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J. Biol. Chem., Vol. 280, Issue 33, 29849-29855, August 19, 2005

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WAVE2 Signaling Mediates Invasion of Polarized Epithelial Cells by Salmonella typhimurium^*

Jing Shi, Giorgio Scita¶, and James E. Casanova||

From the Department of Cell Biology, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908-0732, the IFOM Istituto FIRC di Oncologia Molecolare Via Adamello 16, 20134 Milan, Italy, and the ^¶Department of Experimental Oncology, Istituto Europeo di Oncologia (IEO), Via Ripamonti 435, 20141 Milan, Italy

The bacterial pathogen Salmonella penetrates the intestinal epithelium by inducing its own phagocytosis into epithelial cells. The dramatic reorganization of the actin cytoskeleton required for internalization is driven by bacterial manipulation of host signaling pathways, including activation of the Rho family GTPase Rac1 and subsequent activation of the Arp2/3 complex. However, the mechanisms linking these two events remain poorly understood. Rac1 is thought to promote activation of the Arp2/3 complex through its interaction with suppressor of cAMP receptor/WASP family verprolin-homologous (SCAR/WAVE) family proteins, but this interaction is apparently indirect. Two different Rac1 effectors have been shown to bind WAVE2: IRSp53, the SH3 domain of which binds the WAVE2 proline-rich domain, and PIR121/Sra-1, which forms a pentameric complex containing WAVE, Abi1, Nap1, and HSPC300. However, the extent to which each of these complexes contributes to Arp2/3 complex activation in the context of Salmonella infection is unclear. Here, we show that WAVE2 is necessary for efficient invasion of epithelial cells by Salmonella typhimurium. We found that although Salmonella infection strongly promotes the formation of an IRSp53/WAVE2 complex, IRSp53 is not necessary for bacterial internalization. In contrast, disruption of the PIR121/Nap1/Abi1/WAVE2/HSPC300 complex potently inhibits bacterial uptake. These results indicate that WAVE2 is an important component in signaling pathways leading to Salmonella invasion. Although infection leads to the formation of an IRSp53/WAVE2 complex, it is the association of WAVE2 with the Abi1/Nap1/PIR121/HSPC300 complex that regulates bacterial internalization.

Received for publication, January 18, 2005 , and in revised form, May 24, 2005.

^* This work was supported by grants from the National Institutes of Health (Grant DK52351) and the Crohn's and Colitis Foundation of America (to J. E. C.). 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 two supplemental figures.

^|| To whom correspondence should be addressed: Dept. of Cell Biology, University of Virginia Health Sciences Center, Box 800732, 1300 Jefferson Park Ave., Charlottesville, VA 22908-0732. Tel.: 434-243-4821; Fax: 434-982-3912; E-mail: jec9e{at}virginia.edu.

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