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

Jiyeon Lee, Claudio Retamal, Loreto Cuitiño, Amy Caruano-Yzermans, Jung Eun Shin, Peter Van Kerkhof, Maria Paz Marzolo, Guojun Bu

Research output: Contribution to journalArticle

112 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)11501-11508
Number of pages8
JournalJournal of Biological Chemistry
Volume283
Issue number17
DOIs
StatePublished - Apr 25 2008

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Lee, J., Retamal, C., Cuitiño, L., Caruano-Yzermans, A., Shin, J. E., Van Kerkhof, P., Marzolo, M. P., & Bu, G. (2008). Adaptor protein sorting nexin 17 regulates amyloid precursor protein trafficking and processing in the early endosomes. Journal of Biological Chemistry, 283(17), 11501-11508. https://doi.org/10.1074/jbc.M800642200