CHARACTERISATION OF ¿-GLUTAMYL TRANSPEPTIDASE AND ELUCIDATING ITS ROLES IN THE PATHOGENESIS OF HELICOBACTER PYLORI

Abstract

Gamma-glutamyl transpeptidase (GGT) is an important pathogenic factor of Helicobacter pylori, however the mechanisms underlying its virulence is still not well understood. In this study, GGT was found to generate hydrogen peroxide through thiol-dependent iron reduction. Subsequent NF-kappaB activation and IL-8 upregulation were also observed, indicating a pro-inflammatory effect. GGT was further discovered to be internalized by host cells via clathrin-mediated endocytosis and subsequently imported into the nucleus in an importin beta 1-dependent manner. Interestingly, this coincided with a decrease in nuclear glutathione, leading to a redox imbalance in host cells. Finally, GGT was also found to strongly potentiate VacA-dependent vacuolation by hydrolyzing glutamine to generate ammonia, a weak base required in the vacuolating process. This phenomenon was inhibited by neutralizing monoclonal antibodies raised against recombinant GGT. Taken together, the results from this work have clearly shown that GGT is a potent virulence factor of H. pylori that ignites multiple pathways, ultimately resulting in host cell damage.