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.

  • Letter
  • Published:

A Salmonella protein antagonizes Rac-1 and Cdc42 to mediate host-cell recovery after bacterial invasion

Nature volume 401, pages 293–297 (1999)Cite this article

Abstract

An essential feature of the bacterial pathogen Salmonella spp. is its ability to enter cells that are normally non-phagocytic, such as those of the intestinal epithelium1. The bacterium achieves entry by delivering effector proteins into the host-cell cytosol by means of a specialized protein-secretion system (termed type III), which causes reorganization of the cell's actin cytoskeleton and ruffling of its membrane2,3,4. One of the bacterial effectors that stimulates these cellular responses is SopE, which acts as a guanyl-nucleotide-exchange factor on Rho GTPase proteins such as Cdc42 and Rac (ref. 5). As the actin-cytoskeleton reorganization induced by Salmonella is reversible and short-lived, infected cells regain their normal architecture after bacterial internalization6,7. We show here that the S. Typhimurium effector protein SptP, which is delivered to the host-cell cytosol by the type-III secretion system, is directly responsible for the reversal of the actin cytoskeletal changes induced by the bacterium. SptP exerts this function by acting as a GTPase-activating protein (GAP) for Rac-1 and Cdc42.

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: SptP mediates the recovery of the normal organization of the actin cytoskeleton after S. Typhimurium internalization.
Figure 2: SptP and SopE antagonize each other's function.
Figure 3: Effect of SptP on S. Typhimurium-mediated JNK activation.
Figure 4: SptP is a GAP for CDC42 and Rac.
Figure 5: An ‘arginine finger’ characteristic of Rho-GTPase-activating proteins is required for SptP function.

Similar content being viewed by others

References

  1. Galán,J. E. Interaction of Salmonella with host cells through the centisome 63 type III secretion system. Curr. Opin. Microbiol. 2, 46–50 (1999).

    Article  Google Scholar 

  2. Chen,L. M., Hobbie,S. & Galán,J. E. Requirement of CDC42 for Salmonella typhimurium-induced cytoskeletal reorganization and nuclear responses in cultured cell. Science 274, 2115–2118 (1996).

    Article  ADS  CAS  Google Scholar 

  3. Chen,L. M., Bagrodia,S., Cerione,R. A. & Galán,J. E. Requirement of p21-activated kinase (PAK) for Salmonella typhimurium-induced nuclear responses. J. Exp. Med. 189, 1479–1488 (1999).

    Article  CAS  Google Scholar 

  4. Zhou,D., Mooseker,M. & Galán,J. E. Role of the S. Typhimurium actin-binding protein SipA in bacterial internalization. Science 283, 2092–2095 (1999).

    Article  ADS  CAS  Google Scholar 

  5. Hardt, W.-D., Chen, L.-M., Schuebel,K. E., Bustelo,X. R. & Galán,J. E. Salmonella typhimurium encodes an activator of Rho GTPases that induces membrane ruffling and nuclear responses in host cells. Cell 93, 815–826 (1998).

    Article  Google Scholar 

  6. Takeuchi,A. Electron microscopic studies of experimental Salmonella infection. 1. Penetration into the intestinal epithelium by Salmonella typhimurium. Am. J. Pathol. 50, 109–136 (1967).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Ginocchio,C., Pace,J. & Galán,J. E. Identification and molecular characterization of a Salmonella typhimurium gene involved in triggering the internalization of salmonellae into cultured epithelial cells. Proc. Natl Acad. Sci. USA 89, 5976–5980 (1992).

    Article  ADS  CAS  Google Scholar 

  8. Kaniga,K., Uralil,J., Bliska,J. B. & Galán,J. E. A secreted tyrosine phosphatase with modular effector domains encoded by the bacterial pathogen Salmonella typhimurium. Mol. Microbiol. 21, 633–641 (1996).

