Mechanism of Helicobacter pylonVacAintoxication

• Project/Area Number: 16017280
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Nagasaki University
• Principal Investigator: HIRAYAMA Toshiya Nagasaki University, Institute of Tropical Medicine, Professor, 熱帯医学研究所, 教授 (50050696)
• Co-Investigator(Kenkyū-buntansha): MASHIMA Hirosato The University of Tokyo Hospital, Research Associate, 医学部付属病院, 助手 (10261869)
• Project Period (FY): 2004 – 2005
• Project Status: Completed (Fiscal Year 2005)
• Budget Amount: ¥15,000,000 (Direct Cost: ¥15,000,000); Fiscal Year 2005: ¥7,500,000 (Direct Cost: ¥7,500,000); Fiscal Year 2004: ¥7,500,000 (Direct Cost: ¥7,500,000)
• Keywords: Helicobacter pylori / vacuolating cytotoxin / VacA / Mechanism of intoxication / 阻害物質 / 血清成分

Research Abstract

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 that
1)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.

Research Products

• [Journal Article] Helicobacter pylori vacuolating cytotoxin induces activation of the proapoptotic protein Bax, leading to cytochrome c release and cell death, independent of vacuolation (2006)
  • Author(s): Yamasaki E. et al.
  • Journal Title: J. Biol. Chem. 281 Pages: 11250-11259
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Helicobacter pylori vacuolating cytotoxin induces activation of the proapoptotic protein Bax, leading to cytochrome c release and cell death, independent of vacuolation (2006)
  • Author(s): Yamasaki E., Wada A., Kumatori A., Nakagawa I., Funao J., Nakayama M., Hisatsune J., Kimura M., Moss J., Hirayama T.
  • Journal Title: J. Biol. Chem. 281 Pages: 11250-11259
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Helicobacter pylori vacuolating cytotoxin induces activation of the proapoptotic protein Bax, leading to cytochrome c release and cell death, independent of vacuolation (2006)
  • Author(s): Yamasaki E et al.
  • Journal Title: J Biol Chem (印刷中)
• [Journal Article] Cytotoxicity and recognition of receptor-like protein tyrosine phosphatases, RPTPα and RPTPβ, by Helicobacter pylori m2VacA (2005)
  • Author(s): De Guzman B.B. et al.
  • Journal Title: Cell Microbiol 7 Pages: 1285-293
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Functional antagonism between Helicobacter pylori CagA and VacA in control of the NFAT signaling pathway in gastric epithelial cells (2005)
  • Author(s): Yokoyama K. et al.
  • Journal Title: Proc. Natl. Acad. Sci. USA. 201 Pages: 9661-9666
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Inhibitory effects of polyphenols on gastric injury by Helicobacter pylori VacA toxin. (2005)
  • Author(s): Yahiro K. et al.
  • Journal Title: Helicobacter 10 Pages: 231-239
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Cytotoxicity and recognition of receptor-like protein tyrosine phosphatases, RPTPa and RPTPO, by Helicobacter pylori m2VacA. (2005)
  • Author(s): De Guzman, B.B., Hisatsune, J., Nakayama, M., Yahiro, K., Wada, A., Yamasaki, E., Nishi, Y., Yamazaki, S., Azuma, T., Ito, Y., Ohtani, M., van der Wijk, T., den Hertog, J., Moss, M., Hirayama T.
  • Journal Title: Cell Microbiol 7 Pages: 1285-293
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Functional antagonism between Helicobacter pylori CagA and VacA in control of the NFAT signaling pathway in gastric epithelial cells (2005)
  • Author(s): Yokoyama, K., Higashi, H., Ishikawa, S., Fujii, Y., Kondo, S., Kato, H., Azuma, T., Wada, A., Hirayama, T., Aburatani, H., Hatakeyama, M.
  • Journal Title: Proc. Natl. Acad. Sci. USA. 102 Pages: 9661-9666
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Inhibitory effects of polyphenols on gastric injury by Helicobacter pylori VacA toxin. (2005)
  • Author(s): Yahiro K, Shirasaka D, Tagashira M, Wada A, Morinaga N, Kuroda F, Choi 0, Inoue M, Aoyama N, Ikeda M, Hirayama T, Moss J, Noda M.
  • Journal Title: Helicobacter. 10 Pages: 231-239
