title: 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, beta-catenin, p120(ctn), and alpha-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 (DeltacagA), interaction between E-cadherin and alpha-catenin dissociated rapidly, while binding of E-cadherin to beta-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, beta-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/beta-catenin/p120(ctn) complex from the actin cytoskeleton by disrupting binding to alpha-catenin.
authors: Junior Research Group, Paul-Ehrlich Institute, Paul-Ehrlich Str 51-59, D-63225, Langen, Germany.
authors: Christiane
authors: C
authors: Weydig
authors: Anna
authors: A
authors: Starzinski-Powitz
authors: Gert
authors: G
authors: Carra
authors: Johannes
authors: J
authors: Löwer
authors: Silja
authors: S
authors: Wessler
mesh_terms: D022005:Adherens Junctions / Q000378:metabolism*; D000818:Animals; D000942:Antigens, Bacterial / Q000378:metabolism; D001426:Bacterial Proteins / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism*; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D016764:Cell Polarity; D004285:Dogs; D004847:Epithelial Cells / Q000378:metabolism / Q000382:microbiology; D016481:Helicobacter Infections / Q000382:microbiology; D016480:Helicobacter pylori / Q000472:pathogenicity*; D006801:Humans; D010766:Phosphorylation; D021381:Protein Transport; D015533:Transcriptional Activation / Q000235:genetics; D051176:beta Catenin / Q000235:genetics
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D015820:Cadherins; D051176:beta Catenin; C080866:cagA protein, Helicobacter pylori