Low-density Lipoprotein Receptor-related Protein-1 (LRP1) Mediates Autophagy and Apoptosis Caused by Helicobacter pylori VacA
Low-density Lipoprotein Receptor-related Protein-1 (LRP1) Mediates Autophagy and Apoptosis Caused by Helicobacter pylori VacA
复制标题
DOI：
10.1074/jbc.m112.387498
复制
发表时间：
2012-09-07
影响因子：
4.8
通讯作者：
Hirayama, Toshiya
中科院分区：
文献类型：
--
作者：
Yahiro, Kinnosuke;Satoh, Mamoru;Hirayama, Toshiya
在幽门螺杆菌感染中，空泡毒素(VacA)诱导的线粒体损伤导致细胞凋亡被认为是细胞死亡的主要原因。也有人提出，VacA诱导的自噬是限制毒素诱导的细胞损伤的宿主机制。细胞凋亡和自噬是两个动态的、对立的过程，必须加以平衡才能调节细胞的死亡和存活。在这里，我们发现低密度脂蛋白受体相关蛋白-1(LRP1)是毒素诱导的胃上皮细胞AZ-521自噬的VacA受体，并表明通过与LRP1结合内化VacA调节自噬过程，包括从Lc3-I产生Lc3-II，这参与了自噬小体和自溶酶体的形成。敲除LRP1和ATG5可抑制VacA诱导的自噬，并抑制VacA诱导的自噬，提示VacA通过LRP1结合诱导的自噬先于VacA诱导的自噬。其他VacA受体如RPTPα、RPTPβ和纤维连接蛋白不影响VacA诱导的自噬或细胞凋亡。因此，我们认为细胞表面受体LRP1介导了VacA诱导的自噬和凋亡。
In Helicobacter pylori infection, vacuolating cytotoxin (VacA)-induced mitochondrial damage leading to apoptosis is believed to be a major cause of cell death. It has also been proposed that VacA-induced autophagy serves as a host mechanism to limit toxin-induced cellular damage. Apoptosis and autophagy are two dynamic and opposing processes that must be balanced to regulate cell death and survival. Here we identify the low-density lipoprotein receptor-related protein-1 (LRP1) as the VacA receptor for toxin-induced autophagy in the gastric epithelial cell line AZ-521, and show that VacA internalization through binding to LRP1 regulates the autophagic process including generation of LC3-II from LC3-I, which is involved in formation of autophagosomes and autolysosomes. Knockdown of LRP1 and Atg5 inhibited generation of LC3-II as well as cleavage of PARP, a marker of apoptosis, in response to VacA, whereas caspase inhibitor, benzyloxycarbonyl-VAD-fluoromethylketone (Z-VAD-fmk), and necroptosis inhibitor, Necrostatin-1, did not inhibit VacA-induced autophagy, suggesting that VacA-induced autophagy via LRP1 binding precedes apoptosis. Other VacA receptors such as RPTP alpha, RPTP beta, and fibronectin did not affect VacA-induced autophagy or apoptosis. Therefore, we propose that the cell surface receptor, LRP1, mediates VacA-induced autophagy and apoptosis.