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J. Biol. Chem., Vol. 281, Issue 10, 6589-6600, March 10, 2006

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BopC Is a Novel Type III Effector Secreted by Bordetella bronchiseptica and Has a Critical Role in Type III-dependent Necrotic Cell Death^*

Asaomi Kuwae¹, Takeshi Matsuzawa, Naoto Ishikawa, Hiroyuki Abe^¶, Takashi Nonaka^||, Hiroyuki Fukuda^**, Shinobu Imajoh-Ohmi^**, and Akio Abe

From the Laboratory of Bacterial Infection, Kitasato Institute for Life Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, The Kitasato Institute, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8642, the ^¶Division of Applied Bacteriology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita-shi, Osaka 565-0871, the ^||Department of Molecular Neurobiology, Tokyo Institute of Psychiatry, Tokyo Metropolitan Organization for Medical Research, 2-1-8 Kamikitazawa, Setagaya-ku, Tokyo 156-8585, and the ^**Laboratory Center for Proteomics Research, Department of Basic Medical Sciences, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan

In Bordetella bronchiseptica, the functional type III secretion system (TTSS) is required for the induction of necrotic cell death in infected mammalian cells. To identify the factor(s) involved in necrotic cell death, type III-secreted proteins from B. bronchiseptica were analyzed using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and electrospray ionization tandem mass spectrometry. We identified a 69-kDa secreted protein designated BopC. The gene encoding BopC is located outside of the TTSS locus and is also highly conserved in both Bordetella parapertussis and Bordetella pertussis. The results of a lactate dehydrogenase release assay and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling assay demonstrated that BopC is required for necrotic cell death. It has been reported that tyrosine-phosphorylated proteins (PY) of host cells are dephosphorylated during B. bronchiseptica infection in a TTSS-dependent manner. We found that BopC is also involved in PY dephosphorylation in infected host cells. It appears that the necrotic cell death triggered by BopC occurs prior to the PY reduction in host cells, because Bordetella-induced cell death was not affected even in the presence of a dephosphorylation inhibitor. Furthermore, a translocation assay showed that the signal sequence for both secretion into culture supernatant and translocation into the host cell is located in 48 amino acid residues of the BopC N terminus. This report reveals for the first time that a novel type III effector, BopC, is required for the induction of necrotic cell death during Bordetella infection.

Received for publication, November 28, 2005

^* This work was supported by a Grant-in-aid for Young Scientists (Area B, Grant 16790260, 2004–2005), by a Grant-in-aid for Scientific Research (Area C, Grant 16590370, 2004–2005), and by a grant from the 21st Century COE Program, 2002–2006, all from the Ministry of Education, Science, Sports, and Culture of Japan. Support was also received in the form of a Kitasato University Research Grant for Young Researchers 2003, 2004. 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 Figs. S1–S4.

¹ To whom correspondence should be addressed. Tel./Fax: 81-3-5791-6125; E-mail: kuwae{at}lisci.kitasato-u.ac.jp.

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