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J. Biol. Chem. 279 (24): 25134-25142

© 2004 by The American Society for Biochemistry and Molecular Biology, Inc.

Targeting Rac1 by the Yersinia Effector Protein YopE Inhibits Caspase-1-mediated Maturation and Release of Interleukin-1{beta}*

Peter Schotte{ddagger}§, Geertrui Denecker§¶||, Aeke Van Den Broeke{ddagger}, Peter Vandenabeele¶, Guy R. Cornelis||**, , and Rudi Beyaert{ddagger}**{ddagger}{ddagger}

{ddagger}Unit of Molecular Signal Transduction in Inflammation, and the Unit of Molecular Signalling and Cell Death, Department of Molecular Biomedical Research, Flanders Interuniversity Institute for Biotechnology (VIB), Ghent University, B-9052 Ghent, Belgium, and the ||Division of Molecular Microbiology, Biozentrum der Universität Basel, CH4056 Basel, Switzerland

Abstract: Yersinia bacteria can take control of the host cell by injecting so-called Yop effector proteins into the cytosol of the cells to which they adhere. Using Yersinia enterocolitica strains that are deficient for one or more Yops, we could show that YopE and, to a lesser extent, YopT interfere with the caspase-1-mediated maturation of prointerleukin-1{beta} in macrophages. In addition, overexpression of YopE and YopT was shown to prevent the autoproteolytic activation of caspase-1 in a way that is dependent on their inhibitory effect on Rho GTPases. Expression of constitutive-active or dominant-negative Rho GTPase mutants or treatment with Rho GTPase inhibitors confirmed the role of Rho GTPases and, in particular, Rac1 in the autoactivation of caspase-1. Rac1-induced caspase-1 activation was mediated by its effect on LIM kinase-1, which is targeting the actin cytoskeleton. Rac-1 and LIM kinase-1 dominant-negative mutants were shown to inhibit caspase-1 activation induced by overexpression of Asc, which is a caspase-1-activating adaptor protein. Moreover, Rac1 as well as YopE and YopT significantly modulated caspase-1 oligomerization. These results highlight a previously unknown function of Rho GTPases in the activation of caspase-1 and give new insight on the role of YopE in immune-escape mechanisms of Yersinia.

Received for publication February 4, 2004. Revision received March 23, 2004.

* This work was supported in part by the Swiss National Science Foundation, the Fund for Scientific Research-Flanders (FWO-Vlaanderen), the Interuniversity Attraction Poles (IUAP-V), and a European Community-Research and Technical Development grant. 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.

§ These authors contributed equally to this work as first authors and are postdoctoral researchers with the Flemish Institute for the Promotion of Scientific-Technological Research in the Industry (IWT) and the FWO-Vlaanderen, respectively.

** Both authors contributed equally to this work as senior authors.

{ddagger}{ddagger} To whom correspondence should be addressed: Department of Molecular Biomedical Research, Unit of Molecular Signal Transduction in Inflammation, VIB, Ghent University, Technologiepark 927, B-9052 Ghent, Belgium. Tel.: 32-93313770; Fax: 32-93313609; E-mail: rudi{at}dmbr.ugent.be.

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