Retention in Endoplasmic Reticulum 1 (RER1) Modulates Amyloid-β (Aβ) Production by Altering Trafficking of γ-Secretase and Amyloid Precursor Protein (APP)
Retention in Endoplasmic Reticulum 1 (RER1) Modulates Amyloid-β (Aβ) Production by Altering Trafficking of γ-Secretase and Amyloid Precursor Protein (APP)
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DOI：
10.1074/jbc.m112.418442
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发表时间：
2012-11-23
影响因子：
4.8
通讯作者：
Kim, Seong-Hun
中科院分区：
文献类型：
--
作者：
Park, Hyo-Jin;Shabashvili, Daniil;Kim, Seong-Hun
在脑实质中存在含有聚集的淀粉样β（A β）肽的神经炎斑是阿尔茨海默病（AD）的病理学标志。β是通过β-和γ-分泌酶分别连续切割淀粉样β前体蛋白（APP）产生的。由于APP加工成A β需要通过分泌途径转运，底物的运输和对分泌酶的接近是可以影响A β产生的关键因素（Thinakaran，G.，和Koo，E. H.（2008）淀粉样蛋白前体蛋白运输，加工和功能。J. Biol. Chem. 283，29615-29619）。在这里，我们报告，滞留在内质网1（RER 1）与γ-分泌酶在早期分泌室和调节细胞内运输的γ-分泌酶。RER 1过表达降低了细胞表面上的γ-分泌酶定位和A β分泌，相反，RER 1敲低增加了细胞表面γ-分泌酶的水平并增加A β分泌。此外，我们发现，增加RER 1水平降低成熟APP和增加未成熟APP，导致APP表面积累减少。这些数据表明，RER 1影响的运输和定位的γ-分泌酶和APP，从而调节A β肽的生产和分泌。
The presence of neuritic plaques containing aggregated amyloid-beta (A beta) peptides in the brain parenchyma is a pathological hallmark of Alzheimer disease (AD). A beta is generated by sequential cleavage of the amyloid beta precursor protein (APP) by beta- and gamma-secretase, respectively. As APP processing to A beta requires transport through the secretory pathway, trafficking of the substrate and access to the secretases are key factors that can influence A beta production (Thinakaran, G., and Koo, E. H. (2008) Amyloid precursor protein trafficking, processing, and function. J. Biol. Chem. 283, 29615-29619). Here, we report that retention in endoplasmic reticulum 1 (RER1) associates with gamma-secretase in early secretory compartments and regulates the intracellular trafficking of gamma-secretase. RER1 overexpression decreases both gamma-secretase localization on the cell surface and A beta secretion and conversely RER1 knockdown increases the level of cell surface gamma-secretase and increases A beta secretion. Furthermore, we find that increased RER1 levels decrease mature APP and increase immature APP, resulting in less surface accumulation of APP. These data show that RER1 influences the trafficking and localization of both gamma-secretase and APP, thereby regulating the production and secretion of A beta peptides.