Adaptor protein sorting nexin 17 regulates amyloid precursor protein trafficking and processing in the early endosomes

LEE, JY; Retamal, C; Cuitino, L; Caruano-Yzermans, A; Shin, JE; Van Kerkhof, P; Marzolo, MP; Bu, GJ

Abstract

Accumulation of extracellular amyloid β peptide (Aβ), generated from amyloid precursor protein (APP) processing by β- and γ-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 steadystate 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. © 2008 by The American Society for Biochemistry and Molecular Biology, Inc.

Más información

Título según WOS: Adaptor protein sorting nexin 17 regulates amyloid precursor protein trafficking and processing in the early endosomes
Título según SCOPUS: Adaptor protein sorting nexin 17 regulates amyloid precursor protein trafficking and processing in the early endosomes
Título de la Revista: JOURNAL OF BIOLOGICAL CHEMISTRY
Volumen: 283
Número: 17
Editorial: AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
Fecha de publicación: 2008
Página de inicio: 11501
Página final: 11508
Idioma: English
URL: http://www.jbc.org/cgi/doi/10.1074/jbc.M800642200
DOI:

10.1074/jbc.M800642200

Notas: ISI, SCOPUS