Helicobacter pylori CagL Activates ADAM17 to Induce Repression of the Gastric H, K-ATPase α Subunit

Background & AimsInfection with Helicobacter pylori represses expression of the gastric H, K–adenosine triphosphatase α-subunit (HKα), which could contribute to transient hypochlorhydria. CagL, a pilus protein component of the H pylori type IV secretion system, binds to the integrin α5β1 to mediate translocation of virulence factors into the host cell and initiate signaling. α5β1 binds a disintegrin and metalloprotease (ADAM) 17, a metalloenzyme that catalyzes ectodomain shedding of receptor tyrosine kinase ligands. We investigated whether H pylori–induced repression of HKα is mediated by CagL activation of ADAM17 and release of heparin-binding epidermal growth factor (HB-EGF).MethodsHKα promoter and ADAM17 activity were measured in AGS gastric epithelial cells transfected with HKα promoter-reporter constructs or ADAM17-specific small interfering RNAs and infected with H pylori. HB-EGF secretion was measured by enzyme-linked immunosorbent assay analysis, and ADAM17 interaction with integrins was investigated by coimmunoprecipitation analyses.ResultsInfection of AGS cells with wild-type H pylori or an H pylori cagL-deficient isogenic mutant that also contained a wild-type version of cagL (P12ΔcagL/cagL) repressed HKα promoter-Luc reporter activity and stimulated ADAM17 activity. Both responses were inhibited by point mutations in the nuclear factor–κB binding site of HKα or by infection with P12ΔcagL. Small interfering RNA–mediated silencing of ADAM17 in AGS cells inhibited the repression of wild-type HKα promoter and reduced ADAM17 activity and HB-EGF production, compared to controls. Coimmunoprecipitation studies of AGS lysates showed that wild-type H pylori disrupted ADAM17–α5β1 complexes.ConclusionsDuring acute H pylori infection, CagL dissociates ADAM17 from the integrin α5β1 and activates ADAM17-dependent, nuclear factor–κB-mediated repression of HKα. This might contribute to transient hypochlorhydria in patients with H pylori infection.