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J. Biol. Chem., Vol. 283, Issue 17, 11501-11508, April 25, 2008

This Article Full Text Full Text (PDF) All Versions of this Article: 283/17/11501    most recent M800642200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Lee, J. Articles by Bu, G. PubMed PubMed Citation Articles by Lee, J. Articles by Bu, G. Social Bookmarking                      What's this?

Adaptor Protein Sorting Nexin 17 Regulates Amyloid Precursor Protein Trafficking and Processing in the Early Endosomes^*

Jiyeon Lee¹, Claudio Retamal, Loreto Cuitiño, Amy Caruano-Yzermans², Jung-Eun Shin, Peter van Kerkhof^¶, Maria-Paz Marzolo, and Guojun Bu³

From the Departments of Pediatrics and Cell Biology and Physiology, Washington University School of Medicine, St. Louis, Missouri 63110, the Centro de Regulación Celular y Patología "Joaquín V. Luco," Departamento de Biología Celular y Molecular, Millennium Institute For Fundamental and Applied Biology, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 340, Chile, and the ^¶Department of Cell Biology and Institute of Biomembranes, University Medical Center, Utrecht 3584 CX, The Netherlands

Accumulation of extracellular amyloid β peptide (Aβ), generated from amyloid precursor protein (APP) processing by β- and -secretases, is toxic to neurons and is central to the pathogenesis of Alzheimer disease. Production of Aβ from APP is greatly affected by the subcellular localization and trafficking of APP. Here we have identified a novel intracellular adaptor protein, sorting nexin 17 (SNX17), that binds specifically to the APP cytoplasmic domain via the YXNPXY motif that has been shown previously to bind several cell surface adaptors, including Fe65 and X11. Overexpression of a dominant-negative mutant of SNX17 and RNA interference knockdown of endogenous SNX17 expression both reduced steady-state levels of APP with a concomitant increase in Aβ production. RNA interference knockdown of SNX17 also decreased APP half-life, which led to the decreased steady-state levels of APP. Immunofluorescence staining confirmed a colocalization of SNX17 and APP in the early endosomes. We also showed that a cell surface adaptor protein, Dab2, binds to the same YXNPXY motif and regulates APP endocytosis at the cell surface. Our results thus provide strong evidence that both cell surface and intracellular adaptor proteins regulate APP endocytic trafficking and processing to Aβ. The identification of SNX17 as a novel APP intracellular adaptor protein highly expressed in neurons should facilitate the understanding of the relationship between APP intracellular trafficking and processing to Aβ.

Received for publication, January 24, 2008 , and in revised form, February 13, 2008.

^* This work was supported in part by NIA Grant R01 AG027924 from the National Institutes of Health, a grant from the Alzheimer's Association, and a grant from the American Health Assistant Foundation (to G. B.). This work was also supported by Fogarty International Research Collaboration Award Grant TW006456 (to G. B. and M.-P. M.), Fondo de Investigación Avanzada en Areas Prioritarias Grant 13980001, and a grant from the Millenniums Institute for Fundamental and Applied Biology (to M.-P. M.). 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 Partially supported by a predoctoral fellowship from the American Heart Association.

² Present address: Divergence Inc., 893 North Warson Rd., St. Louis, MO 63141.

³ To whom correspondence should be addressed: Dept. of Pediatrics, WA University School of Medicine, Campus Box 8208, 660 South Euclid Ave., St. Louis, MO 63110. E-mail: bu{at}wustl.edu.

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