title: Helicobacter pylori activates calpain via toll-like receptor 2 to disrupt adherens junctions in human gastric epithelial cells.
abstract: Helicobacter pylori is a risk factor for the development of gastritis, gastroduodenal ulcers, and gastric adenocarcinoma. H. pylori-induced disruption of epithelial adherens junctions (AJs) is thought to promote the development of severe disease; however, the mechanisms whereby H. pylori alters AJ structure remain incompletely understood. The present study demonstrates that H. pylori infection in human patients is associated with elevated serum levels of an 80-kDa E-cadherin ectodomain, whose presence is independent of the presence of serum antibodies against CagA. In vitro, a heat-labile H. pylori surface component activates the host protease calpain in human gastric MKN45 cells independently of the virulence factors CagA and VacA. H. pylori-induced calpain activation results in cleavage of E-cadherin to produce a 100-kDa truncated form and induce relocalization of E-cadherin and β-catenin. Stimulation of MKN45 cells with the toll-like receptor 2 (TLR2) ligand P3C activated calpain and disrupted E-cadherin and β-catenin in a pattern similar to that induced by H. pylori. Inhibition of TLR2 prevented H. pylori-induced calpain activation and AJ disassembly. Together, these findings identify a novel pathway whereby H. pylori activates calpain via TLR2 to disrupt gastric epithelial AJ structure.
authors.affiliation: Department of Biological Sciences and Inflammation Research Network, University of Calgary, Calgary, Alberta T2N 1N4, Canada.
authors.forename: Pamela M
authors.initials: PM
authors.lastname: O'Connor
authors.forename: Tamia K
authors.initials: TK
authors.lastname: Lapointe
authors.forename: Shannon
authors.initials: S
authors.lastname: Jackson
authors.forename: Paul L
authors.initials: PL
authors.lastname: Beck
authors.forename: Nicola L
authors.initials: NL
authors.lastname: Jones
authors.forename: Andre G
authors.initials: AG
authors.lastname: Buret
mesh_terms: D022005:Adherens Junctions / Q000473:pathology*; D015820:Cadherins / Q000097:blood / Q000378:metabolism; D002154:Calpain / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000382:microbiology / Q000473:pathology; D005753:Gastric Mucosa / Q000166:cytology / Q000382:microbiology* / Q000473:pathology; D016481:Helicobacter Infections / Q000097:blood / Q000382:microbiology; D016480:Helicobacter pylori / Q000378:metabolism / Q000472:pathogenicity*; D054884:Host-Pathogen Interactions; D006801:Humans; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D051176:beta Catenin / Q000097:blood / Q000378:metabolism
chemical_list: D015820:Cadherins; D051195:Toll-Like Receptor 2; D051176:beta Catenin; D002154:Calpain