BACE1 activity is modulated by cell-associated sphingosine-1-phosphate.
BACE1 activity is modulated by cell-associated sphingosine-1-phosphate.
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DOI：
10.1523/jneurosci.6467-10.2011
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发表时间：
2011-05-04
期刊：
影响因子：
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通讯作者：
Iwatsubo T
中科院分区：
文献类型：
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作者：
Takasugi N;Sasaki T;Suzuki K;Osawa S;Isshiki H;Hori Y;Shimada N;Higo T;Yokoshima S;Fukuyama T;Lee VM;Trojanowski JQ;Tomita T;Iwatsubo T
鞘氨醇激酶（SphK）1和2磷酸化鞘氨醇以产生鞘氨醇-1-磷酸（S1 P），一种涉及多种细胞事件的多能亲脂性介质。我们发现β-site APP cleaving enzyme-1（BACE 1）是淀粉样β肽（Aβ）生成的限速酶，其活性受神经元中S1 P的调节。SphK抑制剂、SphK的RNAi敲低或S1 P降解酶的过表达降低BACE 1活性以减少Aβ产生。S1 P特异性结合全长BACE 1并增加其蛋白水解活性，表明细胞S1 P直接调节BACE 1活性。值得注意的是，SphK 2的相对活性在阿尔茨海默病患者的大脑中上调。细胞S1 P对BACE 1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。
Sphingosine kinases (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 neurons. Treatment by SphK inhibitor, RNAi knockdown of SphK or overexpression of S1P degrading enzymes decreased BACE1 activity to reduce Aβ production. S1P specifically bound to full-length BACE1 and increased its proteolytic activity, suggesting that the cellular S1P directly modulates BACE1 activity. Notably, the relative activity of SphK2 was upregulated in the brains of patients with Alzheimer disease. The unique modulatory effect of cellular S1P on BACE1 activity is a novel potential therapeutic target for Alzheimer disease.