Adaptor protein sorting nexin 17 regulates amyloid precursor protein trafficking and processing in the early endosomes.
Accumulation of extracellular amyloid beta peptide (Abeta), generated from amyloid precursor protein (APP) processing by beta- and gamma-secretases, is toxic to neurons and is central to the pathogenesis of Alzheimer disease. Production of Abeta 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 Abeta 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 Abeta. 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 Abeta.
Lee
Jiyeon
J
Department of Pediatrics and Cell Biology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Retamal
Claudio
C
Cuitiño
Loreto
L
Caruano-Yzermans
Amy
A
Shin
Jung-Eun
JE
van Kerkhof
Peter
P
Marzolo
Maria-Paz
MP
Bu
Guojun
G
D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D058305:Sorting Nexins; D033921:Vesicular Transport Proteins / Q000378:metabolism / Q000502:physiology*
D016229:Amyloid beta-Peptides; C465498:Snx17 protein, mouse; D058305:Sorting Nexins; D033921:Vesicular Transport Proteins