Mechanism of Helicobacter pylonVacAintoxication

幽门螺杆菌的持续感染引起慢性活动性胃炎，其使粘膜易于消化性溃疡，并且被认为参与胃癌和原发性胃淋巴瘤的发病机制（即，粘膜相关淋巴组织或MALT型）。虽然H.幽门螺杆菌是一种非侵入性细菌，生存在胃粘膜中，是H. pylori产生并分泌一种有效的空泡细胞毒素VacA。在这项研究中，我们检测并分析了以下两个受试者：1）确定了与VacA结合所需的受体胞外区序列，阐明了毒素内化的机理; 2）VacA引起细胞死亡的机制。我们的结果表明：1）这些数据确定了RPTPO胞外区中与VacA结合的关键区域，特别是，747-751位的序列QTTQP与748和749位的关键苏氨酸，并且与末端唾液酸的作用一致，可能是由于苏氨酸糖基化。此外，VacA诱导的空泡化以及p38 MAP激酶/ATF-2的激活（提交中）。2）VacA通过不同的信号通路起作用，通过Bax激活诱导凋亡，而不依赖于空泡化。

Persistent infection with Helicobacter pylori causes chronic active gastritis, which predisposes the mucosa to peptic ulceration, and is believed to participate in the pathogenesis of gastric carcinoma and primary gastric lymphoma (i.e., mucosa-associated lymphoid tissue, or MALT type). Although H. pylori is a noninvasive bacterium that survives in the stomach mucosa, pathogenic strains of H. pylori produce and secrete a potent vacuolating cytotoxin, VacA.In this study, we examined and analyzed following two subjects : 1) Identification of the extracellular sequence of the receptor required for VacA binding and clarification of toxin internalization, and 2) Mechanism of cell death caused by VacA.Our results lead that1)These data define the region in the RPTPO extracellular domain critical for VacA binding, in particular, the sequence QTTQP at positions 747-751 with crucial threonines at positions 748 and 749, and are consisitent with a role for terminal sialic acids, possibly due to threonine glycosylation.VacA is concentrated in lipid rafts after binding to RPTP in non-lipid raft microdomains on AZ-521 cell surface. In addition, VacA-induced vacuolation as well as activation of p38 MAP kinase/ATF-2 (in submission).2) VacA acts through different signaling pathways to induce apoptosis via Bax activation, independent of vacuolation.