title: A novel inhibitory domain of Helicobacter pylori protein CagA reduces CagA effects on host cell biology.
abstract: The Helicobacter pylori protein CagA (cytotoxin-associated gene A) is associated with an increased risk for gastric cancer formation. After attachment to epithelial cells, the bacteria inject CagA via a type IV secretion apparatus into host cells, where it exerts its biological activity. Host cell responses to intracellular CagA have been linked exclusively to signaling motifs in the C terminus of the CagA protein. Little is known about the functional role of the remaining CagA protein. Using transgenic expression of CagA mutants in epithelial cells, we were able to identify a novel CagA inhibitory domain at the N terminus consisting of the first 200 amino acids. This domain localizes to cell-cell contacts and increases the rate and strength of cell-cell adhesion in epithelial cells. Thus, it compensates for the loss of cell-cell adhesion induced by the C terminus of the CagA protein. Consistent with its stabilizing role on cell-cell adhesion, the CagA N terminus domain reduces the CagA-induced β-catenin transcriptional activity in the nucleus. Furthermore, it inhibits apical surface constriction and cell elongations, host cell phenotypes induced by the C terminus in polarized epithelia. Therefore, our study suggests that CagA contains an intrinsic inhibitory domain that reduces host cell responses to CagA, which have been associated with the formation of cancer.
authors.affiliation: Second Department of Internal Medicine, Klinikum rechts der Isar, Technical University Munich, 81675 Munich, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Pelz
authors.forename: Sylvia
authors.initials: S
authors.lastname: Steininger
authors.forename: Claudia
authors.initials: C
authors.lastname: Weiss
authors.forename: Fabian
authors.initials: F
authors.lastname: Coscia
authors.forename: Roger
authors.initials: R
authors.lastname: Vogelmann
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D000942:Antigens, Bacterial / Q000235:genetics / Q000378:metabolism*; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D004285:Dogs; D004847:Epithelial Cells / Q000378:metabolism / Q000382:microbiology*; D016480:Helicobacter pylori / Q000502:physiology*; D054884:Host-Pathogen Interactions; D009154:Mutation; D017434:Protein Structure, Tertiary; D012307:Risk Factors; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism / Q000382:microbiology; D014158:Transcription, Genetic / Q000235:genetics; D051176:beta Catenin / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D051176:beta Catenin; C080866:cagA protein, Helicobacter pylori