CagA-independent disruption of adherence junction complexes involves E-cadherin shedding and implies multiple steps in Helicobacter pylori pathogenicity

Abstract

Infection with Helicobacter pylori ( H. pylori) leads to depolarization and migration of polarized epithelial cells, both strongly enhanced by injection of the pathogenic factor CagA (cytotoxin-associated gene A) into the host cytoplasm. Depolarization and migration of epithelial cells imply the disruption of cell adhesion junctions (AJs) comprising a protein complex of E-cadherin, β-catenin, p120 ctn, and α-catenin. Here, we analyzed the disintegration of E-cadherin-mediated AJs and demonstrated that loss of E-cadherin-dependent cell–cell contacts is entirely independent of CagA. Upon infection with H. pylori, either wild-type (wt) or a cagA mutant (Δ cagA), interaction between E-cadherin and α-catenin dissociated rapidly, while binding of E-cadherin to β-catenin and p120 ctn was hardly affected. Simultaneously, loss of cell adhesion involved E-cadherin cleavage induced by a bacterial factor secreted by H. pylori. Finally, β-catenin-mediated transcription, a hallmark of many carcinomas, was not activated in H. pylori-infected epithelial cells at this stage of infection. Altogether, our data indicate that H. pylori-induced pathogenesis is a multi-step process initiated by CagA-independent mechanisms. These include proteolytical cleavage of E-cadherin and dissociation of the E-cadherin/β-catenin/p120 ctn complex from the actin cytoskeleton by disrupting binding to α-catenin.