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

• Published in: Experimental cell research 2007-10, Vol.313 (16), p.3459-3471
• Main Authors: Weydig, Christiane, Starzinski-Powitz, Anna, Carra, Gert, Löwer, Johannes, Wessler, Silja
• Format: Article
• Language: English
• Subjects: Adherens Junctions - metabolism; Animals; Antigens, Bacterial - metabolism; Bacteria; Bacterial Proteins - metabolism; beta Catenin - genetics; Cadherins - metabolism; CagA; Catenin; Cell Adhesion; Cell adhesion & migration; Cell Line, Tumor; Cell migration; Cell Movement; Cell Polarity; Cellular biology; Dogs; E-cadherin; Epithelial Cells - metabolism; Epithelial Cells - microbiology; Helicobacter Infections - microbiology; Helicobacter pylori; Helicobacter pylori - pathogenicity; Humans; Molecular biology; Phosphorylation; Protein Transport; Transcriptional Activation - genetics
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2007.07.015

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.