Bacterial Virulence Factors and Rho GTPases pp 29-42

Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 291)

Triggered Phagocytosis by Salmonella: Bacterial Molecular Mimicry of RhoGTPase Activation/Deactivation

  • M. C. Schlumberger
  • W.-D. Hardt


Salmonella Typhimurium uses the type III secretion system encoded in the Salmonella pathogenicity island I (SPI-1 TTSS) to inject toxins (effector proteins) into host cells. Here, we focus on the functional mechanism of three of these toxins: SopE, SopE2, and SptP. All three effector proteins change the GTP/GDP loading state of RhoGTPases by transient interactions. SopE and SopE2 mimic eukaryotic G-nucleotide exchange factors and thereby activate RhoGTPase signaling pathways in infected host cells. In contrast, a domain of SptP inactivates RhoGTPases by mimicking the activity of eukaryotic GTPase-activating proteins. The Salmonella-host cell interaction provides an excellent example for the use of molecular mimicry by bacterial pathogens.


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  1. 1.
    Bakshi, C. S., V. P. Singh, M.W. Wood, P.W. Jones, T. S.Wallis, and E. E. Galyov. 2000. Identification of SopE2, a Salmonella secreted protein which is highly homologous to SopE and involved in bacterial invasion of epithelial cells. J Bacteriol 182:2341–4.CrossRefPubMedGoogle Scholar
  2. 2.
    Brumell, J. H., and S. Grinstein. 2003. Role of lipid-mediated signal transduction in bacterial internalization. Cell Microbiol 5:287–97.CrossRefPubMedGoogle Scholar
  3. 3.
    Brumell, J. H., and S. Grinstein. 2004. Salmonella redirects phagosomal maturation. Curr Opin Microbiol 7:78–84.CrossRefPubMedGoogle Scholar
  4. 4.
    Buchwald, G., A. Friebel, J. E. Galan, W.D. Hardt, A. Wittinghofer, and K. Scheffzek. 2002. Structural basis for the reversible activation of a Rho protein by the bacterial toxin SopE. EMBO J 21:3286–95.CrossRefPubMedGoogle Scholar
  5. 5.
    Chen, L.M., S. Bagrodia, R. A. Cerione, and J. E. Galan. 1999. Requirement of p21-activated kinase (PAK) for Salmonella Typhimurium-induced nuclear responses. J Exp Med 189:1479–88.CrossRefPubMedGoogle Scholar
  6. 6.
    Chen, L.M., S. Hobbie, and J. E. Galan. 1996. Requirement of CDC42 for Salmonella-induced cytoskeletal and nuclear responses. Science 274:2115–8.CrossRefPubMedGoogle Scholar
  7. 7.
    Criss, A. K., D. M. Ahlgren, T. S. Jou, B. A. McCormick, and J. E. Casanova. 2001. The GTPase Rac1 selectively regulates Salmonella invasion at the apical plasma membrane of polarized epithelial cells. J Cell Sci 114:1331–41.PubMedGoogle Scholar
  8. 8.
    Criss, A. K., and J. E. Casanova. 2003. Coordinate regulation of Salmonella enterica serovar Typhimurium invasion of epithelial cells by the Arp2/3 complex and Rho GTPases. Infect Immun 71:2885–91.CrossRefPubMedGoogle Scholar
  9. 8a.
    Dai, Sarmiere et al. 2004. Efficient Salmonella entry requires activity cycles of host ADF and cofilin. Cell Microbiol 6: 459–71.CrossRefPubMedGoogle Scholar
  10. 9.
    Ehrbar, K., A. Friebel, S. I. Miller, and W. D. Hardt. 2003. Role of the Salmonella pathogenicity island 1 (SPI-1) protein InvB in type III secretion of SopE and SopE2, two Salmonella effector proteins encoded outside of SPI-1. J Bacteriol 185:6950–67.CrossRefPubMedGoogle Scholar
  11. 10.
    Friebel, A., H. Ilchmann, M. Aelpfelbacher, K. Ehrbar, W. Machleidt, and W. D. Hardt. 2001. SopE and SopE2 from Salmonella Typhimurium activate different sets of RhoGTPases of the host cell. J Biol Chem 276:34035–34040.CrossRefPubMedGoogle Scholar
  12. 11.
    Fu, Y., and J. E. Galan. 1999. A Salmonella protein antagonizes Rac-1 and Cdc42 to mediate host-cell recovery after bacterial invasion. Nature 401:293–7.CrossRefPubMedGoogle Scholar
  13. 12.
    Fu, Y., and J. E. Galan. 1998. The Salmonella typhimurium tyrosine phosphatase SptP is translocated into host cells and disrupts the actin cytoskeleton. Mol Microbiol 27:359–68.CrossRefPubMedGoogle Scholar
  14. 13.
