Molecular Cellular and Developmental Biology Graduate Program, Division of Pulmonary, The Ohio State University, Columbus, OH 43210, USA.
Proc Natl Acad Sci U S A. 2013 Jun 11;110(24):E2153-62. doi: 10.1073/pnas.1303726110. Epub 2013 May 22.
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.
类黄酮是膳食植物化学成分中最大的一类，为我们的饮食增添了重要的健康价值，并且正在成为关键的营养保健品。膳食植物化学成分的细胞靶标在很大程度上仍然未知，这给膳食补充剂的监管和理解营养保健品如何提供健康价值带来了重大挑战。在这里，我们使用一种创新的高通量方法，结合噬菌体展示和第二代测序，描述了芹菜素（一种在水果和蔬菜中大量存在的类黄酮）的人类细胞靶标的鉴定。鉴定出的 160 个高可信度的芹菜素候选靶标在三个主要功能类别中显著富集：GTP 酶激活、膜转运和 mRNA 代谢/可变剪接。后一类包括异质核核糖核蛋白 A2（hnRNPA2），这是一种参与剪接调控、mRNA 稳定性和 mRNA 转运的因子。芹菜素与 hnRNPA2 的 C 端富含甘氨酸的结构域结合，阻止 hnRNPA2 形成同源二聚体，从而扰乱了几个人类 hnRNPA2 靶标的可变剪接。我们的结果为理解膳食植物化学成分如何通过与许多功能多样的细胞靶标结合来发挥作用提供了一个框架。反过来，其中一些可能会调节大量下游基因的活性，这里以芹菜素对 hnRNPA2 的可变剪接活性的影响为例。因此，与针对特定靶标设计的小分子药物不同，膳食植物化学成分以不同亲和力影响大量的细胞靶标，这些靶标结合在一起，产生了它们公认的健康益处。
