Skip to main content
SpringerLink
Log in

Bacterial Toxins Activating Rho GTPases

  • Chapter
Bacterial Virulence Factors and Rho GTPases

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

Abstract

The CNF1 toxin is produced by some uropathogenic (UPECs) and meningitiscausing Escherichia coli strains. It belongs to a large family of bacterial virulence factors and toxins modifying cellular regulators of the actin cytoskeleton, namely the Rho GTPases. CNF1 autonomously enters the host cell cytosol, where it catalyzes the constitutive activation of Rho GTPases by deamidation. This activation is, however, attenuated because of activated Rho protein ubiquitin-mediated proteasomal degradation. Both Rho protein activation and deactivation confer phagocytic properties on epithelial and endothelial cells, as well as epithelial cell motility and cell-cell junction dynamics. Transcriptome analysis using DNA microarray revealed that endothelial cells respond to high doses of CNF1 by launching a genetic program of host alarm. This host cell reaction to CNF1 intoxication also indicates that degradation of activated Rho proteins by the proteasome may lead to a lowering of the threshold of the intoxicated cell inflammatory response. These results are consistent with growing evidence that Rho proteins control the cell inflammatory responses. It is tempting to assume that Rho deregulation may participate in various immunological disorders also involved in cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Falbo V, Pace T, Picci L, Pizzi E & Caprioli A (1993) Isolation and nucleotide sequence of the gene encoding cytotoxic necrotizing factor 1 of Escherichia coli. Infect Immun. 61:4909–4914.

    PubMed  CAS  Google Scholar 

  2. Landraud L, Gauthier M, Fosse T & Boquet P (2000) Frequency of Escherichia coli strains producing the cytotoxic necrotizing factor (CNF1) in nosocomial urinary tract infections. Lett. Appl. Microbiol. 30:213–216.

    Article  PubMed  CAS  Google Scholar 

  3. De Rycke J, Gonzalez EA, Blanco J, Oswald E, Blanco M & Boivin R (1990) Evidence for two types of cytotoxic necrotizing factor in human and animal clinical isolates of Escherichia coli. J. Clin. Microbiol. 28:694–699.

    PubMed  Google Scholar 

  4. Lockman HA, Gillespie RA, Baker BD & Shakhnovich E (2002) Yersinia pseudotuberculosis produces a cytotoxic necrotizing factor. Infect. Immun. 70:2708–2714.

    Article  PubMed  CAS  Google Scholar 

  5. Horiguchi Y (2001) Escherichia coli cytotoxic necrotizing factors and Bordetella dermonecrotic toxin: the dermonecrosis-inducing toxins activating Rho small GTPases. Toxicon 39:1619–1627.

    Article  PubMed  CAS  Google Scholar 

  6. Swenson DL, Bukanov NO, Berg DE & Welch RA (1996) Two pathogenicity islands in uropathogenic Escherichia coli J96: cosmid cloning and sample sequencing. Infect Immun. 64:3736–3743.

    PubMed  CAS  Google Scholar 

  7. Oswald E & De Rycke J (1990) A single protein of 110 kDa is associated with the multinucleating and necrotizing activity coded by the Vir plasmid of Escherichia coli. FEMS Microbiol Lett. 56:279–284.

    PubMed  CAS  Google Scholar 

  8. Landraud L, Gibert M, Popoff MR, Boquet P & Gauthier M (2003) Expression of cnf1 by Escherichia coli J96 involves a large upstream DNA region including the hlyCABD operon, and is regulated by the RfaH protein. Mol. Microbiol. 47:1653–1667.

    Article  PubMed  CAS  Google Scholar 

  9. Artsimovitch I & Landick R (2002) The transcriptional regulator RfaH stimulates RNA chain synthesis after recruitment to elongation complexes by the exposed nontemplate DNA strand. Cell 109:193–203.

    Article  PubMed  CAS  Google Scholar 

  10. Leeds JA & Welch RA (1997) Enhancing transcription through the Escherichia coli hemolysin operon, hlyCABD: RfaH and upstream JUMPStart DNA sequences function together via a postinitiation mechanism. J Bacteriol 179:3519–3527.

    PubMed  CAS  Google Scholar 

  11. Bailey MJ, Hughes C & Koronakis V (1997) RfaH and the ops element, components of a novel system controlling bacterial transcription elongation. Mol. Microbiol. 26:845–851.