    Galan, J. E. 2001. Salmonella interactions with host cells: type III secretion at work. Annu Rev Cell Dev Biol 17:53–86.CrossRefPubMedGoogle Scholar
  15. 14.
    Galan, J. E., and R. Curtiss, 3rd. 1989. Cloning and molecular characterization of genes whose products allow Salmonella typhimurium to penetrate tissue culture cells. Proc Natl Acad Sci USA 86:6383–7.PubMedGoogle Scholar
  16. 15.
    Galkin, V. E., A. Orlova, M. S. VanLoock, D. Zhou, J. E. Galan, and E.H. Egelman. 2002. The bacterial protein SipA polymerizes G-actin and mimics muscle nebulin. Nat Struct Biol 9:518–21.PubMedGoogle Scholar
  17. 16.
    Hapfelmeier, S., K. Ehrbar, B. Stecher, M. Barthel, M. Kremer, and W. D. Hardt. 2004. Role of the salmonella pathogenicity island 1 effector proteins SipA, SopB, SopE, and SopE2 in Salmonella enterica subspecies 1 serovar Typhimurium colitis in streptomycin-pretreated mice. Infect Immun 72:795–809.CrossRefPubMedGoogle Scholar
  18. 17.
    Hardt, W. D., L. M. Chen, K. E. Schuebel, X. R. Bustelo, and J. E. Galan. 1998. S. typhimurium encodes an activator of Rho GTPases that induces membrane ruffling and nuclear responses in host cells. Cell 93:815–26.CrossRefPubMedGoogle Scholar
  19. 18.
    Hardt, W. D., H. Urlaub, and J. E. Galan. 1998. A substrate of the centisome 63 type III protein secretion system of Salmonella typhimurium is encoded by a cryptic bacteriophage. Proc Natl Acad Sci USA 95:2574–9.CrossRefPubMedGoogle Scholar
  20. 19.
    Hayward, R. D., and V. Koronakis. 1999. Direct nucleation and bundling of actin by the SipC protein of invasive Salmonella. EMBO J 18:4926–34.CrossRefPubMedGoogle Scholar
  21. 20.
    Higashide, W., S. Dai, V. P. Hombs, and D. Zhou. 2002. Involvement of SipA in modulating actin dynamics during Salmonella invasion into cultured epithelial cells. Cell Microbiol 4:357–65.CrossRefPubMedGoogle Scholar
  22. 21.
    Jepson, M. A., B. Kenny, and A. D. Leard. 2001. Role of sipA in the early stages of Salmonella Typhimurium entry into epithelial cells. Cell Microbiol 3:417–26.CrossRefPubMedGoogle Scholar
  23. 22.
    Kaniga, K., J. Uralil, J. B. Bliska, and J. E. Galan. 1996. A secreted protein tyrosine phosphatase with modular effector domains in the bacterial pathogen Salmonella typhimurium. Mol Microbiol 21:633–41.PubMedGoogle Scholar
  24. 23.
    Kubori, T., and J. E. Galan. 2003. Temporal regulation of salmonella virulence effector function by proteasome-dependent protein degradation. Cell 115:333–42.CrossRefPubMedGoogle Scholar
  25. 24.
    Lilic, M., V. E. Galkin, A. Orlova, M. S. Van Loock, E.H. Egelman, and C. E. Stebbins. 2003. Salmonella SipA polymerizes actin by stapling filaments with nonglobular protein arms. Science 301:1918–21.CrossRefPubMedGoogle Scholar
  26. 25.
    McGhie, E. J., R. D. Hayward, and V. Koronakis. 2004. Control of actin turnover by a salmonella invasion protein. Mol Cell 13:497–510.CrossRefPubMedGoogle Scholar
  27. 26.
    McGhie, E. J., R. D. Hayward, and V. Koronakis. 2001. Cooperation between actin-binding proteins of invasive Salmonella: SipA potentiates SipC nucleation and bundling of actin. EMBO J 20:2131–9.CrossRefPubMedGoogle Scholar
  28. 27.
    Mirold, S., K. Ehrbar, A. Weissmüller, R. Prager, H. Tschäpe, H. Rüssmann, and W.D. Hardt. 2001. Salmonella host cell invasion emerged by acquisition of amosaic of separate genetic elements, including Salmonella pathogenicity island 1 (SPI1), SPI5, and sopE2. J Bacteriol 183:2348–2358.CrossRefPubMedGoogle Scholar
  29. 28.
    Mitra, K., D. Zhou, and J. E. Galan. 2000. Biophysical characterization of SipA, an actin-binding protein from Salmonella enterica. FEBS Lett 482:81–4.CrossRefPubMedGoogle Scholar
  30. 29.
    Mukherjee, K., S. Parashuraman, M. Raje, and A. Mukhopadhyay. 2001. SopE acts as an Rab5-specific nucleotide exchange factor and recruits non-prenylated Rab5 on Salmonella-containing phagosomes to promote fusion with early endosomes. J Biol Chem 276:23607–15.CrossRefPubMedGoogle Scholar
