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J. Biol. Chem., Vol. 280, Issue 4, 2998-3011, January 28, 2005

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Targeting of Enteropathogenic Escherichia coli EspF to Host Mitochondria Is Essential for Bacterial Pathogenesis

CRITICAL ROLE OF THE 16TH LEUCINE RESIDUE IN EspF^*

Takeshi Nagai, Akio Abe, and Chihiro Sasakawa¶

From the Department of Microbiology and Immunity, Institute of Medical Science, University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan and the Laboratory of Bacterial Infection, Kitasato Institute for Life Science, Kitasato University, 5-9-1, Shirokanedai, Minato-ku, Tokyo 108-8642, Japan

The attachment of enteropathogenic Escherichia coli (EPEC) to host cells and the induction of attaching and effacing (A/E) lesions are prominent pathogenic features. EPEC infection also leads to host cell death and damage to the intestinal mucosa, which is partly dependent upon EspF, one of the effectors. In this study, we demonstrate that EspF is a mitochondrial import protein with a functional mitochondrial targeting signal (MTS), because EspF activity for importing into the mitochondria was abrogated by MTS deletion mutants. Substitution of the 16th leucine with glutamic acid (EspF(L16E)) completely abolished EspF activity. Infection of HeLa cells with wild type but not the espF mutant (espF) decreased mitochondrial membrane potential (_m), leading to cell death. The _m decrease and cell death were restored in cells infected with espF/pEspF but not espF/pEspF(L16E), suggesting that the 16th leucine in the MTS is a critical amino acid for EspF function. To demonstrate the impact of EspF in vivo, we exploited Citrobacter rodentium by infecting C3H/HeJ mice with espF_CR, espF_CR/pEspF_CR, or espF_CR/pEspF(L16E)_CR. These results indicate that EspF activity contributes to bacterial pathogenesis, as judged by murine lethality and intestinal histopathology, and promotion of bacterial colonization of the intestinal mucosa.

Received for publication, October 12, 2004

^* This work was supported by a grant-in-aid for scientific research on Priority Areas from the Ministry of Education, Culture, Sports, Science, and Technology and CREST, Japan Science and Technology Corporation. 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 on-line version of this article (available at http://www.jbc.org) contains Supplemental Materials.

^¶ To whom correspondence should be addressed. Tel.: 81-3-5449-5252; Fax: 81-3-5449-5405; E-mail: sasakawa{at}ims.u-tokyo.ac.jp.

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