Analysis on multifunctional receptors for Helicobacter pylori VacA

幽门螺杆菌产生的空泡毒素的多效性可能是通过与多种上皮细胞受体，如受体蛋白酪氨酸磷酸酶β和α以及纤维连接蛋白来激活不同的信号转导通路而产生的。在这里，我们从人胃上皮细胞系AZ-521细胞中纯化了与VacA结合的表膜蛋白P500，并将其鉴定为低密度脂蛋白受体相关蛋白-1(LRP1)。VacA的LRP1结合被证明是VacA诱导的自噬和凋亡的特异性原因，但不是Wnt/β-catenin信号通路的激活。与rpppα和rpppβ相似，Lrp1在AZ-5 2 1细胞中介导VacA内化，但与rpppα和rpppβ不同的是，lrp1靶向于导致自噬和凋亡的下游通路。VacA通过LRP1结合诱导的自噬先于细胞凋亡，这表明过度的自噬活性也可能导致细胞死亡。这是第一个提供LRP1介导自噬的证据的研究。

The pleiotropic effects of vacuolating cytotoxin (VacA) produced by Helicobacter pylori appear to result from activation of different signal transduction pathways through binding to several epithelial cell receptors, e.g., receptor protein tyrosine phosphatase (RPTP) β and α, and fibronectin. Here we purified from AZ-521 cells, a human gastric epithelial ell line, a surface membrane protein, p500, which binds VacA, and identified it as low-density lipoprotein receptor-related protein-1 (LRP1). LRP1 binding of VacA was shown to be specifically responsible for VacA-induced autophagy and apoptosis, but not activation of the Wnt/β-catenin signaling pathway. Similar to RPTPα and RPTP β, LRP1 mediates VacA internalization in AZ-521 cells, but in contrast to RPTPα and RPTP β, LRP1 targeted downstream pathways leading to autophagy and apoptosis. VacA-induced autophagy via LRP1 binding precedes apoptosis suggesting that an excessive autophagic activity can also lead to cell death. This is the first study to provide evidence that LRP1 mediates autophagy.