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Infection and Immunity, December 2006, p. 6571-6580, Vol. 74, No. 12
0019-9567/06/$08.00+0     doi:10.1128/IAI.00356-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Clustering of Helicobacter pylori VacA in Lipid Rafts, Mediated by Its Receptor, Receptor-Like Protein Tyrosine Phosphatase ß, Is Required for Intoxication in AZ-521 Cells{triangledown}

Masaaki Nakayama,1 Jyunzo Hisatsune,1 Eiki Yamasaki,1 Yoshito Nishi,1 Akihiro Wada,1 Hisao Kurazono,2 Jan Sap,3 Kinnosuke Yahiro,4 Joel Moss,4 and Toshiya Hirayama1*

Department of Bacteriology, Institute of Tropical Medicine, Nagasaki University, Nagasaki 852-8523, Japan,1 Laboratory of Veterinary Public Health, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, Sakai, Osaka 599-8531,2 Department of Molecular Pathology, University of Copenhagen, Copenhagen DK-2100, Denmark,3 Pulmonary-Critical Care Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892-15904

Received 5 March 2006/ Returned for modification 3 May 2006/ Accepted 20 September 2006

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 ß (RPTPß) as a receptor, of which five residues (QTTQP) at positions 747 to 751 are involved in binding. In AZ-521 cells, which mainly express RPTPß, VacA, after binding to RPTPß in non-lipid raft microdomains on the cell surface, is localized with RPTPß in lipid rafts in a temperature- and VacA concentration-dependent process. Methyl-ß-cyclodextrin (MCD) did not block binding to RPTPß but inhibited translocation of VacA with RPTPß 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, RPTPß. Thus, receptor-dependent translocation of VacA to lipid rafts is critical for signaling pathways leading to p38 MAP kinase/ATF-2 activation and vacuolation.

* Corresponding author. Mailing address: Department of Bacteriology, Institute of Tropical Medicine, Nagasaki University, Nagasaki 8528523, Japan. Phone: 81-95-849-7831. Fax: 81-95-849-7805. E-mail: hirayama{at}net.nagasaki-u.ac.jp.

{triangledown} Published ahead of print on 9 October 2006.

Editor: V. J. DiRita

Infection and Immunity, December 2006, p. 6571-6580, Vol. 74, No. 12
0019-9567/06/$08.00+0     doi:10.1128/IAI.00356-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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