Pleiotropic Actions of Helicobacter pylori Vacuolating Cytotoxin, VacA

Invited Review for the 90^th Anniversary

Pleiotropic Actions of Helicobacter pylori Vacuolating Cytotoxin, VacA

HAJIME ISOMOTO,¹ JOEL MOSS² and TOSHIYA HIRAYAMA³

¹Department of Endoscopy, Nagasaki University Hospital, Nagasaki, Japan
²Translational Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA
³Department of Bacteriology, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan

Helicobacter pylori produces a vacuolating cytotoxin, VacA, and most virulent H. pylori strains secrete VacA. VacA binds to two types of receptor-like protein tyrosine phosphatase (RPTP), RPTPα and RPTPβ, on the surface of host cells. VacA bound to RPTPβ, relocates and concentrates in lipid rafts in the plasma membrane. VacA causes vacuolization, membrane anion-selective channel and pore formation, and disruption of endosomal and lysosomal activity in host cells. Secreted VacA is processed into p33 and p55 fragments. The p55 domain not only plays a role in binding to target cells but also in the formation of oligomeric structures and anionic membrane channels. Oral administration of VacA to wild-type mice, but not to RPTPβ knockout mice, resulted in gastric ulcers, in agreement with the clinical effect of VacA. VacA with s1/m1 allele has more potent cytotoxic activity in relation to peptic ulcer disease and appears to be associated with human gastric cancer. VacA activates pro-apoptotic Bcl-2 family proteins, and induces apoptosis via a mitochondria-dependent pathway. VacA can disrupt other signal transduction pathways; VacA activates p38 MAPK, enhancing production of IL-8 and PGE₂, and PI3K/Akt, suppressing GSK-3β activity. VacA has immunomodulatory actions on T cells and other immune cells, possibly contributing to the chronic infection seen with this organism. H. pylori virulence factors including VacA and CagA, which is encoded by cytotoxin-associated gene A, along with host genetic and environmental factors, constitute a complex network to regulate chronic gastric injury and inflammation, which is involved in a multistep process leading to gastric carcinogenesis.

keywords —— Helicobacter pylori; vacuolating toxin; VacA

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Tohoku J. Exp. Med., 2010, 220, 3-14

Correspondence: Toshiya Hirayama, Ph.D., Department of Bacteriology, Institute of Tropical Medicine, Nagasaki University, 1-12-4 Sakamoto, Nagasaki 852-8523, Japan.

e-mail: hirayama@nagasaki-u.ac.jp