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.
Jonas
Mary Cabell
MC
Department of Medicine, University of Wisconsin-Madison, VAH-GRECC 11G, 2500 Overlook Terrace, Madison, Wisconsin 53705, USA.
Costantini
Claudio
C
Puglielli
Luigi
L
D000107:Acetylation; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D051379:Mice; D009154:Mutation; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D034741:RNA, Small Interfering / Q000235:genetics; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D034741:RNA, Small Interfering; D053829:Amyloid Precursor Protein Secretases; C472125:PCSK9 protein, human; C472126:Pcsk9 protein, mouse; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse