Endocytosis of the amyloid precursor protein (APP) is critical for generation of β-amyloid, aggregating in Alzheimer's disease. APP endocytosis depending on the intracellular NPTY motif is well investigated, whereas involvement of the YTSI (also termed BaSS) motif remains controversial. Here, we show that APP lacking the YTSI motif (ΔYTSI) displays reduced localization to early endosomes and decreased internalization rates, similar to APP ΔNPTY. Additionally, we show that the YTSI-binding protein, PAT1a interacts with the Rab5 activator RME-6, as shown by several independent assays. Interestingly, knockdown of RME-6 decreased APP endocytosis, whereas overexpression increased the same. Similarly, APP ΔNPTY endocytosis was affected by PAT1a and RME-6 overexpression, whereas APP ΔYTSI internalization remained unchanged. Moreover, we could show that RME-6 mediated increase of APP endocytosis can be diminished upon knocking down PAT1a. Together, our data identify RME-6 as a novel player in APP endocytosis, involving the YTSI-binding protein PAT1a.

译文

淀粉样前体蛋白 (APP) 的内吞作用对于 β-淀粉样蛋白的生成至关重要,在阿尔茨海默氏病中聚集。取决于细胞内NPTY基序的APP内吞作用已得到很好的研究,而YTSI (也称为低音) 基序的参与仍存在争议。在这里,我们显示缺少YTSI基序 (Δ YTSI) 的APP显示出对早期内体的定位降低,内化率降低,类似于APP Δ npty。此外,我们显示YTSI结合蛋白PAT1a与Rab5激活剂RME-6相互作用,如几个独立的试验所示。有趣的是,RME-6的敲低降低了APP内吞作用,而过表达却增加了。同样,APP Δ npty内吞作用受PAT1a和RME-6过表达的影响,而APP Δ ytsi内化保持不变。此外,我们可以表明,在击倒PAT1a时,RME-6介导的APP内吞作用的增加可以减少。总之,我们的数据将RME-6识别为APP内吞作用的新参与者,涉及YTSI结合蛋白PAT1a。

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