Sun Miao, Zhang Huaye
Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.
Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, Piscataway, NJ, USA.
Neurobiol Aging. 2017 Dec;60:129-140. doi: 10.1016/j.neurobiolaging.2017.08.024. Epub 2017 Sep 21.
The cleavage of amyloid precursor protein (APP) by β-site APP cleaving enzyme 1 (BACE1) is the rate-limiting step in beta amyloid generation during Alzheimer's disease (AD) pathogenesis. In AD brains, BACE1 is abnormally accumulated in endocytic compartments, where the acidic pH is optimal for its activity. However, mechanisms regulating the endosome-to-trans-Golgi network (TGN) retrieval of BACE1 remain unclear. Here, we show that partitioning defective 3 (Par3) facilitates BACE1 retrograde trafficking from endosomes to the TGN. Par3 functions through aPKC-mediated phosphorylation of BACE1 on Ser498, which in turn promotes the interaction between BACE1 and phosphofurin acidic cluster sorting protein 1 and facilitates the retrograde trafficking of BACE1 to the TGN. In human AD brains, there is a significant decrease in Ser498 phosphorylation of BACE1 suggesting that defective phosphorylation-dependent retrograde transport of BACE1 is important in AD pathogenesis. Together, our studies provide mechanistic insight into a novel role for Par3 and aPKC in regulating the retrograde endosome-to-TGN trafficking of BACE1 and shed light on the mechanisms of AD pathogenesis.
在阿尔茨海默病（AD）发病过程中，β-位点淀粉样前体蛋白裂解酶1（BACE1）对淀粉样前体蛋白（APP）的裂解是β淀粉样蛋白生成的限速步骤。在AD大脑中，BACE1异常积聚在内吞小室中，酸性pH值最适合其发挥活性。然而，调节BACE1从内体到反式高尔基体网络（TGN）回收的机制仍不清楚。在这里，我们表明，分区缺陷蛋白3（Par3）促进BACE1从内体到TGN的逆行运输。Par3通过aPKC介导的BACE1第498位丝氨酸磷酸化发挥作用，这反过来促进了BACE1与磷呋喃酸性簇分选蛋白1之间的相互作用，并促进了BACE1向TGN的逆行运输。在人类AD大脑中，BACE1第498位丝氨酸的磷酸化显著减少，这表明BACE1磷酸化依赖性逆行运输缺陷在AD发病机制中很重要。总之，我们的研究为Par3和aPKC在调节BACE1从内体到TGN的逆行运输中的新作用提供了机制性见解，并揭示了AD发病机制。
