Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Biochem Biophys Res Commun. 2010 Jan 8;391(2):1240-5. doi: 10.1016/j.bbrc.2009.12.051. Epub 2009 Dec 16.
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 Abeta protein, a deeper knowledge into its metabolism could contribute to a better elucidation of AD pathogenesis.
γ-分泌酶是一种酶复合物，由早老素 1（PS1）、尼卡斯特林、Pen-2 和 Aph-1 组成，负责各种Ⅰ型跨膜蛋白的膜内切割。在细胞内，通过蛋白酶体降解，每个成分的水平都受到严格的调节。另一方面，先前已经报道 PS1/γ-分泌酶参与磷酸肌醇-3 激酶/蛋白激酶 B（PI3K/Akt）途径的激活。在阿尔茨海默病（AD）大脑中，PI3K 被抑制，而 PI3K 抑制对 PS1/γ-分泌酶代谢的影响尚未阐明。在这里，我们证明 PI3K 抑制剂处理神经元会通过抑制其降解来增加 PS1/γ-分泌酶成分的水平。此外，PI3K 抑制会加速 PS1 的泛素化。我们进一步表明，PI3K 抑制后 PS1 的泛素化是由多个单泛素化而不是多泛素化表示的。因此，PI3K 抑制剂的处理会导致 PS1 从蛋白酶体抑制后观察到的细胞内重新分布。这些结果表明，PI3K 抑制可能触发 PS1 的多个单泛素化，从而阻止 PS1/γ-分泌酶通过蛋白酶体途径降解。由于 PS1/γ-分泌酶在 Abeta 蛋白的产生中起着重要作用，因此对其代谢的深入了解可能有助于更好地阐明 AD 的发病机制。
