Sabine Bernegger

Abstract

High temperature requirement A (HtrA) is a chaperone and serine protease expressed by the human pathogen and class I carcinogen Helicobacter pylori (H. pylori).  During infection HtrA is able to actively cleave the adherens junction protein and tumor suppressor E-Cadherin on gastric epithelial cells, which leads to disruption of the integrity of the gastric epithelium and thereby enables the bacterium to enter the intercellular space. How the following destabilization of adherens junctions interferes with signaling pathways in the host cell is widely unclear.
The functionality of adherence junctions is established by Ca2+ dependent, homophilic interactions of the extracellular domains of E-Cadherin between neighboring cells. Together with the finding that HtrA possibly presents a metal- binding loop in the N-terminus, I will investigate the hypothesis that different divalent cations affect E-Cadherin cleavage as well as HtrA activity and structure. Moreover, as an intact adherens junction complex is crucially important for proliferation, migration and polarization of cells, the consequences of HtrA mediated E-Cadherin cleavage on intracellular signaling in the host cell will be determined.
Taken together this project should provide new insights into the regulation and functionality of H. pylori HtrA, which would be important for the generation of new, potent HtrA inhibitors as alternative treatment for H. pylori infection. Further, this project should indicate the consequences of E-Cadherin shedding in H. pylori pathogenesis especially regarding carcinogenesis.