim C, Hilbert F, Huang H et al. Conflicting needs for a Salmonella hypervirulence gene in host and nonhost environments. Mol Microbiol 2002; 54:1019–1027.CrossRefGoogle Scholar
  41. 41.
    Shi Y, Cromic MJ, Hsu FF et al. PhoP-regulated Salmonella resistance to the antimicrobial peptides magainin 2 and polymyxin B. Mol Microbiol 2004; 53:229–241.PubMedCrossRefGoogle Scholar
  42. 42.
    Kox LF, Wosten MM, Groisman EA. A small protein that mediates the activation of a two-component system by another two-component system. EMBO J 2000; 19:1861–1872.PubMedCrossRefGoogle Scholar
  43. 43.
    Mouslim C, Groisman EA. Control of the Salmonella ugd gene by three two-component regulatory systems. Mol Microbiol 2003; 47:335–344.PubMedCrossRefGoogle Scholar
  44. 44.
    Minagawa S, Ogasawara H, Kato A et al. Identification and molecular characterization of the Mg2+ stimulon of Escherichia coli. J Bacteriol 2003; 185:3696–3702.PubMedCrossRefGoogle Scholar
  45. 45.
    Lejona S, Aguirre A, Cabeza ML et al. Molecular characterization of the Mg2+-responsive PhoP-PhoQ regulon in Salmonella enterica. J Bacteriol 2003; 185:6287–6294.PubMedCrossRefGoogle Scholar
  46. 46.
    Shi Y, Latifi T, Cromie MJ et al. Transcriptional control of the antimicrobial peptide resistance ugtL gene by the Salmonella PhoP and SlyA regulatory proteins. J Biol Chem 2004; 279:38618–38625.PubMedCrossRefGoogle Scholar
  47. 47.
    Zwir I, Huang H, Groisman EA. Analysis of differentially-regulated genes within a regulatory network by GPS genome navigation. Bioinformatics 2005; 21:4073–4083.PubMedCrossRefGoogle Scholar
  48. 48.
    Monsieurs P, De Keersmaecker S, Navarre WW et al. Comparison of the PhoPQ regulation in Escherichia coli and Salmonella typhimurium. J Mol Evol 2005; 60:462–474.PubMedCrossRefGoogle Scholar
  49. 49.
    Winfield MD, Latifi T, Groisman EA. Transcriptional regulation of the 4-amino-4-deoxy-L-arabinose biosynthetic genes in Yersinia pestis. J Biol Chem 2005; 280:14765–14772.PubMedCrossRefGoogle Scholar
  50. 50.
    Soncini FC, García Véscovi E, Groisman EA. Transcriptional autoregulation of the Salmonella typhimurium phoPQ operon. J Bacteriol 1995; 177:4364–4371.PubMedGoogle Scholar
  51. 51.
    Kato A, Tanabe H, Utsumi R. Molecular characterization of the PhoP-PhoQ two-component system in Escherichia coli K-12: identification of extracellular Mg2+-responsive promoters. J Bacteriol 1999; 181:5516–5520.PubMedGoogle Scholar
  52. 52.
    Yamamoto K, Ogasawara H, Fujita N et al. Novel mode of transcriptional regulation of divergently overlapping promoters by PhoP, the regulator of two-component system sensing external magnesium availability. Mol Microbiol 2002; 45:423–438.PubMedCrossRefGoogle Scholar
  53. 53.
    Zhou D, Han Y, Qin L et al. Transcriptome analysis of the Mg2+-responsive PhoP regulator in Yersinia pestis. FEMS Microbiol Lett 2005; 250:85–95.PubMedCrossRefGoogle Scholar
  54. 54.
    Ochman H, Lawrence JG, Groisman EA. Lateral gene transfer and the nature of bacterial innovation. Nature 2000; 405:299–304.PubMedCrossRefGoogle Scholar
  55. 55.
    Navarre WW, Halsey TA, Walthers D et al. Coregulation of Salmonella enterica genes required for virulence and resistance to antimicrobial peptides by SlyA and PhoP/PhoQ. Mol Microbiol 2005; 56: 492–508.PubMedCrossRefGoogle Scholar
  56. 56.
    Bijlsma JJ, Groisman EA. Making informed decisions: regulatory interactions between two-component systems. Trends Microbiol 2003; 11:359–366.PubMedCrossRefGoogle Scholar
  57. 57.
    Kato A, Mitrophanov AY, Groisman EA. A connector of two-component regulatory systems promotes signal amplification and persistence of expression. Proc Natl Acad Sci USA 2007; 104:12063–12068.PubMedCrossRefGoogle Scholar
  58. 58.
