CAPZA1 determines the risk of gastric carcinogenesis by inhibiting Helicobacter pylori CagA-degraded autophagy
CAPZA1 determines the risk of gastric carcinogenesis by inhibiting Helicobacter pylori CagA-degraded autophagy
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DOI：
10.1080/15548627.2018.1515530
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发表时间：
2019-02-01
期刊：
影响因子：
13.3
通讯作者：
Suzuki, Hidekazu
中科院分区：
文献类型：
--
作者：
Tsugawa, Hitoshi;Mori, Hideki;Suzuki, Hidekazu
幽门螺杆菌衍生的CagA是一种Ⅳ型分泌系统效应物，在胃上皮细胞中作为致癌驱动因子发挥作用。然而，在被递送到胃上皮细胞后，CagA通常会被巨自噬/自噬降解。因此，在幽门螺杆菌感染的上皮细胞中诱导自噬是一种对抗胃癌发生的重要宿主保护能力。然而，自噬体 - 溶酶体融合的调控机制尚不清楚。在此，我们报道溶酶体相关膜蛋白1（LAMP1）表达的增强对于自溶酶体的形成是必要的。LAMP1的表达是由核转位的低密度脂蛋白受体相关蛋白1（LRP1）胞内结构域（LRP1 - ICD）与LAMP1近端启动子区域结合所诱导的。幽门螺杆菌感染会增强LRP1 - ICD的核转位。相反，肌Z线α亚基1的加帽肌动蛋白（CAPZA1）通过在细胞核中与LRP1 - ICD结合抑制LAMP1的表达。CAPZA1与LRP1 - ICD的结合阻止了LRP1 - ICD与LAMP1近端启动子的结合。因此，在幽门螺杆菌感染的CAPZA1过表达的胃上皮细胞中，自溶酶体的形成受到抑制，并且CagA逃避了自噬降解。这些发现确定CAPZA1是自溶酶体形成的一种新型负调控因子，并表明CAPZA1表达的失调会导致胃癌发生风险增加。
Helicobacter pylori-derived CagA, a type IV secretion system effector, plays a role as an oncogenic driver in gastric epithelial cells. However, upon delivery into gastric epithelial cells, CagA is usually degraded by macroautophagy/autophagy. Hence, the induction of autophagy in H. pylori-infected epithelial cells is an important host-protective ability against gastric carcinogenesis. However, the mechanisms by which autophagosome-lysosome fusion is regulated, are unknown. Here, we report that enhancement of LAMP1 (lysosomal associated membrane protein 1) expression is necessary for autolysosome formation. LAMP1 expression is induced by nuclear translocated LRP1 (LDL receptor related protein 1) intracellular domain (LRP1-ICD) binding to the proximal LAMP1 promoter region. Nuclear translocation of LRP1-ICD is enhanced by H. pylori infection. In contrast, CAPZA1 (capping actin protein of muscle Z-line alpha subunit 1) inhibits LAMP1 expression via binding to LRP1-ICD in the nuclei. The binding of CAPZA1 to LRP1-ICD prevents LRP1-ICD binding to the LAMP1 proximal promoter. Thus, in CAPZA1-overexpressing gastric epithelial cells infected with H. pylori, autolysosome formation is inhibited and CagA escapes autophagic degradation. These findings identify CAPZA1 as a novel negative regulator of autolysosome formation and suggest that deregulation of CAPZA1 expression leads to increased risk of gastric carcinogenesis.