    Article  PubMed  CAS  Google Scholar 

  12. Lemichez E, Flatau G, Bruzzone M, Boquet P & Gauthier M (1997) Molecular localization of the Escherichia coli cytotoxic necrotizing factor CNF1 cell-binding and catalytic domains. Mol. Microbiol. 24:1061–1070.

    Article  PubMed  CAS  Google Scholar 

  13. Contamin S, Galmiche A, Doye A, Flatau G, Benmerah A & Boquet P (2000) The p21 Rho-activating toxin cytotoxic necrotizing factor 1 is endocytosed by a clathrin-independent mechanism and enters the cytosol by an acidic-dependent membrane translocation step. Mol. Biol. Cell 11:1775–1787.

    PubMed  CAS  Google Scholar 

  14. Chung JW, Hong SJ, Kim KJ, Goti D, Stins MF, Shin S, Dawson VL, Dawson TM & Kim KS (2003) 37-kDa laminin receptor precursor modulates cytotoxic necrotizing factor 1-mediated RhoA activation and bacterial uptake. J. Biol. Chem. 278:16857–16862.

    Article  PubMed  CAS  Google Scholar 

  15. Pei S, Doye A & Boquet P (2001) Mutation of specific acidic residues of the CNF1 T domain into lysine alters cell membrane translocation of the toxin. Mol. Microbiol. 41:1237–1247.

    Article  PubMed  CAS  Google Scholar 

  16. Lemichez E & Boquet P (2003) To be helped or not helped, that is the question. J. Cell Biol. 160:991–992.

    Article  PubMed  CAS  Google Scholar 

  17. Flatau G, Lemichez E, Gauthier M, Chardin P, Paris S, Fiorentini C & Boquet P (1997) Toxin-induced activation of the G protein p21 Rho by deamidation of glutamine. Nature 387:729–733.

    Article  PubMed  CAS  Google Scholar 

  18. Schmidt G, Sehr P, Wilm M, Selzer J, Mann M & Aktories K (1997) Gln 63 of Rho is deamidated by Escherichia coli cytotoxic necrotizing factor-1. Nature 387:725–729.

    Article  PubMed  CAS  Google Scholar 

  19. Matsuzawa T, Fukui A, Kashimoto T, Nagao K, Oka K, Miyake M & Horiguchi Y (2004) Bordetella dermonecrotic toxin undergoes proteolytic processing to be translocated from a dynamin-related endosome into the cytoplasm in an acidification-independent manner. J Biol Chem. 279:2866–2872.

    Article  PubMed  CAS  Google Scholar 

  20. Matsuzawa T, Kashimoto T, Katahira J & Horiguchi Y (2002) Identification of a receptor-binding domain of Bordetella dermonecrotic toxin. Infect. Immun. 70:3427–3432.

    Article  PubMed  CAS  Google Scholar 

  21. Oswald E, Sugai M, Labigne A, Wu HC, Fiorentini C, Boquet P & O'Brien AD (1994) Cytotoxic necrotizing factor type 2 produced by virulent Escherichia coli modifies the small GTP-binding proteins Rho involved in assembly of actin stress fibers. Proc. Natl. Acad. Sci. USA. 91:3814–388.

    PubMed  CAS  Google Scholar 

  22. Horiguchi Y, Senda T, Sugimoto N, Katahira J & Matsuda M (1995) Bordetella bronchiseptica dermonecrotizing toxin stimulates assembly of actin stress fibers and focal adhesions by modifying the small GTP-binding protein rho. J. Cell Sci. 108:3243–3251.

    PubMed  CAS  Google Scholar 

  23. Masuda M, Betancourt L, Matsuzawa T, Kashimoto T, Takao T, Shimonishi Y & Horiguchi Y (2000) Activation of rho through a cross-link with polyamines catalyzed by Bordetella dermonecrotizing toxin. EMBO J. 19:521–530.

    Article  PubMed  CAS  Google Scholar 

  24. Lerm M, Schmidt G, Goehring UM, Schirmer J & Aktories K (1999) Identification of the region of rho involved in substrate recognition by Escherichia coli cytotoxic necrotizing factor 1 (CNF1). J. Biol. Chem. 274:28999–29004.

