| First Author | Jonas MC | Year | 2008 |
| Journal | EMBO Rep | Volume | 9 |
| Issue | 9 | Pages | 916-22 |
| PubMed ID | 18660751 | Mgi Jnum | J:138995 |
| Mgi Id | MGI:3807090 | Doi | 10.1038/embor.2008.132 |
| Citation | Jonas MC, et al. (2008) PCSK9 is required for the disposal of non-acetylated intermediates of the nascent membrane protein BACE1. EMBO Rep 9(9):916-22 |
| abstractText | 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. |
