Helicobacter pylori VacA disrupts apical membrane-cytoskeletal interactions in gastric parietal cells
Helicobacter pylori VacA disrupts apical membrane-cytoskeletal interactions in gastric parietal cells
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幽门螺杆菌 VacA 破坏胃壁细胞顶膜-细胞骨架相互作用
DOI：
10.1074/jbc.m800527200
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发表时间：
2008-09-26
影响因子：
4.8
通讯作者：
Yao, Xuebiao
中科院分区：
文献类型：
--
作者：
Wang, Fengsong;Xia, Peng;Yao, Xuebiao
幽门螺杆菌持续定植于人类胃中，并与萎缩性胃炎和胃癌有关。尽管众所周知，幽门螺杆菌感染可导致胃酸过少，但这种现象背后的分子机制仍知之甚少。在这里，我们发现 VacA 可以透化胃壁细胞的顶膜并诱导胃酸过少。使用新鲜分离的兔胃腺和培养的壁细胞研究了 VacA 感染对壁细胞生理学的功能影响。通过氨基比林摄取测定和共聚焦显微镜检查来判断壁细胞的分泌活性。 VacA 透化诱导细胞外钙流入，随后激活钙蛋白酶，随后在 Met(469) -Thr(470) 处对埃兹蛋白进行蛋白水解，从而导致埃兹蛋白从壁细胞顶膜中释放。 VacA 治疗通过阻止含有 H, K-ATP 酶的管泡募集到胃壁细胞顶膜来抑制胃酸分泌。电子显微镜检查显示，由于壁细胞中埃兹蛋白完整性的丧失，VacA 处理破坏了顶端微绒毛中肌动蛋白丝的径向排列。值得注意的是，在 VacA 存在的情况下，钙蛋白酶抗性埃兹蛋白的表达恢复了壁细胞的功能活性。 VacA 感染的壁细胞中埃兹蛋白的蛋白水解是幽门螺杆菌诱导的酸分泌抑制的一种新机制。我们的结果表明，VacA 破坏胃壁细胞的顶膜-细胞骨架相互作用，从而导致胃酸过少。
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.