Adaptor protein sorting nexin 17 regulates amyloid precursor protein trafficking and processing in the early endosomes
Adaptor protein sorting nexin 17 regulates amyloid precursor protein trafficking and processing in the early endosomes
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DOI：
10.1074/jbc.m800642200
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发表时间：
2008-04-25
影响因子：
4.8
通讯作者：
Bu, Guojun
中科院分区：
文献类型：
--
作者：
Lee, Jiyeon;Retamal, Claudio;Bu, Guojun
由β-和γ-分泌酶加工淀粉样前体蛋白（APP）产生的细胞外淀粉样β肽（A β）的积累对神经元有毒，是阿尔茨海默病发病机制的核心。APP的亚细胞定位和运输极大地影响了APP的A β的产生。在这里，我们已经确定了一种新的细胞内接头蛋白，分选连接蛋白17（SNX 17），它通过YXNPXY基序特异性地结合APP的胞质结构域，以前已被证明可以结合几种细胞表面接头，包括Fe 65和X11。SNX 17的显性负突变体的过表达和内源性SNX 17表达的RNA干扰敲低都降低了APP的稳态水平，同时增加了A β的产生。SNX 17的RNA干扰敲除也降低了APP的半衰期，这导致APP的稳态水平降低。免疫荧光染色证实了SNX 17和APP在早期内体中的共定位。我们还发现，细胞表面的衔接蛋白，Dab 2，结合到相同的YXNPXY基序和调节APP内吞在细胞表面。因此，我们的研究结果提供了强有力的证据表明，细胞表面和细胞内的衔接蛋白调节APP内吞运输和加工A β。SNX 17作为一种在神经元中高度表达的新型APP细胞内衔接蛋白的鉴定应有助于理解APP细胞内运输和加工成A β之间的关系。
Accumulation of extracellular amyloid beta peptide (A beta), 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 A beta 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 A beta 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 A beta. 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 A beta.