Helicobacter pylori VacA disrupts apical membrane-cytoskeletal interactions in gastric parietal cells.
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 Met(469)-Thr(470), 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.
Wang
Fengsong
F
Morehouse School of Medicine, Atlanta, Georgia 30310, USA.
Xia
Peng
P
Wu
Fang
F
Wang
Dongmei
D
Wang
Wei
W
Ward
Tarsha
T
Liu
Ya
Y
Aikhionbare
Felix
F
Guo
Zhen
Z
Powell
Michael
M
Liu
Bingya
B
Bi
Feng
F
Shaw
Andrew
A
Zhu
Zhenggang
Z
Elmoselhi
Adel
A
Fan
Daiming
D
Cover
Timothy L
TL
Ding
Xia
X
Yao
Xuebiao
X
D000126:Achlorhydria / Q000378:metabolism* / Q000382:microbiology; D008841:Actin Cytoskeleton / Q000378:metabolism* / Q000648:ultrastructure; D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002154:Calpain / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism* / Q000382:microbiology / Q000648:ultrastructure; D002463:Cell Membrane Permeability; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000378:metabolism; D005757:Gastritis, Atrophic / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D016481:Helicobacter Infections / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology; D016480:Helicobacter pylori / Q000378:metabolism*; D006801:Humans; D010295:Parietal Cells, Gastric / Q000378:metabolism* / Q000382:microbiology / Q000648:ultrastructure; D011817:Rabbits; D013274:Stomach Neoplasms / Q000378:metabolism / Q000382:microbiology / Q000648:ultrastructure; D000099149:Ezrin
D001426:Bacterial Proteins; D002118:Calcium; D002154:Calpain; D003598:Cytoskeletal Proteins; D000099149:Ezrin; C074689:VacA protein, Helicobacter pylori