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Cytotoxicity and recognition of receptor-like protein tyrosine phosphatases, RPTPα and RPTPβ, by Helicobacter pylori m2VacA. (2005)
  • Author(s): De Guzman, B.B et al.
  • Journal Title: Cell Microbiol 7 Pages: 1285-1293
• [Journal Article] Functional antagonism between Helicobacter pylori CagA and VacA in control of the NFAT signaling pathway in gastric epithelial cells (2005)
  • Author(s): Yokoyama, K., et al.
  • Journal Title: Proc.Natl.Acad.Sci.USA. 102 Pages: 9661-9666
• [Journal Article] Inhibitory effects of polyphenols on gastric injury by Helicobacter pylori VacA toxin (2005)
  • Author(s): Yahiro K, et al.
  • Journal Title: Helicobacter 10 Pages: 231-239
• [Journal Article] High concentrations of human beta-defensin 2 in gastric juice of patients with Helicobacter pylori infection (2005)
  • Author(s): Isomoto H, et al.
  • Journal Title: World J Gastroenterol 11 Pages: 4782-4787
• [Journal Article] Vacuolating cytotoxin A is associated with increased thrombin generation in gastric mucosa (2005)
  • Author(s): Suzuki Y, et al.
  • Journal Title: Helicobacter 10 Pages: 323-331
• [Journal Article] Helicobacter pylori VacA activates the p38/ATF-2-mediated signal pathway in AZ-521 cells. (2004)
  • Author(s): Nakayama M. et al.
  • Journal Title: J. Biol. Chem. 279 Pages: 7024-7028
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Essential domain of receptor tyrosine phosphatase β, RPTPβ, for interaction with Helicobacter pylori vacuolating cytotoxin. (2004)
  • Author(s): Yahiro K. et al.
  • Journal Title: J. Biol. Chem. 279 Pages: 51013-51021
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Helicobacter pylori VacA activates the p38/ATF-2-mediated signal pathway in AZ-521 cells. (2004)
  • Author(s): Nakayama, M., Kimura, M., Wada, A., Yahiro, K., Ogushi, 'K., Niidome, T., Fujikawa, A., Shirasaka, D., Aoyama, N., Kurazono, H., Noda, M., Moss, J., Hirayama, T.
  • Journal Title: J. Biol. Chem. 279 Pages: 7024-7028
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Essential domain of receptor tyrosine phosphatase 3, RPTP0, for interaction with Helicobacter pylori vacuolating cytotoxin. (2004)
  • Author(s): Yahiro, K., Wada, A., Yamasaki, E., Nakayama, M., Nishi, Y., Hisatsune, J., Morinaga, N., Sap, J., Noda, M., Moss, J., Hirayama, T.
  • Journal Title: J. Biol. Chem. 299 Pages: 51013-51021
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Helicobacter pylori VacA activates the p38/ATF-2- mediated signal pathway in AZ-521 cells. (2004)
  • Author(s): Nakayama, M., et al.
  • Journal Title: J.Biol.Chem. 279 Pages: 7024-7028
• [Journal Article] Role of nicotinamide adenine dinucleotide phosphate oxidase 1 in oxidative burst response to toll-like receptor 5 signaling in large intestinal epithelial cells. (2004)
  • Author(s): Kawahara, T., et al.
  • Journal Title: J.Immunol. 172 Pages: 3051-3058
• [Journal Article] Gangliosides act as co-receptors for Salmonella enteritidis FliC and promote FliC-induction of human β-defensin-2 expression in Caco-2 cells. (2004)
  • Author(s): Ogushi, K., et al.
  • Journal Title: J.Biol.Chem. 279 Pages: 12213-12219
• [Journal Article] An antibody to VacA of Helicobacter pylori in the CSF of patients with Miller-Fisher syndrome. (2004)
  • Author(s): Chiba S., et al.
  • Journal Title: Neurology 63 Pages: 2184-2186
• [Journal Article] Elevated concentrations of α-defensins in gastric juice of patients with Helicobacter pylori Infection. (2004)
  • Author(s): Isomoto, H., et al.
  • Journal Title: Am.J.Gastroenterol. 99 Pages: 1916-1923
• [Journal Article] Essential domain of receptor tyrosine phosphatase β, RPTPβ, for interaction with Helicobacter pylori vacuolating cytotoxin. (2004)
  • Author(s): Yahiro, K., et al.
  • Journal Title: J.Biol.Chem. 279 Pages: 51013-51021