Phosphorylation regulates intracellular trafficking of beta-secretase

beta -Secretase (BACE) is a transmembrane aspartyl protease, which generate s the N terminus of Alzheimer's disease amyloid beta -peptide, Here, we rep ort that BACE can be phosphorylated within its cytoplasmic domain at serine residue 498 by casein kinase 1. Phosphorylation exclusively occurs after f ull maturation of BACE by propeptide cleavage and complex N-glycosylation, Phosphorylation/dephosphorylation affects the subcellular localization of B ACE, BACE wild type and an S498D mutant that mimics phosphorylated BACE are predominantly located within juxtanuclear Golgi compartments and endosomes , whereas nonphosphorylatable BACE S498A accumulates in peripheral EEA1-pos itive endosomes, Antibody uptake assays revealed that reinternalization of BACE from the cell surface is independent of its phosphorylation state. Aft er reinternalization, BACE wild type as well as BACE S498D are efficiently retrieved from early endosomal compartments and further targeted to later e ndosomal compartments and/or the trans-Golgi network. In contrast, nonphosp horylatable BACE S498A is retained within early endosomes. Our results ther efore demonstrate regulated trafficking of BACE within the secretory and en docytic pathway.