Presenilins and γ-secretase inhibitors affect intracellular trafficking and cell surface localization of the γ-secretase complex components
Presenilins and γ-secretase inhibitors affect intracellular trafficking and cell surface localization of the γ-secretase complex components
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DOI：
10.1074/jbc.m404345200
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发表时间：
2004-09-24
影响因子：
4.8
通讯作者：
Xu, HX
中科院分区：
文献类型：
--
作者：
Wang, H;Luo, WJ;Xu, HX
阿尔茨海默病β-淀粉样蛋白前体蛋白和信号受体Notch的膜内裂解是由早老素(PS、PS1/PS2)-γ-分泌酶复合物介导的，其成分还包括尼卡斯特林、APH-1和PEN-2。除了在 γ 分泌酶活性中发挥重要作用外，我们和其他人还报道了 PS1 在包括烟碱酯在内的选定膜蛋白的细胞内运输中发挥作用。在这里，我们检查了在 PS 表达或 γ 分泌酶活性缺失的情况下 PEN-2 的命运。我们发现 PEN-2 保留在内质网中，并且在 PS 缺陷细胞中的半衰期比野生型细胞短得多，这表明 PS 是维持 PEN-2 的稳定性和适当的亚细胞运输所必需的。然而，PS 在 PEN-2 运输中的功能不同于其对 γ 分泌酶活性的贡献，因为 γ 分泌酶抑制剂对 γ 分泌酶活性的抑制并不影响 PEN-2 水平或其从内质网的排出。相反，膜可渗透的γ-分泌酶抑制剂（而非膜不可渗透的衍生物）显着增加了细胞表面PS1和PEN-2的水平，而不影响尼卡斯特林的水平。为了支持其在 PEN-2 运输中的作用，γ-分泌酶抑制剂诱导的 PEN-2 质膜积累也需要 PS1。我们进一步表明，γ-分泌酶抑制剂特异性加速高尔基体向细胞表面转运 PS1 和 PEN-2。综上所述，我们证明了 PS 在 γ-分泌酶组分的细胞内运输中发挥着重要作用，并且选择性 γ-分泌酶抑制剂对 γ-分泌酶组分的运输有不同的影响，这可能导致 γ-分泌酶失活。
The intramembranous cleavage of Alzheimer beta-amyloid precursor protein and the signaling receptor Notch is mediated by the presenilin (PS, PS1/PS2)-gamma-secretase complex, the components of which also include nicastrin, APH-1, and PEN-2. In addition to its essential role in gamma-secretase activity, we and others have reported that PS1 plays a role in intracellular trafficking of select membrane proteins including nicastrin. Here we examined the fate of PEN-2 in the absence of PS expression or gamma-secretase activity. We found that PEN-2 is retained in the endoplasmic reticulum and has a much shorter half-life in PS-deficient cells than in wild type cells, suggesting that PSs are required for maintaining the stability and proper subcellular trafficking of PEN-2. However, the function of PS in PEN-2 trafficking is distinct from its contribution to gamma-secretase activity because inhibition of gamma-secretase activity by gamma-secretase inhibitors did not affect the PEN-2 level or its egress from the endoplasmic reticulum. Instead, membrane-permeable gamma-secretase inhibitors, but not a membrane-impermeable derivative, markedly increased the cell surface levels of PS1 and PEN-2 without affecting that of nicastrin. In support of its role in PEN-2 trafficking, PS1 was also required for the gamma-secretase inhibitor-induced plasma membrane accumulation of PEN-2. We further showed that gamma-secretase inhibitors specifically accelerated the Golgi to the cell surface transport of PS1 and PEN-2. Taken together, we demonstrate an essential role for PSs in intracellular trafficking of the gamma-secretase components, and that selective gamma-secretase inhibitors differentially affect the trafficking of the gamma-secretase components, which may contribute to an inactivation of gamma-secretase.