Clustering of Helicobacter pylori VacA in lipid rafts, mediated by its receptor, receptor-like protein tyrosine phosphatase β, is required for intoxication in AZ-521 cells

Masaaki Nakayama, Jyunzo Hisatsune, Eiki Yamasaki, Yoshito Nishi, Akihiro Wada, Hisao Kurazono, Jan Sap, Kinnosuke Yahiro, Joel Moss, Toshiya Hirayama

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45 Citations (Scopus)


Helicobacter pylori vacuolating cytotoxin, VacA, induces multiple effects on epithelial cells through different cellular events: one involves pore formation, leading to vacuolation, mitochondrial damage, and apoptosis, and the second involves cell signaling, resulting in stimulation of proinflammatory responses and cell detachment. Our recent data demonstrated that VacA uses receptor-like protein tyrosine phosphatase β (RPTPβ) as a receptor, of which five residues (QTTQP) at positions 747 to 751 are involved in binding. In AZ-521 cells, which mainly express RPTPβ, VacA, after binding to RPTPβ in non-lipid raft microdomains on the cell surface, is localized with RPTPβ in lipid rafts in a temperature- and VacA concentration-dependent process. Methyl-β-cyclodextrin (MCD) did not block binding to RPTPβ but inhibited translocation of VacA with RPTPβ to lipid rafts and all subsequent events. On the other hand, 5-nitro-2-(3-phenylpropylamino)-benzoic acid (NPPB), which disrupts anion channels, did not inhibit translocation of VacA to lipid rafts or VacA-induced activation of p38 mitogen-activated protein (MAP) kinase, but inhibited VacA internalization followed by vacuolation. Thus, p38 MAP kinase activation did not appear to be required for internalization. In contrast, phosphatidylinositol-specific phospholipase C (PI-PLC) inhibited translocation, as well as p38 MAP kinase/ATF-2 activation, internalization, and VacA-induced vacuolation. Neither NPPB nor PI-PLC affected VacA binding to cells and to its receptor, RPTPβ. Thus, receptor-dependent translocation of VacA to lipid rafts is critical for signaling pathways leading to p38 MAP kinase/ATF-2 activation and vacuolation.

Original languageEnglish
Pages (from-to)6571-6580
Number of pages10
JournalInfection and Immunity
Issue number12
Publication statusPublished - Dec 1 2006
Externally publishedYes


ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Immunology
  • Infectious Diseases

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