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

BACKGROUND & AIMS: Infection with Helicobacter pylori represses expression of the gastric H, K-adenosine triphosphatase alpha-subunit (HK alpha), which could contribute to transient hypochlorhydria. CagL, a pilus protein component of the H pylori type IV secretion system, binds to the integrin alpha(5)beta 1 to mediate translocation of virulence factors into the host cell and initiate signaling. alpha(5)beta 1 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 HK alpha is mediated by CagL activation of ADAM17 and release of heparin-binding epidermal growth factor (HB-EGF). METHODS: HK alpha promoter and ADAM17 activity were measured in AGS gastric epithelial cells transfected with HK alpha 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. RESULTS: Infection 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 (P12 Delta cagL/cagL) repressed HK alpha promoter-Luc reporter activity and stimulated ADAM17 activity. Both responses were inhibited by point mutations in the nuclear factor-kappa B binding site of HK alpha or by infection with P12 Delta cagL. Small interfering RNA-mediated silencing of ADAM17 in AGS cells inhibited the repression of wild-type HK alpha 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-alpha(5)beta 1 complexes. CONCLUSIONS: During acute H pylori infection, CagL dissociates ADAM17 from the integrin alpha(5)beta 1 and activates ADAM17-dependent, nuclear factor-kappa B-mediated repression of HK alpha. This might contribute to transient hypochlorhydria in patients with H pylori infection.