Bauer Bianca, Bartfeld Sina, Meyer Thomas F
Department of Molecular Biology, Max Planck Institute for Infection Biology, Charitéplatz 1, Campus Charité Mitte, 10117 Berlin, Germany.
Cell Microbiol. 2009 Jan;11(1):156-69. doi: 10.1111/j.1462-5822.2008.01246.x. Epub 2008 Oct 22.
Helicobacter pylori infection is a primary cause of peptic ulcers and is associated with gastric carcinogenesis. The H. pylori-induced pathophysiology may be linked to the deregulation of EGFR signalling. Elevated mucosal levels of EGF and the EGFR have been found in antral gastric biopsies of H. pylori-infected patients. A critical mechanism for regulating EGFR signalling is ligand-induced endocytosis. The internalized receptor recycles back to the plasma membrane for continued signalling or is targeted for degradation terminating receptor signalling. Here, we show that H. pylori blocks EGFR endocytosis and receptor degradation upon prolonged infection of gastric epithelial cells. Moreover, this inhibition occurs via a CagA-dependent, but CagA phosphorylation-independent activation of the non-receptor kinase c-Abl, which in turn phosphorylates the EGFR target site pY1173. This suggests a novel CagA-induced host cell response that is independent of CagA tyrosine phosphorylation. Our data indicate an intriguing strategy of H. pylori in host cell manipulations by altering selective receptor populations via a CagA-dependent endocytic mechanism. Furthermore, we identified a new role for c-Abl in phosphorylation of the EGFR target site pY1173 during H. pylori infection.
幽门螺杆菌感染是消化性溃疡的主要病因，且与胃癌发生相关。幽门螺杆菌诱导的病理生理学可能与表皮生长因子受体（EGFR）信号传导失调有关。在幽门螺杆菌感染患者的胃窦活检组织中，已发现表皮生长因子（EGF）和EGFR的黏膜水平升高。调节EGFR信号传导的一个关键机制是配体诱导的内吞作用。内化的受体循环回到质膜以持续发出信号，或被靶向降解以终止受体信号传导。在此，我们表明，幽门螺杆菌在长期感染胃上皮细胞后会阻断EGFR的内吞作用和受体降解。此外，这种抑制作用是通过非受体激酶c-Abl的CagA依赖性但CagA磷酸化非依赖性激活而发生的，c-Abl进而磷酸化EGFR靶位点pY1173。这表明了一种新的CagA诱导的宿主细胞反应，该反应独立于CagA酪氨酸磷酸化。我们的数据表明，幽门螺杆菌通过一种CagA依赖性内吞机制改变选择性受体群体，在宿主细胞操纵方面采取了一种有趣的策略。此外，我们确定了c-Abl在幽门螺杆菌感染期间对EGFR靶位点pY1173磷酸化的新作用。