    Article  CAS  Google Scholar 

  9. Fu,Y. & Galán,J. E. The Salmonella spp. protein tyrosine phosphase SptP is translocated into host cells and disrupts the host-cell cytoskeleton. Mol. Microbiol. 27, 359–368 (1998).

    Article  CAS  Google Scholar 

  10. Kulich,S. M., Yahr,T. L., Mende-Mueller,L. M., Barbieri,J. T. & Frank,D. W. Cloning the structural gene for the 49-kDa form of exoenzyme S (exoS) from Pseudomonas aeruginosa strain 388. J. Biol. Chem. 269, 10431–10437 (1994).

    CAS  PubMed  Google Scholar 

  11. Forsberg,A. & Wolf-Watz,H. Genetic analysis of the yopE region of Yersinia spp.: Identification of a novel conserved locus, yerA, regulating yopE expression. J. Bacteriol. 172, 1547–1555 (1990).

    Article  CAS  Google Scholar 

  12. Michiels,T., Wattiau,P., Brasseur,R., Ruysschaert,J. M. & Cornelis,G. Secretion of Yop proteins by Yersiniae. Infect. Immun. 58, 2840–2849 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Rosqvist,R., Forsberg,A. & Wolf,W. H. Intracellular targeting of the Yersinia YopE cytotoxin in mammalian cells induces actin microfilament disruption. Infect. Immun. 59, 4562–4569 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Vallis,A. J., Finck-Barbancon,V., Yahr,T. L. & Frank,D. W. Biological effects of Pseudomonas aeruginosa type III-secreted proteins on CHO cells. Infect. Immun. 67, 2040–2044 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Frithz-Lindsten,E., Du,Y., Rosqvist,R. & Forsberg,A. Intracellular targeting of exoenzyme S of Pseudomonas aeruginosa via type III-dependent translocation induces phagocytosis resistance, cytotoxicity and disruption of actin microfilaments. Mol. Microbiol. 25, 1125–1139 (1997).

    Article  CAS  Google Scholar 

  16. Cornelis,G. R. & Wolf-Watz,H. The Yersinia Yop virulon: a bacterial system for subverting eukaryotic cells. Mol. Microbiol. 23, 861–867 (1997).

    Article  CAS  Google Scholar 

  17. Hobbie,S., Chen,L. M., Davis,R. & Galán,J. E. Involvement of the mitogen-activated protein kinase pathways in the nuclear responses and cytokine production induced by Salmonella typhimurium in cultured intestinal cells. J. Immunol. 159, 5550–5559 (1997).

    CAS  PubMed  Google Scholar 

  18. Van Aelst,L. & D'Souza-Schorey,C. Rho GTPases and signaling networks. Genes Dev. 11, 2295–2322 (1997).

    Article  CAS  Google Scholar 

  19. Hall,A. Rho GTPases and the actin cytoskeleton. Science 279, 509–514 (1998).

    Article  ADS  CAS  Google Scholar 

  20. Scheffzek,K., Ahmadian,M. R. & Wittinghofer,A. GTPase-activating proteins: helping hands to complement an active site. Trends Biochem. 23, 7257–7262 (1998).

    Article  Google Scholar 

  21. Self,A. J. & Hall,A. Measurements of intrinsic nucleotide exchange and GTP hydrolysis rates. Methods Enzymol. 256, 67–76 (1995).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Li-Lin Du for help with GAP assays, Dafna Bar-Sagi for discussion and for reviewing this manuscript, and members of J.E.G.'s laboratory for critical reviews. This work was supported by the NIH.

Author information

Authors and Affiliations

  1. Section of Microbial Pathogenesis, Boyer Center for Molecular Medicine, Yale School of Medicine, New Haven, 06536, Connecticut, USA

    Yixin Fu & Jorge E. Galán

Authors
  1. Yixin Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jorge E. Galán
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jorge E. Galán.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fu, Y., Galán, J. A Salmonella protein antagonizes Rac-1 and Cdc42 to mediate host-cell recovery after bacterial invasion. Nature 401, 293–297 (1999). https://doi.org/10.1038/45829

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/45829

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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