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J. Biol. Chem., Vol. 283, Issue 21, 14257-14268, May 23, 2008

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A Novel Sorting Nexin Modulates Endocytic Trafficking and -Secretase Cleavage of the Amyloid Precursor Protein^*

Susanne Schöbel¹, Stephanie Neumann¹, Maren Hertweck, Bastian Dislich, Peer-Hendrik Kuhn, Elisabeth Kremmer^¶, Brian Seed^||, Ralf Baumeister^**, Christian Haass, and Stefan F. Lichtenthaler²

From the Center for Integrated Protein Science and the Adolf-Butenandt-Institut, Ludwig Maximilians University, Schillerstrasse 44, 80336 Munich, Germany, Center for Biochemistry and Molecular Cell Research (ZBMZ, Faculty of Medicine), Bioinformatics and Molecular Genetics (Faculty of Biology), Institute of Biology 3, and ^**Center for Systems Biology (ZBSA), University of Freiburg, Schaenzlestrasse 1, 79104 Freiburg, Germany, ^¶Helmholtz Center Munich, Institute of Molecular Immunology, Marchioninistrasse 25, 81377 Munich, Germany, and the Department of Molecular Biology, ^||Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts 02114

Ectodomain shedding of the amyloid precursor protein (APP) by the two proteases - and β-secretase is a key regulatory event in the generation of the Alzheimer disease amyloid β peptide (Aβ). β-Secretase catalyzes the first step in Aβ generation, whereas -secretase cleaves within the Aβ domain, prevents Aβ generation, and generates a secreted form of APP with neuroprotective properties. At present, little is known about the cellular mechanisms that control APP -secretase cleavage and Aβ generation. To explore the contributory pathways, we carried out an expression cloning screen. We identified a novel member of the sorting nexin (SNX) family of endosomal trafficking proteins, called SNX33, as a new activator of APP -secretase cleavage. SNX33 is a homolog of SNX9 and was found to be a ubiquitously expressed phosphoprotein. Exogenous expression of SNX33 in cultured cells increased APP -secretase cleavage 4-fold but surprisingly had little effect on β-secretase cleavage. This effect was similar to the expression of the dominant negative dynamin-1 mutant K44A. SNX33 bound the endocytic GTPase dynamin and reduced the rate of APP endocytosis in a dynamin-dependent manner. This led to an increase of APP at the plasma membrane, where -secretase cleavage mostly occurs. In summary, our study identifies SNX33 as a new endocytic protein, which modulates APP endocytosis and APP -secretase cleavage, and demonstrates that the rate of APP endocytosis is a major control factor for APP -secretase cleavage.

Received for publication, February 25, 2008

^* This work was supported by a fellowship from the Boehringer Ingelheim Foundation (to S. N.); Deutsche Forschungsgemeinschaft SFB596 Project B12 (to S. F. L.), Project A9 (to C. H.), and Project Z2 (to E. K.); the European Commission for NeuroNE (to C. H.); and the Fonds der Chemischen Industrie (to S. F. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed. Tel.: 49-89-218075453; Fax: 49-89-218075415; E-mail: Stefan.Lichtenthaler{at}med.uni-muenchen.de.

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