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J. Biol. Chem., Vol. 283, Issue 39, 26714-26725, September 26, 2008

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Helicobacter pylori VacA Disrupts Apical Membrane-Cytoskeletal Interactions in Gastric Parietal Cells^*

Fengsong Wang, Peng Xia, Fang Wu, Dongmei Wang, Wei Wang^¶, Tarsha Ward, Ya Liu, Felix Aikhionbare, Zhen Guo, Michael Powell, Bingya Liu^||, Feng Bi^**, Andrew Shaw, Zhenggang Zhu^||, Adel Elmoselhi, Daiming Fan, Timothy L. Cover, Xia Ding^¶1, and Xuebiao Yao²

From the Division of Cellular Dynamics, University of Science and Technology of China and Hefei National Laboratory for Physical Sciences at Nanoscale, Hefei 230027, China, ^¶Beijing University of Chinese Medicine, Beijing 100029, China, Morehouse School of Medicine, Atlanta, Georgia 30310, ^**Department of Abdominal Cancer, West China Hospital, Sichuan University, Chengdu 610041, China, Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, Shanxi 710032, China, Departments of Medicine and Microbiology and Immunology, Vanderbilt University of School of Medicine, and Veterans Affairs Tennessee Valley Healthcare System, Nashville, Tennessee 37232, and ^||Institute of Digestive Surgery, Shanghai Jiaotong University, Shanghai 210026, China

Helicobacter pylori persistently colonize the human stomach and have been linked to atrophic gastritis and gastric carcinoma. Although it is well known that H. pylori infection can result in hypochlorhydria, the molecular mechanisms underlying this phenomenon remain poorly understood. Here we show that VacA permeabilizes the apical membrane of gastric parietal cells and induces hypochlorhydria. The functional consequences of VacA infection on parietal cell physiology were studied using freshly isolated rabbit gastric glands and cultured parietal cells. Secretory activity of parietal cells was judged by an aminopyrine uptake assay and confocal microscopic examination. VacA permeabilization induces an influx of extracellular calcium, followed by activation of calpain and subsequent proteolysis of ezrin at Met⁴⁶⁹-Thr⁴⁷⁰, which results in the liberation of ezrin from the apical membrane of the parietal cells. VacA treatment inhibits acid secretion by preventing the recruitment of H,K-ATPase-containing tubulovesicles to the apical membrane of gastric parietal cells. Electron microscopic examination revealed that VacA treatment disrupts the radial arrangement of actin filaments in apical microvilli due to the loss of ezrin integrity in parietal cells. Significantly, expression of calpain-resistant ezrin restored the functional activity of parietal cells in the presence of VacA. Proteolysis of ezrin in VacA-infected parietal cells is a novel mechanism underlying H. pylori-induced inhibition of acid secretion. Our results indicate that VacA disrupts the apical membrane-cytoskeletal interactions in gastric parietal cells and thereby causes hypochlorhydria.

Received for publication, January 22, 2008 , and in revised form, June 18, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants DK56292, CA89019, CA132389, AI39657, DK53623, and G-12-RR03034. This work was also supported by Chinese Academy of Science Grants KSCX1-YW-R65 and KSCX2-YW-H-10; Chinese 973 project Grants 2002CB713700, 2007CB914503, and 2006CB943603; Chinese Natural Science Foundation Grants 30270654, 39925018, 30500183, and 30570926; Chinese 863 Project Grants 2001AA215331 and 2006AA02A247; Chinese Minister of Education Grant 200203580851 (to X. Y.); 111 Project 07007 (to X. D.); and the Department of Veterans Affairs. 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 Table S1 and Figs. S1-S3.

¹ To whom correspondence may be addressed. E-mail: xding{at}bucm.edu.cn.

² An American Digestive Health Foundation Research Scholar and a Georgia Cancer Coalition Eminent Cancer Scholar. To whom correspondence may be addressed. E-mail: yaoxb{at}ustc.edu.cn.

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