Mechanism of Helicobacter pylonVacAintoxication

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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.