Helicobacter pylori CagA induces a transition from polarized to invasive phenotypes in MDCK cells.
CagA is a bacterial effector protein of Helicobacter pylori that is translocated via a type IV secretion system into gastric epithelial cells. We previously described that H. pylori require CagA to disrupt the organization and assembly of apical junctions in polarized epithelial cells. In this study, we provide evidence that CagA expression is not only sufficient to disrupt the apical junctions but also perturbs epithelial differentiation. CagA-expressing cells lose apicobasal polarity and cell-cell adhesion, extend migratory pseudopodia, and degrade basement membranes, acquiring an invasive phenotype. Expression of the CagA C-terminal domain, which contains the tyrosine phosphorylated EPIYA motifs, induces pseudopodial activity but is not sufficient to induce cell migration. Conversely, the N terminus targets CagA to the cell-cell junctions. Neither domain is sufficient to disrupt cell adhesion or cell polarity, but coexpressed in trans, the N terminus determines the localization of both polypeptides. We show that CagA induces a morphogenetic program in polarized Madin-Darby canine kidney cells resembling an epithelial-to-mesenchymal transition. We propose that altered cell-cell and cell matrix interactions may serve as an early event in H. pylori-induced carcinogenesis.
Bagnoli
Fabio
F
Cellular Microbiology and BioInformatics Unit, Chiron Vaccines, Via Fiorentina 1, 53100 Siena, Italy.
Buti
Ludovico
L
Tompkins
Lucy
L
Covacci
Antonello
A
Amieva
Manuel R
MR
D020816:Amino Acid Motifs; D000818:Animals; D000942:Antigens, Bacterial / Q000737:chemistry / Q000502:physiology*; D001426:Bacterial Proteins / Q000737:chemistry / Q000502:physiology*; D002448:Cell Adhesion; D002460:Cell Line; D002465:Cell Movement; D016764:Cell Polarity; D002471:Cell Transformation, Neoplastic; D004285:Dogs; D005109:Extracellular Matrix / Q000502:physiology; D016480:Helicobacter pylori / Q000472:pathogenicity*; D010641:Phenotype; D013274:Stomach Neoplasms / Q000209:etiology
D000942:Antigens, Bacterial; D001426:Bacterial Proteins; C080866:cagA protein, Helicobacter pylori