Helicobacter pylori CagA Phosphorylation-Independent Function in Epithelial Proliferation and Inflammation
Helicobacter pylori CagA Phosphorylation-Independent Function in Epithelial Proliferation and Inflammation
复制标题
DOI：
10.1016/j.chom.2008.11.010
复制
发表时间：
2009-01-22
影响因子：
30.3
通讯作者：
Sasakawa, Chihiro
中科院分区：
文献类型：
--
作者：
Suzuki, Masato;Mimuro, Hitomi;Sasakawa, Chihiro
CagA是幽门螺杆菌（Helicobacter pylori，Hp）的一个主要毒力因子，主要以磷酸化和非磷酸化形式存在于胃上皮细胞中。磷酸化形式的生物活性已得到充分证实;然而，非磷酸化形式的功能仍然难以捉摸。在这里，我们报告说，在C-末端区域的CagA，这是不同于用于磷酸化的EPIYA基序，我们指定CRPIA（保守重复负责磷酸化独立的活动）的保守基序，在Hp的发病机制中起着关键作用。非磷酸化CagA中的CRPIA基序参与与活化的肝细胞生长因子受体Met相互作用，导致响应于Hp感染的磷脂酰肌醇3-激酶/Akt信号转导的持续活化。这又导致β-连环蛋白和NF-κ B信号传导的激活，其分别促进增殖和炎症。因此，非磷酸化的CagA活性有助于与慢性胃炎和胃癌的发展相关的上皮增殖和促炎反应。
CagA, a major virulence factor of Helicobacter pylori (Hp), is delivered into gastric epithelial cells and exists in phosphorylated and nonphosphorylated forms. The biological activity of the phosphorylated form is well established; however, function(s) of the nonphosphorylated form remain elusive. Here, we report that a conserved motif in the C-terminal region of CagA, which is distinct from the EPIYA motifs used for phosphorylation and which we designate CRPIA (conserved repeat responsible for phosphorylation-independent activity), plays pivotal roles in Hp pathogenesis. The CRPIA motif in nonphosphorylated CagA was involved in interacting with activated Met, the hepatocyte growth factor receptor, leading to the sustained activation of phosphatidlylinositol 3-kinase/Akt signaling in response to Hp infection. This in turn led to the activation of beta-catenin and NF-kappa B signaling, which promote proliferation and inflammation, respectively. Thus, nonphosphorylated CagA activity contributes to the epithelial proliferative and proinflammatory responses associated with development of chronic gastritis and gastric cancer.