BACE1 Retrograde Trafficking Is Uniquely Regulated by the Cytoplasmic Domain of Sortilin
BACE1 Retrograde Trafficking Is Uniquely Regulated by the Cytoplasmic Domain of Sortilin
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DOI：
10.1074/jbc.m110.170217
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发表时间：
2011-04-08
影响因子：
4.8
通讯作者：
Kim, Tae-Wan
中科院分区：
文献类型：
--
作者：
Finan, Gina M.;Okada, Hirokazu;Kim, Tae-Wan
BACE1(β-Siteβ-淀粉样前体蛋白(APP)裂解酶1)介导APP的第一次蛋白水解性裂解，导致淀粉样β多肽(Aβ)的产生。据报道，BACE1的细胞内转运，特别是内小体到TGN的分离，是由接头复合体介导的，例如逆转聚体和高尔基体定位的含有伽玛耳的ARF结合蛋白(GGAs)。在这里，我们调查了索迪林，一个Vps10p结构域分类受体，据信参与逆转录介导的选择膜货物的运输，是否有助于BACE1的亚细胞运输和活性。我们的初步研究显示，AD患者死后脑组织中的山梨素水平增加，并且山梨素的过度表达导致培养细胞中BACE1介导的APP裂解增加。相反，抑制山梨素的RNAi导致BACE1介导的APP切割减少。我们还发现，山梨素与BACE1相互作用，并且没有细胞质结构域的山梨素结构仍然与BACE1结合，该结构含有可能的逆转录分选基序。然而，这种截短的山梨素的表达将BACE1从跨高尔基网络重新分配到内体，并显著减少了BACE1的逆行运输。定点突变和嵌合体实验表明，山梨素的细胞质尾部在BACE1的转运中起着独特的作用，而不是其他VPS10p结构域受体(如SorCs1b和Sorla)的细胞质尾部。我们的研究表明，山梨素作为BACE1逆行运输和随后产生的Aβ的调节剂具有新的功能。
BACE1 (beta-site beta-amyloid precursor protein (APP)-cleaving enzyme 1) mediates the first proteolytic cleavage of APP, leading to amyloid beta-peptide (A beta) production. It has been reported that BACE1 intracellular trafficking, in particular endosome-to-TGN sorting, is mediated by adaptor complexes, such as retromer and Golgi-localized gamma-ear-containing ARF-binding proteins (GGAs). Here we investigated whether sortilin, a Vps10p domain-sorting receptor believed to participate in retromer- mediated transport of select membrane cargoes, contributes to the subcellular trafficking and activity of BACE1. Our initial studies revealed increased levels of sortilin in post-mortem brain tissue of AD patients and that overexpression of sortilin leads to increased BACE1-mediated cleavage of APP in cultured cells. In contrast, RNAi suppression of sortilin results in decreased BACE1-mediated cleavage of APP. We also found that sortilin interacts with BACE1 and that a sortilin construct lacking its cytoplasmic domain, which contains putative retromer sorting motifs, remains bound to BACE1. However, expression of this truncated sortilin redistributes BACE1 from the trans-Golgi network to the endosomes and substantially reduces the retrograde trafficking of BACE1. Site-directed mutagenesis and chimera experiments reveal that the cytoplasmic tail of sortilin, but not those from other VPS10p domain receptors (e. g. SorCs1b and SorLA), plays a unique role in BACE1 trafficking. Our studies suggest a new function for sortilin as a modulator of BACE1 retrograde trafficking and subsequent generation of A beta.