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J. Biol. Chem., Vol. 281, Issue 48, 36897-36904, December 1, 2006

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VP1686, a Vibrio Type III Secretion Protein, Induces Toll-like Receptor-independent Apoptosis in Macrophage through NF-B Inhibition^*

Rabindra N. Bhattacharjee, Kwon-Sam Park^¶, Yutaro Kumagai^||, Kazuhisa Okada, Masahiro Yamamoto^||, Satoshi Uematsu^||, Kosuke Matsui^||, Himanshu Kumar^||, Taro Kawai, Tetsuya Iida, Takeshi Honda, Osamu Takeuchi^||, and Shizuo Akira^||1

From the Akira Innate Immunity Project, Exploratory Research for Advance Technology, Japan Science and Technology Agency and ^¶Food Science and Biotechnology Major, College of Ocean Science and Technology, Kunsan National University, San 68, Miryong-dong, Kunsan, Jeollabuk-do 573-701, Korea and ^||Department of Host Defense, Department of Bacterial Infections, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan

Vibrio parahaemolyticus, causative agent of human gastrointestinal diseases, possesses several virulent machineries including thermostable direct hemolysin and type III secretion systems (TTSS1 and -2). In this report, we establish that TTSS1-dependent secretion and translocation of a V. parahaemolyticus effector protein VP1686 into the cytosol induces DNA fragmentation in macrophages. We performed yeast two-hybrid screening to identify the molecules involved in VP1686-mediated cell death pathways and showed that nuclear factor RelA p65/NF-B physically interacts with VP1686. To understand the impact of this interaction on the NF-B DNA binding activities in infected macrophages, we analyzed a series of deletion mutants for the TTSS and its secreted proteins. Induction of DNA binding activity of NF-B was significantly suppressed, and increased macrophage apoptosis has been associated with V. parahaemolyticus strain, which contains both VP1686 and TTSS1. Macrophages lacking Toll-like receptor adaptor molecules MyD88 (myeloid differentiation primary response protein 88) or TRIF (TIR domain-containing adapter-inducing interferon ) showed similar sensitivity to VP1686. As a consequence of NF-B suppression, microarray analysis has revealed that VP1686 translocation alerted the expression of many genes that have known functions in cellular responses to apoptosis, cell growth, and transcriptional regulation. Our results suggest an important role for Vibrio effector protein VP1686 that activate a conserved apoptotic pathway in macrophages through suppression of NF-B activation independent of Toll-like receptor signaling.

Received for publication, June 8, 2006 , and in revised form, August 28, 2006.

^* 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.

¹ To whom correspondence should be addressed: Dept. of Host Defense, Research Institute for Microbial Diseases, 3-1 Yamadaoka, Suita, Osaka 565-0871, Japan. Tel.: 81-6-6879-8303; Fax: 81-6-6879-8305; Email: sakira{at}biken.osaka-u.ac.jp.

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