PCSK9 is required for the disposal of non-acetylated intermediates of the nascent membrane protein BACE1
PCSK9 is required for the disposal of non-acetylated intermediates of the nascent membrane protein BACE1
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DOI：
10.1038/embor.2008.132
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发表时间：
2008-09-01
期刊：
影响因子：
7.7
通讯作者：
Puglielli, Luigi
中科院分区：
文献类型：
--
作者：
Jonas, Mary Cabell;Costantini, Claudio;Puglielli, Luigi
我们最近发现了一种新的BACE1(β位点淀粉样前体蛋白(APP)裂解酶1)的翻译后调节形式，BACE1是一种膜蛋白，在阿尔茨海默病淀粉样β蛋白(Aβ)的产生中起限速酶的作用。具体地说，BACE1在内质网/内质网-高尔基体中间隔室(ER/ERGIC)的管腔内的七个赖氨酸残基上瞬时乙酰化。新生蛋白质的乙酰化中间体能够到达高尔基体，而非乙酰化的中间体保留在内质网后的隔室中并被降解。在这里，我们报告了丝氨酸蛋白酶PCSK9(前蛋白转换酶枯草杆菌可信9型)有助于非乙酰化BACE1的处置。PCSK9的过表达和小干扰RNA均影响BACE1的表达水平。PCSK9的下调影响乙酰化缺失突变体(BACE1(Ala)和BACE1(Arg))的水平，但不影响乙酰化获得突变体(BACE1(Gln))的水平。此外，PCSK9(-/-)小鼠大脑中BACE1和抗体水平增加。最后，我们发现新生的低密度脂蛋白受体，一种已知的PCSK9底物，也是乙酰化的。
We have recently identified a new form of post-translational regulation of BACE1 (beta-site amyloid precursor protein (APP)-cleaving enzyme 1), a membrane protein that acts as the rate-limiting enzyme in the generation of the Alzheimer disease amyloid beta-peptide (A beta). Specifically, BACE1 is transiently acetylated on seven lysine residues in the lumen of the endoplasmic reticulum/endoplasmic reticulum-Golgi intermediate compartment (ER/ERGIC). The acetylated intermediates of the nascent protein are able to reach the Golgi apparatus, whereas the non-acetylated ones are retained and degraded in a post-ER compartment. Here, we report that the serine protease PCSK9 (proprotein convertase subtilisin kexin type 9) contributes to the disposal of non-acetylated BACE1. Both overexpression and small interfering RNA-mediated downregulation of PCSK9 affected the levels of BACE1. The downregulation of PCSK9 affected the levels of the loss-of-acetylation mutants (BACE1(Ala) and BACE1(Arg)) but not those of the gain-of-acetylation mutant (BACE1(Gln)). In addition, Pcsk9(-/-) mice showed increased levels of BACE1 and Ab in the brain. Finally, we found that nascent low-density lipoprotein receptor, a known substrate of PCSK9, is also acetylated.