PI3K inhibition causes the accumulation of ubiquitinated presenilin 1 without affecting the proteasome activity
PI3K inhibition causes the accumulation of ubiquitinated presenilin 1 without affecting the proteasome activity
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DOI：
10.1016/j.bbrc.2009.12.051
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发表时间：
2010-01-08
影响因子：
3.1
通讯作者：
Takahashi, Ryosuke
中科院分区：
文献类型：
--
作者：
Aoyagi, Nobuhisa;Uemura, Kengo;Takahashi, Ryosuke
γ-分泌酶是由早老素1（PS1）、nicastrin、pen-2和aph-1组成的酶复合物，并且负责各种I型膜蛋白的膜内切割。每种组分的水平在细胞中通过蛋白酶体降解受到严格调节。另一方面，先前已报道PS1/γ-分泌酶参与磷脂酰肌醇-3激酶/Akt（PI 3 K/Akt）途径的激活。PI 3 K在阿尔茨海默病（AD）脑中被抑制，而PI 3 K抑制对PS1/γ-分泌酶代谢的影响尚未阐明。在这里，我们证明了用PI 3 K抑制剂治疗神经元导致PS1/γ-分泌酶组分的水平增加，这是通过对它们的降解的抑制作用实现的。此外，PI 3 K抑制加速PS 1的泛素化。我们进一步证明了PI 3 K抑制后PS1的泛素化是由多个单泛素化，而不是多聚泛素化。因此，用PI 3 K抑制剂处理细胞导致PS1在细胞内的再分布与蛋白酶体抑制后观察到的差异。这些结果表明，PI 3 K抑制可能会触发PS 1的多个单泛素化，从而阻止PS 1/γ-分泌酶通过蛋白酶体途径的降解。由于PS1/γ-分泌酶与A β蛋白的产生密切相关，对其代谢的深入了解有助于更好地阐明AD的发病机制。(C)2009 Elsevier Inc. All rights reserved.
gamma-Secretase is an enzymatic complex, composed of presenilin 1 (PS1), nicastrin, pen-2, and aph-1, and is responsible for the intramembranous cleavage of various type-I membrane proteins. The level of each component is tightly regulated in a cell via proteasomal degradation. On the other hand, it has previously been reported that PS1/gamma-secretase is involved in the activation of phosphatidylinositol-3 kinase/Akt (PI3K/Akt) pathway. PI3K is inhibited in Alzheimer's disease (AD) brain, whereas the effects of PI3K inhibition on the metabolism of PS1/gamma-secretase have not been elucidated. Here, we demonstrate that the treatment of neurons with PI3K inhibitors leads to increased levels of PS1/gamma-secretase components through an inhibitory effect on their degradation. Moreover, PI3K inhibition accelerated ubiquitination of PS1. We further show the evidence that the PS1 ubiquitination after PI3K inhibition is represented by the multiple mono-ubiquitination, instead of poly-ubiquitination. Accordingly, treatment of cells with PI3K inhibitor led to a differential intracellular redistribution of PS1 from the one observed after the proteasomal inhibition. These results suggest that PI3K inhibition may trigger the multiple mono-ubiquitination of PS1, which precludes the degradation of PS1/gamma-secretase through the proteasomal pathway. Since PS1/gamma-secretase is deeply involved in the production of A beta protein, a deeper knowledge into its metabolism could contribute to a better elucidation of AD pathogenesis. (C) 2009 Elsevier Inc. All rights reserved.