Molecular basis for the action of a dietary flavonoid revealed by the comprehensive identification of apigenin human targets
Molecular basis for the action of a dietary flavonoid revealed by the comprehensive identification of apigenin human targets
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DOI：
10.1073/pnas.1303726110
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发表时间：
2013-06-11
影响因子：
11.1
通讯作者：
Doseff, Andrea I.
中科院分区：
文献类型：
--
作者：
Arango, Daniel;Morohashi, Kengo;Doseff, Andrea I.
类黄酮是饮食中最大的一类植物化学物质，为我们的饮食增加了基本的健康价值，并正在成为关键的营养食品。膳食植物化学物质的细胞靶标在很大程度上仍不清楚，这对膳食补充剂的监管和对营养食品如何提供健康价值的理解构成了重大挑战。在这里，我们描述了利用一种结合噬菌体展示和第二代测序的创新的高通量方法来鉴定芹菜素的人类细胞靶标。芹菜素是一种丰富存在于水果和蔬菜中的黄酮类化合物。已确定的160个高可信候选芹菜素靶标在三个主要功能类别中显著丰富：GTP酶激活、膜转运和mRNA代谢/选择性剪接。最后一类包括异质性核糖核蛋白A2(HnRNPA2)，它是一种参与剪接调节、mRNA稳定性和mRNA运输的因子。芹菜素与hnRNPA2的C-末端富含甘氨酸的结构域结合，阻止hnRNPA2形成同源二聚体，因此，它干扰了几个人类hnRNPA2靶标的选择性剪接。我们的结果为理解膳食植物化学物质如何通过与许多功能不同的细胞靶点结合而发挥作用提供了一个框架。反过来，它们中的一些可能调节大量下游基因的活性，这里的例子是芹菜素对hnRNPA2选择性剪接活性的影响。因此，与为特定靶点而设计的小分子药物不同，膳食植物化学物质影响大量具有不同亲和力的细胞靶点，它们结合在一起，导致它们公认的健康益处。
Flavonoids constitute the largest class of dietary phytochemicals, adding essential health value to our diet, and are emerging as key nutraceuticals. Cellular targets for dietary phytochemicals remain largely unknown, posing significant challenges for the regulation of dietary supplements and the understanding of how nutraceuticals provide health value. Here, we describe the identification of human cellular targets of apigenin, a flavonoid abundantly present in fruits and vegetables, using an innovative high-throughput approach that combines phage display with second generation sequencing. The 160 identified high-confidence candidate apigenin targets are significantly enriched in three main functional categories: GTPase activation, membrane transport, and mRNA metabolism/alternative splicing. This last category includes the heterogeneous nuclear ribonucleoprotein A2 (hnRNPA2), a factor involved in splicing regulation, mRNA stability, and mRNA transport. Apigenin binds to the C-terminal glycine-rich domain of hnRNPA2, preventing hnRNPA2 from forming homodimers, and therefore, it perturbs the alternative splicing of several human hnRNPA2 targets. Our results provide a framework to understand how dietary phytochemicals exert their actions by binding to many functionally diverse cellular targets. In turn, some of them may modulate the activity of a large number of downstream genes, which is exemplified here by the effects of apigenin on the alternative splicing activity of hnRNPA2. Hence, in contrast to small-molecule pharmaceuticals designed for defined target specificity, dietary phytochemicals affect a large number of cellular targets with varied affinities that, combined, result in their recognized health benefits.