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J. Biol. Chem., Vol. 276, Issue 18, 14634-14641, May 4, 2001

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Phosphorylation Regulates Intracellular Trafficking of -Secretase^*

Jochen Walter^§, Regina Fluhrer, Bianka Hartung, Michael Willem, Christoph Kaether, Anja Capell, Sven Lammich, Gerd Multhaup^¶, and Christian Haass

From the  Adolf Butenandt-Institute, Department of Biochemistry, Laboratory for Alzheimer's and Parkinson's Disease Research, Ludwig-Maximilians-University, 44 Schillerstrasse, 80336 Munich, Germany and ^¶ Center for Molecular Biology Heidelberg, Im Neuenheimer Feld 282, 69120 Heidelberg, Germany

-Secretase (BACE) is a transmembrane aspartyl protease, which generates the N terminus of Alzheimer's disease amyloid -peptide. Here, we report that BACE can be phosphorylated within its cytoplasmic domain at serine residue 498 by casein kinase 1. Phosphorylation exclusively occurs after full maturation of BACE by propeptide cleavage and complex N-glycosylation. Phosphorylation/dephosphorylation affects the subcellular localization of BACE. 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-positive endosomes. Antibody uptake assays revealed that reinternalization of BACE from the cell surface is independent of its phosphorylation state. After reinternalization, BACE wild type as well as BACE S498D are efficiently retrieved from early endosomal compartments and further targeted to later endosomal compartments and/or the trans-Golgi network. In contrast, nonphosphorylatable BACE S498A is retained within early endosomes. Our results therefore demonstrate regulated trafficking of BACE within the secretory and endocytic pathway.

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