CagA-independent disruption of adherence junction complexes involves E-cadherin shedding and implies multiple steps in Helicobacter pylori pathogenicity.
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.
Weydig
Christiane
C
Junior Research Group, Paul-Ehrlich Institute, Paul-Ehrlich Str 51-59, D-63225, Langen, Germany.
Starzinski-Powitz
Anna
A
Carra
Gert
G
Löwer
Johannes
J
Wessler
Silja
S
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
D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D015820:Cadherins; D051176:beta Catenin; C080866:cagA protein, Helicobacter pylori