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J. Biol. Chem., Vol. 282, Issue 40, 29634-29645, October 5, 2007

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Hierarchical Delivery of an Essential Host Colonization Factor in Enteropathogenic Escherichia coli^*

Nikhil A. Thomas^¶1, Wanyin Deng, Noel Baker, Jose Puente^||2, and B. Brett Finlay³

From the Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z4, the ^||Departamento de Microbiología Molecular, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca, Morelos México 62210, and the Departments of Microbiology and Immunology and ^¶Medicine, Dalhousie University, Halifax, Nova Scotia, Canada B3X 1H5

Many significant bacterial pathogens use a type III secretion system to inject effector proteins into host cells to disrupt specific cellular functions, enabling disease progression. The injection of these effectors into host cells is often dependent on dedicated chaperones within the bacterial cell. In this report, we demonstrate that the enteropathogenic Escherichia coli (EPEC) chaperone CesT interacts with a variety of known and putative type III effector proteins. Using pull-down and secretion assays, a degenerate CesT binding domain was identified within multiple type III effectors. Domain exchange experiments between selected type III effector proteins revealed a modular nature for the CesT binding domain, as demonstrated by secretion, chaperone binding, and infection assays. The CesT-interacting type III effector Tir, which is crucial for in vivo intestinal colonization, had to be expressed and secreted for efficient secretion of other type III effectors. In contrast, the absence of other CesT-interacting type III effectors did not abrogate effector secretion, indicating an unexpected hierarchy with respect to Tir for type III effector delivery. Coordinating the expression of other type III effectors with cesT in the absence of tir partially restored total type III effector secretion, thereby implicating CesT in secretion events. Collectively, the results suggest a coordinated mechanism involving both Tir and CesT for type III effector injection into host cells.

Received for publication, July 23, 2007

^* This work was supported by operating grants from the Nova Scotia Health Research Foundation (NSHRF) (to N. T.), the Canadian Institutes of Health Research (CIHR) (to N. T. and B. B. F.), and the Howard Hughes Medical Institute (HHMI) (to B. B. F.). 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.

² Supported by Direccion General de Asuntos del Personal Académico and Consejo Nacional de Ciencia y Tecnologia.

³ A CIHR Distinguished Investigator, an International HHMI Scholar, and the University of British Columbia Peter Wall Distinguished Professor.

¹ Recipient of a CIHR/NSHRF New Investigator Award. To whom correspondence should be addressed: Dept. of Microbiology and Immunology/Medicine, Dalhousie University, Halifax, Nova Scotia, B3X 1H5 Canada. Tel.: 902-494-8065; Fax: 902-494-5125; E-mail: n.thomas{at}dal.ca.

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