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J. Biol. Chem., Vol. 278, Issue 28, 25585-25590, July 11, 2003

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Involvement of Syntaxin 7 in Human Gastric Epithelial Cell Vacuolation Induced by the Helicobacter pylori-produced Cytotoxin VacA^*

Junko Suzuki , Hirohide Ohnishi  ¶, Akihiro Wada ||, Toshiya Hirayama ||, Hideki Ohno , Namiki Ueda , Hiroshi Yasuda **, Taroh Iiri , Yoh Wada , Masamitsu Futai  and Hirosato Mashima 

From the Department of Gastroenterology, University of Tokyo School of Medicine, Tokyo 113-8655, Japan, Department of Gastroenterology, Jichi Medical School, Tochigi 329-0498, Japan, ^||Department of Bacteriology, Institute of Tropical Medicine, Nagasaki University, Nagasaki 852-8523, Japan, ^**Division of Gastroenterology, Showa University Fujigaoka Hospital, Kanagawa 227-8501, Japan, Department of Endocrinology and Nephrology, University of Tokyo School of Medicine, Tokyo 113-8655, Japan, and Division of Biological Sciences, Institute of Scientific and Industrial Research, Osaka University, Osaka 567-0047, Japan

The Helicobacter pylori-produced cytotoxin VacA induces intracellular vacuolation. The formed vacuole is assumed to be a hybrid of late endosome and lysosome. To elucidate the molecular mechanism of VacA-induced vacuolation, we examined the participation of syntaxin 7 in the human gastric epithelial cell line AGS. Immunocytochemistry revealed that endogenous syntaxin 7 was localized to vacuoles induced by VacA. Northern and Western blotting demonstrated that VacA intoxication increased syntaxin 7 mRNA and protein expression, respectively, in a time-dependent manner. Transient transfection of dominant-negative mutant syntaxin 7, which lacks a carboxyl-terminal transmembrane domain, inhibited VacA-induced vacuolation. In contrast, transient transfection of wild-type syntaxin 7, dominant-negative mutant syntaxin 1a, or dominant-negative mutant syntaxin 4 did not alter VacA-induced vacuolation. Furthermore, under VacA treatment, neutral red dye uptake, a parameter of VacA-induced vacuolation, was inhibited in cells stably transfected with mutant syntaxin 7 but not in cells stably transfected with wild-type syntaxin 7, mutant syntaxin 1a, or mutant syntaxin 4. Sequential immunocytochemical observation confirmed that expression of mutant syntaxin 7 did not affect VacA attachment to or internalization into AGS cells. We suggest that syntaxin 7 is involved in the intracellular vacuolation induced by VacA.

Received for publication, December 6, 2002 , and in revised form, April 4, 2003.

^* This work was supported in part by grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology (to H. O., T. H., and H. Y.) and by a grant from the Yamanouchi Foundation (to H. O.). 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.

^¶ To whom correspondence should be addressed: Dept. of Gastroenterology, Jichi Medical School, 3311-1 Yakushiji, Minamikawachi-cho, Kawachi-gun, Tochigi 329-0498, Japan. Tel.: 81-285-58-7348; Fax: 81-285-44-8297; E-mail: hohnishi{at}jichi.ac.jp.

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