    Bajaj V, Hwang C, Lee CA. hilA is a novel ompR/toxR family member that activates the expression of Salmonella typhimurium invasion genes. Mol Microbiol 1995; 18:715–727.PubMedCrossRefGoogle Scholar
  59. 59.
    Deiwick J, Nikolaus T, Erdogan S et al. Environmental regulation of Salmonella pathogenicity island 2 gene expression. Mol Microbiol 1999; 31:1759–1773.PubMedCrossRefGoogle Scholar
  60. 60.
    Ly KT, Casanova JE. Mechanisms of Salmonella entry into host cells. Cell Microbiol 2007; 9:2103–2111.PubMedCrossRefGoogle Scholar
  61. 61.
    Ellermeier CD, Ellermeir JR, Slauch JM. HilD, HilC and RtsA constitute a feed forward loop that controls expression of the SPI1 type three secretion system regulator hilA in Salmonella enterica serovar Typhimurium. Mol Microbiol 2005; 57:691–705.PubMedCrossRefGoogle Scholar
  62. 62.
    Ellermeier JR, Slauch JM. Adaptation to the host environment: regulation of the SPI1 type III secretion system in Salmonella enterica serovar Typhimurium. Curr Opin Microbiol 2007; 10:24–29.PubMedCrossRefGoogle Scholar
  63. 63.
    Ochman H, Soncini FC, Solomon F et al. Identification of a pathogenicity island required for Salmonella survival in host cells. Proc Natl Acad Sci USA 1996; 93:7800–7804.PubMedCrossRefGoogle Scholar
  64. 64.
    Bijlsma JJ, Groisman EA. The PhoP/PhoQ system controls the intramacrophage type three secretion system of Salmonella enterica. Mol Microbiol 2005; 57:85–96.PubMedCrossRefGoogle Scholar
  65. 65.
    Lee AK, Detweiler CS, Falkow S. OmpR regulates the two-component system SsrA-SsrB in Salmonella pathogenicity island 2. J Bacteriol 2000; 182:771–781.PubMedCrossRefGoogle Scholar
  66. 66.
    Feng X, Oropeza R, Kenney LJ. Dual regulation by phospho-OmpR of ssrA/B gene expression in Salmonella pathogenicity island 2. Mol Microbiol 2003; 48:1131–1143.PubMedCrossRefGoogle Scholar
  67. 67.
    Alon U. The feed-forward loop network motif. In: Alon U, ed. An Introduction to Systems Biology: Design Principles of Biological Circuits. Boca Raton: Chapman and Hall/CRC Press, 2006:41–74.Google Scholar
  68. 68.
    Mangan S, Alon U. Structure and function of the feed-forward loop network motif. Proc Natl Acad Sci USA 2003; 100:11980–11985.PubMedCrossRefGoogle Scholar
  69. 69.
    Navarre WW, Porwollik S, Wang Y et al. Selective silencing of foreign DNA with low GC content by the H-NS protein in Salmonella. Science 2006; 313:236–238.PubMedCrossRefGoogle Scholar
  70. 70.
    Mouslim C, Groisman EA. Control of the Salmonella ugd gene by three two-component regulatory systems. Mol Microbiol 2003; 47:335–344.PubMedCrossRefGoogle Scholar
  71. 71.
    Mouslim C, Latifi T, Groisman EA. Signal-dependent requirement for the co-activator protein ResA in transcription of the ResB-regulated ugd gene. J Biol Chem 2003; 278:50588–50595.PubMedCrossRefGoogle Scholar
  72. 72.
    Kato A, Groisman EA. Connecting two-component regulatory systems by a protein that protects a response regulator from dephosphorylation by its cognate sensor. Genes Dev 2004; 18:2302–2313.PubMedCrossRefGoogle Scholar
  73. 73.
    Bougdour A, Wickner S, Gottesman S. Modulating RssB activity: IraP, a novel regulator of sigma(S) stability in Escherichia coli. Genes Dev 2006; 20:884–897.PubMedCrossRefGoogle Scholar
  74. 74.
    Gunn JS, Lim KB, Krueger J et al. PmrA-PmrB-regulated genes necessary for 4-aminoarabinose lipid A modification and polymyxin resistance. Mol Microbiol 1998; 27:1171–1182.PubMedCrossRefGoogle Scholar
  75. 75.
    Lee H, Hsu FF, Turk J et al. The PmrA-regulated pmrC gene mediates phosphoethanolamine modification of lipid A and polymyxin resistance in Salmonella enterica. J Bacteriol 2004; 186:4124–4133.PubMedCrossRefGoogle Scholar
  76. 76.
