A reversible form of lysine acetylation in the ER and Golgi lumen controls the molecular stabilization of BACE1.
The lipid second messenger ceramide regulates the rate of beta cleavage of the Alzheimer's disease APP (amyloid precursor protein) by affecting the molecular stability of the beta secretase BACE1 (beta-site APP cleaving enzyme 1). Such an event is stimulated in the brain by the normal process of aging, and is under the control of the general aging programme mediated by the insulin-like growth factor 1 receptor. In the present study we report that BACE1 is acetylated on seven lysine residues of the N-terminal portion of the nascent protein. This process involves lysine acetylation in the lumen of the ER (endoplasmic reticulum) and is followed by deacetylation in the lumen of the Golgi apparatus, once the protein is fully mature. We also show that specific enzymatic activities acetylate (in the ER) and deacetylate (in the Golgi apparatus) the lysine residues. This process requires carrier-mediated translocation of acetyl-CoA into the ER lumen and is stimulated by ceramide. Site-directed mutagenesis indicates that lysine acetylation is necessary for nascent BACE1 to leave the ER and move ahead in the secretory pathway, and for the molecular stabilization of the protein.
Costantini
Claudio
C
Department of Medicine, University of Madison-Wisconsin, Madison, WI 53705, USA.
Ko
Mi Hee
MH
Jonas
Mary Cabell
MC
Puglielli
Luigi
L
D000107:Acetylation; D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004721:Endoplasmic Reticulum / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D004795:Enzyme Stability / Q000235:genetics; D006056:Golgi Apparatus / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D021381:Protein Transport / Q000235:genetics
D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D008239:Lysine