Presenilin 1 is required for maturation and cell surface accumulation of nicastrin
Presenilin 1 is required for maturation and cell surface accumulation of nicastrin
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DOI：
10.1074/jbc.c200148200
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发表时间：
2002-05-24
影响因子：
4.8
通讯作者：
Thinakaran, G
中科院分区：
文献类型：
--
作者：
Leem, JY;Vijayan, S;Thinakaran, G
淀粉样蛋白前体蛋白的蛋白水解加工产生β-淀粉样蛋白（Abeta）肽，其沉积在老年个体和阿尔茨海默病患者脑中的老年斑中。早老素（PS1和PS2）促进Abeta产生的最后一步，淀粉样前体蛋白的膜内γ-分泌酶切割。生物化学和药理学证据支持PSI在γ-分泌酶裂解中的催化或辅助作用，以及在选择膜蛋白运输中的调节作用。在这份报告中，我们证明，PS1是所需的成熟和细胞表面积累的nicastrin，一个组成部分的多聚体γ-分泌酶复合物。使用动力学标记的研究，我们表明，在PS1（-/-）/PS2（-/-）细胞nicastrin未能达到内侧高尔基室，因此，是不完全糖基化。人PS1的稳定表达恢复了PS1（-/-）成纤维细胞中的这些缺陷。此外，膜分离的研究表明，共定位的PS1片段与成熟nicastrin。这些结果表明，一种新的伴侣型PS1和PS2在促进nicastrin成熟和运输的早期生物合成室的作用。我们的研究结果与PS1在多个步骤中影响γ-分泌酶加工一致，包括γ-分泌酶复合物的底物和组分的成熟和细胞内运输。
Proteolytic processing of amyloid precursor protein generates beta-amyloid (Abeta) peptides that are deposited in senile plaques in brains of aged individuals and patients with Alzheimer's disease. Presenilins (PS1 and PS2) facilitate the final step in Abeta production, the intramembranous gamma-secretase cleavage of amyloid precursor protein. Biochemical and pharmacological evidence support a catalytic or accessory role for PSI in gamma-secretase cleavage, as well as a regulatory role in select membrane protein trafficking. In this report, we demonstrate that PS1 is required for maturation and cell surface accumulation of nicastrin, an integral component of the multimeric gamma-secretase complex. Using kinetic labeling studies we show that in PS1(-/-)/PS2(-/-) cells nicastrin fails to reach the medial Golgi compartment, and as a consequence, is incompletely glycosylated. Stable expression of human PS1 restores these deficiencies in PS1(-/-) fibroblasts. Moreover, membrane fractionation studies show co-localization of PS1 fragments with mature nicastrin. These results indicate a novel chaperone-type role for PS1 and PS2 in facilitating nicastrin maturation and transport in the early biosynthetic compartments. Our findings are consistent with PS1 influencing gamma-secretase processing at multiple steps, including maturation and intracellular trafficking of substrates and component(s) of the gamma-secretase complex.