    Tamayo R, Choudhury B, Septer A et al. Identification of cptA, a PmrA-regulated locus required for phosphoethanolamine modification of the Salmonella enterica serovar typhimurium lipopolysaccharide core. J Bacteriol 2005; 187:3391–3399.PubMedCrossRefGoogle Scholar
  77. 77.
    Delgado MA, Mouslim C, Groisman EA. The PmrA/PmrB and RcsC/YojN/ResB systems control expression of the Salmonella O-antigen chain length determinant. Mol Microbiol 2006; 60:39–50.PubMedCrossRefGoogle Scholar
  78. 78.
    Wösten MM, Kox LF, Chamnongpol S et al. A signal transduction system that responds to extracellular iron. Cell 2000; 103:113–125.PubMedCrossRefGoogle Scholar
  79. 79.
    Winfield MD, Groisman EA. Phenotypic differences between Salmonella and Escherichia coli resulting from the disparate regulation of homologous genes. Proc Natl Acad Sci USA 2004; 101:17162–17167.PubMedCrossRefGoogle Scholar
  80. 80.
    Tzivion G, Avruch J. 14-3-3 proteins: active cofactors in cellular regulation by serine/threonine phosphorylation. J Biol Chem 2002; 277:3061–3064.PubMedCrossRefGoogle Scholar
  81. 81.
    Kato A, Latify T, Groisman EA. Closing the loop: the PmrA/PmrB two-component system negatively controls expression of its postranscriptional activator PmrD. Proc Natl Acad Sci USA 2003; 100:4706–4711.PubMedCrossRefGoogle Scholar
  82. 82.
    Becker G, Klauck E, Hengge-Aronis R. Regulation of RpoS proteolysis in Escherichia coli: the response regulator RssB is a recognition factor that interacts with the turnover element in RpoS. Proc Natl Acad Sci USA 1999; 96:6439–6444.PubMedCrossRefGoogle Scholar
  83. 83.
    Fang FC, Libby SJ, Buchmeier NA et al. The alternative sigma factor katF (rpoS) regulates Salmonella virulence. Proc Natl Acad Sci USA 1992; 89:11978–11982.PubMedCrossRefGoogle Scholar
  84. 84.
    Reinhart RA. Magnesium metabolism: a review with special reference to the relationship between intracellular content and serum levels. Arch Intern Med 1988; 148:2415–2420.PubMedCrossRefGoogle Scholar
  85. 85.
    Madan Babu M, Teichmann SA, Aravind L. Evolutionary dynamics of prokaryotic transcriptional regulatory networks. J Mol Biol 2006; 358:614–633.PubMedCrossRefGoogle Scholar
  86. 86.
    Winfield MD, Groisman EA. Role of nonhost environments in the lifestyles of Salmonella and Escherichia coli. Appl Environ Microbiol 2003; 69:3687–3694.PubMedCrossRefGoogle Scholar
  87. 87.
    Perry RD, Fetherston JD. Yersinia pestis—etiologic agent of plague. Clin Microbiol Rev 1997; 10:35–66.PubMedGoogle Scholar
  88. 88.
    Trent MS, Ribeiro AA, Lin S et al. An inner membrane enzyme in Salmonella and Escherichia coli that transfers 4-amino-4-deoxy-L-arabinose to lipid A: induction on polymyxin-resistant mutants and role of a novel lipid-linked donor. J Biol Chem 2001; 276:43122–43131.PubMedCrossRefGoogle Scholar
  89. 89.
    Nishino K, Hsu FF, Turk J et al. Identification of the lipopolysaccharide modifications controlled by the Salmonella PmrA/PmrB system mediating resistance to Fe(III) and Al(III). Mol Microbiol 2006; 61:645–654.PubMedCrossRefGoogle Scholar
  90. 90.
    Zhao Y, Jansen R, Gaastra W et al. Identification of genes affecting Salmonella enterica serovar enteritidis infection of chicken macrophages. Infect Immun 2002; 70:S319–S321.CrossRefGoogle Scholar
  91. 91.
    Grabenstein JP, Fukuto HS, Palmer LE et al. Characterization of phagosome trafficking and identification of PhoP-regulated genes important for survival of Yersinia pestis in macrophages. Infect Immun 2006; 74:3727–3741.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2008

Authors and Affiliations

  1. 1.Department of Bioscience Graduate School of AgricultureKinki UniversityNaraJapan
  2. 2.Department of Molecular Microbiology, Howard Hughes Medical InstituteWashington University School of MedicineSt. LouisUSA

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