Analysis on multifunctional receptors for Helicobacter pylori VacA

幽门螺杆菌产生的空泡细胞毒素（VacA）的多效性似乎是由于通过与几种上皮细胞受体结合激活不同的信号转导途径，例如受体蛋白酪氨酸磷酸酶(RPTP) β和α，以及纤维连接蛋白。我们从人胃上皮细胞系AZ-521细胞中纯化了一种结合VacA的表面膜蛋白p500，并鉴定其为低密度脂蛋白受体相关蛋白-1 （LRP1）。LRP1结合VacA被证明特异地负责VacA诱导的自噬和凋亡，但不激活Wnt/β-catenin信号通路。与RPTPα和RPTP β类似，LRP1介导AZ-521细胞中VacA的内化，但与RPTPα和RPTP β相反，LRP1靶向下游途径导致自噬和凋亡。通过LRP1结合的vaca诱导的自噬先于细胞凋亡，这表明过度的自噬活性也可导致细胞死亡。这是首次提供证据证明LRP1介导自噬。

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.