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J. Biol. Chem., Vol. 280, Issue 25, 24022-24034, June 24, 2005

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IpgB1 Is a Novel Shigella Effector Protein Involved in Bacterial Invasion of Host Cells

ITS ACTIVITY TO PROMOTE MEMBRANE RUFFLING VIA RAC1 AND CDC42 ACTIVATION^*

Kenji Ohya, Yutaka Handa, Michinaga Ogawa, Masato Suzuki, and Chihiro Sasakawa¶||

From the Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan and ^¶CREST, Japan Science and Technology Agency, Kawaguchi 332-0012, Japan

Shigella, the causative agent of bacillary dysentery, is capable of inducing the large scale membrane ruffling required for the bacterial invasion of host cells. Shigella secrete a subset of effectors via the type III secretion system (TTSS) into the host cells to induce membrane ruffling. Here, we show that IpgB1 is secreted via the TTSS into epithelial cells and plays a major role in producing membrane ruffles via stimulation of Rac1 and Cdc42 activities, thus promoting bacterial invasion of epithelial cells. The invasiveness of the ipgB1 mutant was decreased to less than 50% of the wild-type level (100%) in a gentamicin protection or plaque forming assay. HeLa cells infected with the wild-type or a IpgB1-hyperproducing strain developed membrane ruffles, with the invasiveness and the scale of membrane ruffles being comparable with the level of IpgB1 production in bacteria. Upon expression of EGFP-IpgB1 in HeLa cells, large membrane ruffles are extended, where the EGFP-IpgB1 was predominantly associated with the cytoplasmic membrane. The IpgB1-mediated formation of ruffles was significantly diminished by expressing Rac1 small interfering RNA and Cdc42 small interfering RNA or by treatment with GGTI-298, an inhibitor of the geranylgeranylation of Rho GTPases. When IpgB1 was expressed in host cells or wild-type Shigella-infected host cells, Rac1 and Cdc42 were activated. The results thus indicate that IpgB1 is a novel Shigella effector involved in bacterial invasion of epithelial cells via the activation of Rho GTPases.

Received for publication, March 7, 2005 , and in revised form, April 22, 2005.

^* This work was supported by a grant-in-aid for scientific research from the Japan Ministry of Education, Culture, Sports and Technology and CREST, Japan Science and Technology Corp. 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 an additional figure and three movies.

A research fellow of the Japan Society for the Promotion of Science.

^|| 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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