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

Abstract

We have recently identified a new form of post-translational regulation of BACE1 (b-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 b-peptide (Ab). 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 À/À 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. Keywords: BACE1; PCSK9; lysine acetylation; Alzheimer disease EMBO reports (2008) 9, 916-922.

Pcsk9

“…PCSK9 was reported to contribute to the disposal of nonacetylated BACE1. 73 This interesting observation still requires in vivo validation. (2) In the second example, within the ER/ER-Golgi intermediate compartment of cells, PCSK9 was reported to enhance the degradation of the epithelial Na + channel (ENaC) that is critical for Na + homeostasis and blood pressure control.…”

Alzheimer Disease Aβ Production in the Absence of S-Palmitoylation-dependent Targeting of BACE1 to Lipid Rafts

“…For example, reversible acetylation in the luminal domain of BACE1 regulates its stability as well as exit from the ER (20,57). Moreover, phosphorylation regulates the fate of BACE1 endocytosed from the cell surface; whereas phosphorylated BACE1 is transported from the endosomes to the TGN, non-phosphorylated BACE1 is directly recycled to the cell surface (18,29).…”

PCSK9 is not involved in the degradation of LDL receptors and BACE1 in the adult mouse brain

“…It has also been recently shown that overexpression of PCSK9 in cells decreased cellular levels of the ␤ -site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1), a membrane protease responsible for the production of toxic ␤ -amyloid peptides (A ␤ ) that accumulate in neuritic plaques of AD brains ( 27,28 ). In the present study, we investigated whether PCSK9 participates in the regulation of the steady-state levels of LDLR, VLDLR, and ApoER2, as well as BACE1 in the adult mouse brain.…”