An oxygen-regulated switch in the protein synthesis machinery.
An oxygen-regulated switch in the protein synthesis machinery.
复制标题
DOI：
10.1038/nature11055
复制
发表时间：
2012-05-06
期刊：
影响因子：
64.8
通讯作者：
Lee S
中科院分区：
文献类型：
--
作者：
Uniacke J;Holterman CE;Lachance G;Franovic A;Jacob MD;Fabian MR;Payette J;Holcik M;Pause A;Lee S
蛋白质合成涉及将核糖核酸信息转化为蛋白质（生命的组成部分）。蛋白质合成的第一步包括真核翻译起始因子 4E (eIF4E) 与 mRNA 的 7-甲基鸟苷 (m7-GpppG) 5' 帽结合。低氧张力（缺氧）通过哺乳动物雷帕霉素靶点 (mTOR) 依赖性机制隔离 eIF4E，从而抑制帽介导的翻译。虽然内部核糖体进入位点是另一种翻译起始机制，但仅此途径不能解释缺氧细胞的翻译能力。这就提出了生物学中的一个基本问题：在缺氧和 eIF4E 抑制期间蛋白质是如何合成的。在这里，我们发现了一种氧调节翻译起始复合物，可介导选择性帽子依赖性蛋白质合成。缺氧会刺激复合物的形成，其中包括氧调节缺氧诱导因子 2α (HIF-2α)、RNA 结合蛋白 RBM4 和帽结合 eIF4E2（一种 eIF4E 同源物）。 PAR-CLIP 分析发现了一种 RNA 缺氧反应元件 (rHRE)，该元件将这种复合物招募到多种 mRNA 中，包括表皮生长因子受体 (EGFR)。一旦在 rHRE 上组装，HIF-2α/RBM4/eIF4E2 就会捕获 5'cap 并将 mRNA 靶向多核糖体进行主动翻译，从而避免缺氧诱导的蛋白质合成抑制。这些发现表明，细胞已经进化出一种程序，通过氧张力可以切换基本的翻译起始机制。
Protein synthesis involves the translation of ribonucleic acid information into proteins, the building blocks of life. The initial step of protein synthesis consists of the eukaryotic translation initiation factor 4E (eIF4E) binding to the 7-methylguanosine (m7-GpppG) 5′cap of mRNAs. Low oxygen tension (hypoxia) represses cap-mediated translation by sequestering eIF4E through mammalian target of rapamycin (mTOR)-dependent mechanisms. While the internal ribosome entry site is an alternative translation initiation mechanism, this pathway alone cannot account for the translational capacity of hypoxic cells. This raises a fundamental question in biology as to how proteins are synthesized in periods of oxygen scarcity and eIF4E inhibition. Here, we uncover an oxygen-regulated translation initiation complex that mediates selective cap-dependent protein synthesis. Hypoxia stimulates the formation of a complex that includes the oxygen-regulated hypoxia-inducible factor 2α (HIF-2α), the RNA binding protein RBM4 and the cap-binding eIF4E2, an eIF4E homologue. PAR-CLIP analysis identified an RNA hypoxia response element (rHRE) that recruits this complex to a wide array mRNAs, including the epidermal growth factor receptor (EGFR). Once assembled at the rHRE, HIF-2α/RBM4/eIF4E2 captures the 5′cap and targets mRNAs to polysomes for active translation thereby evading hypoxia-induced repression of protein synthesis. These findings demonstrate that cells have evolved a program whereby oxygen tension switches the basic translation initiation machinery.