Institut de Biochimie et Biophysique Moléculaire et Cellulaire, CNRS UMR 8619, France.
J Biol Chem. 2012 Oct 5;287(41):34583-95. doi: 10.1074/jbc.M112.400010. Epub 2012 Aug 13.
The amyloid precursor protein (APP) can be cleaved by α-secretases in neural cells to produce the soluble APP ectodomain (sAPPα), which is neuroprotective. We have shown previously that activation of the purinergic P2X7 receptor (P2X7R) triggers sAPPα shedding from neural cells. Here, we demonstrate that the activation of ezrin, radixin, and moesin (ERM) proteins is required for the P2X7R-dependent proteolytic processing of APP leading to sAPPα release. Indeed, the down-regulation of ERM by siRNA blocked the P2X7R-dependent shedding of sAPPα. We also show that P2X7R stimulation triggered the phosphorylation of ERM. Thus, ezrin translocates to the plasma membrane to interact with P2X7R. Using specific pharmacological inhibitors, we established the order in which several enzymes trigger the P2X7R-dependent release of sAPPα. Thus, a Rho kinase and the MAPK modules ERK1/2 and JNK act upstream of ERM, whereas a PI3K activity is triggered downstream. For the first time, this work identifies ERM as major partners in the regulated non-amyloidogenic processing of APP.
淀粉样前体蛋白（APP）可被神经细胞中的α-分泌酶切割，产生具有神经保护作用的可溶性 APP 细胞外结构域（sAPPα）。我们之前已经证明，嘌呤能 P2X7 受体（P2X7R）的激活可触发神经细胞中 sAPPα 的脱落。在这里，我们证明 ezrin、radixin 和 moesin（ERM）蛋白的激活对于 P2X7R 依赖性 APP 蛋白水解加工导致 sAPPα 释放是必需的。事实上，siRNA 下调 ERM 可阻断 P2X7R 依赖性 sAPPα 的脱落。我们还表明，P2X7R 刺激触发了 ERM 的磷酸化。因此，ezrin 易位到质膜与 P2X7R 相互作用。使用特定的药理学抑制剂，我们确定了几种酶触发 P2X7R 依赖性 sAPPα 释放的顺序。因此，Rho 激酶和 MAPK 模块 ERK1/2 和 JNK 位于 ERM 的上游，而 PI3K 活性位于下游。这项工作首次确定 ERM 是 APP 受调控的非淀粉样生成加工的主要伴侣。
