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首页> 外文期刊>The Journal of biological chemistry >CutA Divalent Cation Tolerance Homolog (Escherichia coli) (CUTA) Regulates β-Cleavage of β-Amyloid Precursor Protein (APP) through Interacting with β-Site APP Cleaving Protein 1 (BACE1)
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CutA Divalent Cation Tolerance Homolog (Escherichia coli) (CUTA) Regulates β-Cleavage of β-Amyloid Precursor Protein (APP) through Interacting with β-Site APP Cleaving Protein 1 (BACE1)

机译：CUTA二价阳离子耐受同源物质（大肠杆菌）（CARA）通过与β-位点APP蛋白1（BACE1）相互作用来调节β-淀粉样蛋白前体蛋白（APP）的β-切割

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Accumulation of the neurotoxic β-amyloid (Aβ) peptide in the brain is central to the pathogenesis of Alzheimer disease. Aβ is derived from the β-amyloid precursor protein (APP) through sequential cleavages by β- and γ-secretases, and the production of Aβ is greatly affected by the subcellular localization of these factors. CUTA, the mammalian CutA divalent cation tolerance homolog (E. coli), has been proposed to mediate acetylcholinesterase activity and copper homeostasis, which are important in Alzheimer disease pathology. However, the exact function of CUTA remains largely unclear. Here we show that human CUTA has several variants that differ in their N-terminal length and are separated as heavy (H) and light (L) components. The H component has the longest N terminus and is membrane-associated, whereas the L component is N-terminally truncated at various sites and localized in the cytosol. Importantly, we demonstrate that the H component of CUTA interacts through its N terminus with the transmembrane domain of β-site APP cleaving enzyme 1 (BACE1), the putative β-secretase, mainly in the Golgi/trans-Golgi network. Overexpression and RNA interference knockdown of CUTA can reduce and increase BACE1-mediated APP processing/Aβ secretion, respectively. RNA interference of CUTA decelerates intracellular trafficking of BACE1 from the Golgi/trans-Golgi network to the cell surface and reduces the steady-state level of cell surface BACE1. Our results identify the H component of CUTA as a novel BACE1-interacting protein that mediates the intracellular trafficking of BACE1 and the processing of APP to Aβ.
机译：大脑中神经毒性β-淀粉样（Aβ）肽的积累是阿尔茨海默病的发病机制的核心。 Aβ通过β-和γ-分泌酶通过顺序切割来源于β-淀粉样蛋白前体蛋白（APP），并且通过这些因素的亚细胞定位产生αβ的产生极大的影响。已提出哺乳动物切割二价阳离子耐受同源物（大肠杆菌），以介导乙酰胆碱酯酶活性和铜稳态，这在阿尔茨海默病病理学中都很重要。然而，削减的确切功能仍然很大程度上不清楚。在这里，我们表明人类伤口有几种在其N末端长度不同的变体，并且被分离为重（H）和光（L）组分。 H组分具有​​最长的N末端，并且是膜相关的，而L组分在各个位点处是N-末端截短并局部化在细胞溶质中。重要的是，我们证明CUTA的H组分通过其N末端与β-位点APP酶1（BACE1），推定β-分泌酶的跨膜结构域相互作用，主要是在GOLGI / TRANS-GORGI网络中。切割的过表达和RNA干扰敲低分别可以分别减少和增加Bace1介导的APP处理/Aβ分泌。切割的RNA干扰使来自GOLGI / TRANS-GOLGI网络的细胞内运输到细胞表面，降低细胞表面BACE1的稳态水平。我们的结果鉴定了CARA的H组分作为一种新型的Bace1 - 相互作用蛋白，介导细胞内运输Bace1和APP的加工到Aβ。

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