    Article  PubMed  CAS  Google Scholar 

  25. Lerm M, Selzer J, Hoffmeyer A, Rapp UR, Aktories K & Schmidt G (1999) Deamidation of Cdc42 and Rac by Escherichia coli cytotoxic necrotizing factor 1: activation of c-Jun N-terminal kinase in HeLa cells. Infect. Immun. 67:496–503.

    PubMed  CAS  Google Scholar 

  26. Buetow L, Flatau G, Chiu K, Boquet P & Ghosh P (2001) Structure of the Rhoactivating domain of Escherichia coli cytotoxic necrotizing factor 1. Nat. Struct. Biol. 8:584–588.

    Article  PubMed  CAS  Google Scholar 

  27. Takai Y, Sasaki T & Matozaki T (2001) Small GTP-binding proteins. Physiol. Rev. 81:153–208.

    PubMed  CAS  Google Scholar 

  28. Der CJ, Finkel T & Cooper GM (1986) Biological and biochemical properties of human rasH genes mutated at codon 61. Cell 44:167–176.

    Article  PubMed  CAS  Google Scholar 

  29. Doye A et al. (2002) CNF1 exploits the ubiquitin-proteasome machinery to restrict Rho GTPase activation for bacterial host cell invasion. Cell 111:553–564.

    Article  PubMed  CAS  Google Scholar 

  30. Lerm M, Pop M, Fritz G, Aktories K & Schmidt G (2002) Proteasomal degradation of cytotoxic necrotizing factor 1-activated rac. Infect. Immun. 70:4053–4058.

    Article  PubMed  CAS  Google Scholar 

  31. Finley D, Ciechanover A & Varshavsky A (2004) Ubiquitin as a central cellular regulator. Cell 116:S29–S32.

    PubMed  CAS  Google Scholar 

  32. Engel ME, Datta PK & Moses HL (1998) RhoB is stabilized by transforming growth factor βand antagonizes transcriptional activation. J. Biol. Chem. 273:9921–9926.

    Article  PubMed  CAS  Google Scholar 

  33. Wang HR et al. (2003) Regulation of cell polarity and protrusion formation by targeting RhoA for degradation. Science 302:1775–1779.

    Article  PubMed  CAS  Google Scholar 

  34. Hoffmann C, Pop M, Leemhuis J, Schirmer J, Aktories K & Schmidt G (2004) The Yersinia pseudotuberculosis cytotoxic necrotizing factor (CNFY) selectively activates RhoA. J. Biol. Chem. 279:16026–16032.

    Article  PubMed  CAS  Google Scholar 

  35. Pop M, Aktories K & Schmidt G (2004) Isotype-specific degradation of Rac activated by the cytotoxic necrotizing factor 1. J. Biol. Chem. 279:35840–3588.

    Article  PubMed  CAS  Google Scholar 

  36. Munro P, Flatau G, Doye A, Boyer L, Oregioni O, Mege JL, Landraud L & Lemichez E (2004) Activation and proteasomal degradation of rho GTPases by cytotoxic necrotizing factor-1 elicit a controlled inflammatory response. J. Biol. Chem. 279:35849–35857.

    Article  PubMed  CAS  Google Scholar 

  37. Burridge K & Wennerberg K (2004) Rho and Rac take center stage. Cell 116:167–79.

    Article  PubMed  CAS  Google Scholar 

  38. Ridley A J & Hall A (1992) The small GTP-binding protein rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors. Cell 70:389–399.

    Article  PubMed  CAS  Google Scholar 

  39. Ridley AJ, Paterson HF, Johnston CL, Diekmann D & Hall, A (1992) The small GTP-binding protein rac regulates growth factor-induced membrane ruffling. Cell 70:401–410.

    Article  PubMed  CAS  Google Scholar 

  40. Nobes CD & Hall A (1995) Rho, rac, and cdc42 GTPases regulate the assembly of multimolecular focal complexes associated with actin stress fibers, lamellipodia, and filopodia. Cell 81:53–62.

    Article  PubMed  CAS  Google Scholar 

  41. Etienne-Manneville S & Hall A (2002) Rho GTPases in cell biology. Nature 420:629–635.

    Article  PubMed  CAS  Google Scholar 

  42. Cossart P & Sansonetti PJ (2004) Bacterial invasion: the paradigms of enteroinvasive pathogens. Science 304:242–248.

    Article  PubMed  CAS  Google Scholar 

  43. Sahai E & Marshall CJ (2002) Rho-GTPases and cancer. Nat. Rev. Cancer 21:133–142.

    Article  Google Scholar 

  44. Mulvey MA, Lopez-Boado YS, Wilson CL, Roth R, Parks WC, Heuser J & Hultgren SJ (1998) Induction and evasion of host defenses by type 1-piliated uropathogenic Escherichia coli. Science 282:1494–1497.

