Abstract：
Microsomal glutathione transferase 3 (MGST3) regulates eicosanoid and glutathione metabolism. These processes are associated with oxidative stress and apoptosis, suggesting that MGST3 might play a role in the pathophysiology of Alzheimer\'s disease. Here, we report that knockdown (KD) of MGST3 in cell lines reduced the protein level of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) and the resulting amyloidogenesis. Interestingly, MGST3 KD did not alter intracellular reactive oxygen species level but selectively reduced the expression of apoptosis indicators which could be associated with the receptor of cysteinyl leukotrienes, the downstream metabolites of MGST3 in arachidonic acid pathway. We then showed that the effect of MGST3 on BACE1 was independent of cysteinyl leukotrienes but involved a translational mechanism. Further RNA-seq analysis identified that regulator of G-protein signaling 4 (RGS4) was a target gene of MGST3. Silencing of RGS4 inhibited BACE1 translation and prevented MGST3 KD-mediated reduction of BACE1. The potential mechanism was related to AKT activity, as the protein level of phosphorylated AKT was significantly reduced by silencing of MGST3 and RGS4, and the AKT inhibitor abolished the effect of MGST3/RGS4 on phosphorylated AKT and BACE1. Together, MGST3 regulated amyloidogenesis by controlling BACE1 protein expression, which was mediated by RGS4 and downstream AKT signaling pathway.
摘要：
微粒体谷胱甘肽转移酶3(MGST3)调节类花生酸和谷胱甘肽代谢。这些过程与氧化应激和细胞凋亡有关，提示MGST3可能在阿尔茨海默病（AD）的病理生理中起作用。这里,我们报道,细胞系中MGST3的敲除(KD)降低了β-位点淀粉样前体蛋白裂解酶1(BACE1)的蛋白水平,并导致淀粉样蛋白生成.有趣的是,MGST3KD不改变细胞内ROS水平，但选择性地降低了可能与半胱氨酰白三烯（cysLTs）受体相关的凋亡指标的表达，MGST3的下游代谢产物参与花生四烯酸通路。然后，我们表明MGST3对BACE1的作用与cysLTs无关，但涉及翻译机制。进一步的RNA-seq分析鉴定G蛋白信号传导4(RGS4)的调节因子是MGST3的靶基因。RGS4的沉默抑制BACE1翻译并阻止MGST3KD介导的BACE1还原。潜在机制与AKT活性有关，由于MGST3和RGS4的沉默显著降低了磷酸化AKT(p-AKT)的蛋白水平,并且AKT抑制剂消除了MGST3/RGS4对p-AKT和BACE1的作用.一起,MGST3通过控制BACE1蛋白表达调节淀粉样蛋白生成，由RGS4和下游AKT信号通路介导。
