BACE1 的活性受细胞相关的鞘氨醇-1-磷酸调节。
BACE1 activity is modulated by cell-associated sphingosine-1-phosphate.
机构信息
Department of Neuropathology and Neuroscience, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
出版信息
J Neurosci. 2011 May 4;31(18):6850-7. doi: 10.1523/JNEUROSCI.6467-10.2011.
Abstract
Sphingosine kinase (SphK) 1 and 2 phosphorylate sphingosine to generate sphingosine-1-phosphate (S1P), a pluripotent lipophilic mediator implicated in a variety of cellular events. Here we show that the activity of β-site APP cleaving enzyme-1 (BACE1), the rate-limiting enzyme for amyloid-β peptide (Aβ) production, is modulated by S1P in mouse neurons. Treatment by SphK inhibitor, RNA interference knockdown of SphK, or overexpression of S1P degrading enzymes decreased BACE1 activity, which reduced Aβ production. S1P specifically bound to full-length BACE1 and increased its proteolytic activity, suggesting that cellular S1P directly modulates BACE1 activity. Notably, the relative activity of SphK2 was upregulated in the brains of patients with Alzheimer's disease. The unique modulatory effect of cellular S1P on BACE1 activity is a novel potential therapeutic target for Alzheimer's disease.
摘要
鞘氨醇激酶（SphK）1 和 2 将鞘氨醇磷酸化为鞘氨醇-1-磷酸（S1P），这是一种多效性亲脂性介质，参与多种细胞事件。在这里，我们表明，β-位点 APP 切割酶-1（BACE1）的活性，即淀粉样β肽（Aβ）产生的限速酶，受小鼠神经元中 S1P 的调节。SphK 抑制剂处理、SphK 的 RNA 干扰敲低或 S1P 降解酶的过表达降低了 BACE1 的活性，从而减少了 Aβ 的产生。S1P 特异性结合全长 BACE1 并增加其蛋白水解活性，表明细胞 S1P 直接调节 BACE1 的活性。值得注意的是，阿尔茨海默病患者大脑中的 SphK2 相对活性上调。细胞 S1P 对 BACE1 活性的独特调节作用是阿尔茨海默病的一个新的潜在治疗靶点。
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