PCSK9 is required for the disposal of non-acetylated intermediates of the nascent membrane protein BACE1.

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 (Abeta). 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 Abeta in the brain. Finally, we found that nascent low-density lipoprotein receptor, a known substrate of PCSK9, is also acetylated.
Mesh Terms:
Acetylation, Amyloid Precursor Protein Secretases, Animals, Aspartic Acid Endopeptidases, Blotting, Western, CHO Cells, Cricetinae, Cricetulus, Electrophoresis, Polyacrylamide Gel, Humans, Mice, Mutation, Proprotein Convertases, RNA, Small Interfering, Serine Endopeptidases, Transfection
EMBO Rep.
Date: Sep. 01, 2008
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