    Article  PubMed  CAS  Google Scholar 

  45. Caron E & Hall A (1998) Identification of two distinct mechanisms of phagocytosis controlled by different Rho GTPases. Science 282:1717–1721.

    Article  PubMed  CAS  Google Scholar 

  46. Falzano L, Fiorentini C, Donelli G, Michel E, Kocks C, Cossart P, Cabanie L & Oswald E & Boquet P (1993) Induction of phagocytic behaviour in human epithelial cells by Escherichia coli cytotoxic necrotizing factor type 1. Mol. Microbiol. 9:1247–1254.

    PubMed  CAS  Google Scholar 

  47. Schilling JD, Mulvey MA & Hultgren SJ (2001) Dynamic interactions between host and pathogen during acute urinary tract infections. Urology 57:56–61.

    Article  PubMed  CAS  Google Scholar 

  48. Svanborg C, Godaly G & Hedlund M (1999) Cytokine responses during mucosal infections: role in disease pathogenesis and host defense. Curr. Opin. Microbiol. 2:99–105.

    Article  PubMed  CAS  Google Scholar 

  49. Janssens S & Beyaert R (2003) Role of Toll-like receptors in pathogen recognition. Clin. Microbiol. Rev. 16:637–646.

    Article  PubMed  CAS  Google Scholar 

  50. Arbibe L, Mira JP, Teusch N, Kline L, Guha M, Mackman N, Godowski PJ, Ulevitch RJ & Knaus UG (2000) Toll-like receptor 2-mediated NF-κB activation requires a Rac1-dependent pathway. Nat. Immunol. 1:533–540.

    Article  PubMed  CAS  Google Scholar 

  51. Rakoff-Nahoum S, Paglino J, Eslami-Varzaneh F, Edberg S & Medzhitov R (2004) Recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis. Cell 118:229–241.

    Article  PubMed  CAS  Google Scholar 

  52. Neish AS, Gewirtz AT, Zeng H, Young AN, Hobert ME, Karmali V, Rao AS & Madara JL (2000) Prokaryotic regulation of epithelial responses by inhibition of IκB-α ubiquitination. Science. 289:1560–1563.

    Article  PubMed  CAS  Google Scholar 

  53. Mettouchi A, Klein S, Guo W, Lopez-Lago M, Lemichez E, Westwick JK & Giancotti FG (2001) Integrin-specific activation of Rac controls progression through the G1 phase of the cell cycle. Mol. Cell 8:115–127.

    Article  PubMed  CAS  Google Scholar 

  54. Klein S, de Fougerolles AR, Blaikie P, Khan L, Pepe A, Green CD, Koteliansky V & Giancotti FG (2002) α 5 β 1 Integrin activates an NF-κB-dependent program of gene expression important for angiogenesis and inflammation. Mol. Cell Biol. 22:5912–5922.

    Article  PubMed  CAS  Google Scholar 

  55. Boettner B & Van Aelst L (2002) The role of Rho GTPases in disease development. Gene 286:155–74.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Faculté de Médecine, 1/ INSERM, U627, 28 Avenue de Valombrose, 06107, Nice Cedex 2, France

    P. Munro & E. Lemichez

Authors
  1. P. Munro
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E. Lemichez
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Faculty of Medicine, INSERM U627, IFR 50, 28, Avenue de Valombrose, Nice, France

    Patrice Boquet (Professor Dr.) & Emmanuel Lemichez (Professor Dr.) (Professor Dr.) &  (Professor Dr.)

Rights and permissions

Reprints and permissions

Copyright information

© 2005 Springer-Verlag

About this chapter

Cite this chapter

Munro, P., Lemichez, E. (2005). Bacterial Toxins Activating Rho GTPases. In: Boquet, P., Lemichez, E. (eds) Bacterial Virulence Factors and Rho GTPases. Current Topics in Microbiology and Immunology, vol 291. Springer, Berlin, Heidelberg. https://doi.org/10.1007/3-540-27511-8_10

Download citation

Publish with us

Policies and ethics

Search

Navigation