Helicobacter pylori CagL activates ADAM17 to induce repression of the gastric H, K-ATPase alpha subunit.
Helicobacter pylori CagL activates ADAM17 to induce repression of the gastric H, K-ATPase alpha subunit.
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DOI：
10.1053/j.gastro.2010.03.036
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发表时间：
2010-07
期刊：
影响因子：
29.4
通讯作者：
Smolka AJ
中科院分区：
文献类型：
--
作者：
Saha A;Backert S;Hammond CE;Gooz M;Smolka AJ
螺杆菌感染pylori抑制胃H，K-ATP酶α亚单位（HKα）的表达，这可能导致短暂性低氯血症。CagL是H. pylori IV型分泌系统中，与整联蛋白α5β1结合以介导毒力因子易位到宿主细胞中并启动信号传导。α5β1结合ADAM 17，ADAM 17是一种催化受体酪氨酸激酶配体胞外域脱落的金属酶。我们调查了H. pylori诱导的HKα抑制是通过CagL激活ADAM 17和释放肝素结合表皮生长因子（HB-EGF）介导的。用HKα启动子-报告基因或ADAM 17特异性小干扰RNA转染AGS胃上皮细胞，并感染H.幽门螺杆菌。通过ELISA分析测量HB-EGF分泌，并通过免疫共沉淀分析研究ADAM 17与整合素的相互作用。用野生型H. pylori或H. pylori cagL缺陷型（P12ΔcagL/cagL）抑制HKα启动子-Luc报告基因活性并刺激ADAM 17活性。HKα的NF-κB结合位点的点突变或P12ΔcagL感染均能抑制这两种反应。与对照组相比，AGS细胞中siRNA介导的ADAM 17沉默抑制了野生型HKα启动子的抑制，并降低了ADAM 17活性和HB-EGF产生。AGS裂解物的免疫共沉淀研究表明，野生型H。pylori可破坏ADAM 17-α5β1复合物。急性H. pylori感染时，CagL将ADAM 17从整合素α5β1上解离，并激活ADAM 17依赖性、NF-κ B介导的HKα抑制。这可能导致H.幽门感染
Infection with H. pylori represses expression of the gastric H, K-ATPase 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 ADAM17, 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). HKα promoter and ADAM17 activity were measured in AGS gastric epithelial cells transfected with HKα promoter-reporter constructs or ADAM17-specific small interfering (si)RNAs and infected with H. pylori. HB-EGF secretion was measured by ELISA analysis and ADAM17 interaction with integrins were investigated by co-immunoprecipitation analyses. 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 (P12ΔcagL/cagL) repressed HKα promoter-Luc reporter activity and stimulated ADAM17 activity. Both responses were inhibited by point mutations in the NF-κB binding site of HKα or by infection with P12ΔcagL. siRNA-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. During acute H. pylori infection, CagL dissociates ADAM17 from the integrin α5β1 and activates ADAM17-dependent, NF-κB–mediated repression of HKα. This might contribute to transient hypochlorhydria in patients with H. pylori infection.
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