Two endoplasmic reticulum (ER)/ER Golgi intermediate compartment-based lysine acetyltransferases post-translationally regulate BACE1 levels.
We have recently identified a novel form of post-translational regulation of BACE1 (beta-site amyloid precursor protein-cleaving enzyme 1), a membrane protein that acts as the rate-limiting enzyme in the generation of the Alzheimer disease amyloid beta-peptide. Specifically, nascent BACE1 is transiently acetylated in seven lysine residues clustered in a highly disordered region of the protein that faces the lumen of the endoplasmic reticulum (ER)/ER Golgi intermediate compartment (ER/ERGIC). The acetylation protects the nascent protein from degradation by PCSK9/NARC-1 in the ERGIC and allows it to reach the Golgi apparatus. Here we report the identification of two ER/ERGIC-based acetyltransferases, ATase1 and ATase2. Both proteins display acetyl-CoA:lysine acetyltransferase activity, can interact with and acetylate BACE1, and display an ER/ERGIC localization with the catalytic site facing the lumen of the organelle. Both ATase1 and ATase2 regulate the steady-state levels of BACE1 and the rate of amyloid beta-peptide generation. Finally, their transcripts are up-regulated by ceramide treatment. In conclusion, our studies have identified two new enzymes that may be involved in the pathogenesis of late-onset Alzheimer disease. The biochemical characterization of the above events could lead to the identification of novel pharmacological strategies for the prevention of this form of dementia.
Ko
Mi Hee
MH
Department of Medicine, University of Wisconsin-Madison and Geriatric Research Education Clinical Center, Veterans Affairs Medical Center, Madison, Wisconsin 53705, USA.
Puglielli
Luigi
L
D000123:Acetyltransferases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D055162:Biocatalysis; D045744:Cell Line, Tumor; D002518:Ceramides / Q000378:metabolism; D015536:Down-Regulation; D004721:Endoplasmic Reticulum / Q000201:enzymology*; D006056:Golgi Apparatus / Q000201:enzymology*; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D011499:Protein Processing, Post-Translational
D016229:Amyloid beta-Peptides; D002518:Ceramides; D007527:Isoenzymes; D000123:Acetyltransferases; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D008239:Lysine