  31. 30.
    Murli, S., R. O. Watson, and J. E. Galan. 2001. Role of tyrosine kinases and the tyrosine phosphatase SptP in the interaction of Salmonella with host cells. Cell Microbiol 3:795–810.CrossRefPubMedGoogle Scholar
  32. 31.
    Nassar, N., G.R. Hoffman, D. Manor, J. C. Clardy, and R. A. Cerione. 1998. Structures of Cdc42 bound to the active and catalytically compromised forms of Cdc42GAP. Nat Struct Biol 5:1047–52.CrossRefPubMedGoogle Scholar
  33. 32.
    Norris, F. A., M. P.Wilson, T. S.Wallis, E. E. Galyov, and P.W. Majerus. 1998. SopB, a protein required for virulence of Salmonella dublin, is an inositol phosphate phosphatase. Proc Natl Acad Sci USA 95:14057–9.CrossRefPubMedGoogle Scholar
  34. 33.
    Rudolph, M. G., C. Weise, S. Mirold, B. Hillenbrand, B. Bader, A. Wittinghofer, and W. D. Hardt. 1999. Biochemical analysis of SopE from Salmonella typhimurium, a highly efficient guanosine nucleotide exchange factor for RhoGTPases. J Biol Chem 274:30501–9.CrossRefPubMedGoogle Scholar
  35. 34.
    Schlumberger, M. C., A. Friebel, G. Buchwald, K. Scheffzek, A. Wittinghofer, and W. D. Hardt. 2003. Amino acids of the bacterial toxin SopE involved in G-nucleotide exchange on Cdc42. J Biol Chem.Google Scholar
  36. 35.
    Stebbins, C. E., and J. E. Galan. 2001. Maintenance of an unfolded polypeptide by a cognate chaperone in bacterial type III secretion. Nature 414:77–81.CrossRefPubMedGoogle Scholar
  37. 36.
    Stebbins, C. E., and J. E. Galan. 2000. Modulation of host signaling by a bacterial mimic: structure of the Salmonella effector SptP bound to Rac1. Mol Cell 6:1449–60.CrossRefPubMedGoogle Scholar
  38. 37.
    Stender, S., A. Friebel, S. Linder, M. Rohde, S. Mirold, and W. D. Hardt. 2000. Identification of SopE2 from Salmonella typhimurium, a conserved guanine nucleotide exchange factor for Cdc42 of the host cell. Mol Microbiol 36:1206–21.CrossRefPubMedGoogle Scholar
  39. 38.
    Stevens, M. P., A. Friebel, L. A. Taylor, M.W. Wood, P. J. Brown, W. D. Hardt, and E. E. Galyov. 2003. A Burkholderia pseudomallei type III secreted protein, BopE, facilitates bacterial invasion of epithelial cells and exhibits guanine nucleotide exchange factor activity. J Bacteriol 185:4992–6.CrossRefPubMedGoogle Scholar
  40. 39.
    Stocker, B. A., S. K.Hoiseth, and B. P. Smith. 1983. Aromatic-dependent Salmonella spp. as live vaccine in mice and calves. Dev Biol Stand 53:47–54.PubMedGoogle Scholar
  41. 40.
    Terebiznik, M. R., O. V. Vieira, S. L. Marcus, A. Slade, C. M. Yip, W. S. Trimble, T. Meyer, B. B. Finlay, and S. Grinstein. 2002. Elimination of host cell PtdIns(4,5)P(2) by bacterial SigD promotes membrane fission during invasion by Salmonella. Nat Cell Biol 4:766–73.CrossRefPubMedGoogle Scholar
  42. 41.
    Wood, M.W., R. Rosqvist, P.B. Mullan, M. H. Edwards, and E. E. Galyov. 1996. SopE, a secreted protein of Salmonella dublin, is translocated into the target eukaryotic cell via a sip-dependent mechanism and promotes bacterial entry. Mol Microbiol 22:327–38.CrossRefPubMedGoogle Scholar
  43. 42.
    Zhou, D., L. M. Chen, L. Hernandez, S. B. Shears, and J. E. Galan. 2001. ASalmonella inositol polyphosphatase acts in conjunction with other bacterial effectors to promote host cell actin cytoskeleton rearrangements and bacterial internalization. Mol Microbiol 39:248–260.CrossRefPubMedGoogle Scholar
  44. 43.
    Zhou, D., M. S.Mooseker, and J. E. Galan. 1999. An invasion-associated Salmonella protein modulates the actin-bundling activity of plastin. Proc Natl Acad Sci USA 96:10176–81.CrossRefPubMedGoogle Scholar
  45. 44.
    Zhou, D., M. S. Mooseker, and J. E. Galan. 1999. Role of the S. typhimurium actin-binding protein SipA in bacterial internalization. Science 283:2092–5.CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • M. C. Schlumberger
    • 1
  • W.-D. Hardt
    • 1
  1. 1.Institute of MicrobiologyETH ZürichZürichSwitzerland

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