HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 279, Issue 34, 35849-35857, August 20, 2004

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 279/34/35849    most recent M401580200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Munro, P. Articles by Lemichez, E. Search for Related Content PubMed PubMed Citation Articles by Munro, P. Articles by Lemichez, E. Social Bookmarking                      What's this?

Activation and Proteasomal Degradation of Rho GTPases by Cytotoxic Necrotizing Factor-1 Elicit a Controlled Inflammatory Response^*

Patrick Munro, Gilles Flatau, Anne Doye, Laurent Boyer, Olivier Oregioni, Jean-Louis Mege, Luce Landraud, and Emmanuel Lemichez¶

From the INSERM, U627, Faculté de Médecine, 28 Ave. de Valombrose, 06107 Nice Cedex 2 and the Unité des Rickettsies, Université de la Méditerranée, CNRS UMR 6020, Faculté de Médecine, 13385 Marseille Cedex 5, France

The CNF1 toxin is produced by uropathogenic and meningitis-causing Escherichia coli. CNF1 penetrates autonomously into cells and confers phagocytic properties to epithelial and endothelial cells. CNF1 acts at the molecular level by constitutively activating Rho GTPases attenuated by their cellular ubiquitin-mediated proteasomal degradation. Here we report the relationship between the ubiquitin-mediated proteasomal degradation of activated Rho and the endothelial cell response to the toxin. The type of cellular response to CNF1 intoxication, first screened by DNA microarray analysis, revealed the launching of a program oriented toward an inflammatory response. Parallel to Rho protein activation by CNF1, we also established the kinetics of production of monocyte chemotactic protein-1 (MCP-1), interleukin-8 (IL-8), IL-6, monocyte inflammatory protein-3 (MIP-3) and E-selectin. Both the mutation of the catalytic domain of the toxin (CNF1-C866S) and the inhibition of Rho proteins abrogate the CNF1-induced production of the immunomodulators MIP-3, MCP-1, and IL-8. These immunomodulators are also produced upon activation of Cdc42 and Rac preferentially. Our results indicate that, in addition to pathogen molecular pattern recognition by host-receptors, a direct activation of Rho proteins by the CNF1 virulence factor efficiently triggers a cellular reaction of host alert. Consistently, we assume that the CNF1-induced ubiquitin-mediated proteasomal degradation of activated Rho proteins may limit the amplitude of the host cell immune responses.

Received for publication, February 12, 2004 , and in revised form, May 3, 2004.

^* This work was supported by an institutional funding from INSERM. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The online version of this article (available at http://www.jbc.org) contains Supplemental Figs. S1 and S2.

^¶ To whom correspondence should be addressed. Tel.: 33-4-93-37-77-09; Fax: 33-4-93-53-35-09; E-mail: lemichez{at}unice.fr.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				Y. C. Smith, S. B. Rasmussen, K. K. Grande, R. M. Conran, and A. D. O'Brien Hemolysin of Uropathogenic Escherichia coli Evokes Extensive Shedding of the Uroepithelium and Hemorrhage in Bladder Tissue within the First 24 Hours after Intraurethral Inoculation of Mice Infect. Immun., July 1, 2008; 76(7): 2978 - 2990. [Abstract] [Full Text] [PDF]

				Y. Dai, N. L. Dudek, T. B. Patel, and N. A. Muma Transglutaminase-Catalyzed Transamidation: A Novel Mechanism for Rac1 Activation by 5-Hydroxytryptamine2A Receptor Stimulation J. Pharmacol. Exp. Ther., July 1, 2008; 326(1): 153 - 162. [Abstract] [Full Text] [PDF]

				A. G. Miraglia, S. Travaglione, S. Meschini, L. Falzano, P. Matarrese, M. G. Quaranta, M. Viora, C. Fiorentini, and A. Fabbri Cytotoxic Necrotizing Factor 1 Prevents Apoptosis via the Akt/I{kappa}B Kinase Pathway: Role of Nuclear Factor-{kappa}B and Bcl-2 Mol. Biol. Cell, July 1, 2007; 18(7): 2735 - 2744. [Abstract] [Full Text] [PDF]

				L. Boyer, L. Turchi, B. Desnues, A. Doye, G. Ponzio, J.-L. Mege, M. Yamashita, Y. E. Zhang, J. Bertoglio, G. Flatau, et al. CNF1-induced Ubiquitylation and Proteasome Destruction of Activated RhoA Is Impaired in Smurf1-/- Cells Mol. Biol. Cell, June 1, 2006; 17(6): 2489 - 2497. [Abstract] [Full Text] [PDF]