Park Yeonwoo, Reyna-Neyra Andrea, Philippe Lucas, Thoreen Carson C
Department of Cellular and Molecular Physiology, Yale University School of Medicine, 333 Cedar St., New Haven, CT 06510, USA.
Department of Cellular and Molecular Physiology, Yale University School of Medicine, 333 Cedar St., New Haven, CT 06510, USA.
Cell Rep. 2017 May 9;19(6):1083-1090. doi: 10.1016/j.celrep.2017.04.042.
The mammalian target of rapamycin complex 1 (mTORC1) is a master regulator of cell growth that is commonly deregulated in human diseases. Here we find that mTORC1 controls a transcriptional program encoding amino acid transporters and metabolic enzymes through a mechanism also used to regulate protein synthesis. Bioinformatic analysis of mTORC1-responsive mRNAs identified a promoter element recognized by activating transcription factor 4 (ATF4), a key effector of the integrated stress response. ATF4 translation is normally induced by the phosphorylation of eukaryotic initiation factor 2 alpha (eIF2α) through a mechanism that requires upstream open reading frames (uORFs) in the ATF4 5' UTR. mTORC1 also controls ATF4 translation through uORFs, but independently of changes in eIF2α phosphorylation. mTORC1 instead employs the 4E-binding protein (4E-BP) family of translation repressors. These results link mTORC1-regulated demand for protein synthesis with an ATF4-regulated transcriptional program that controls the supply of amino acids to the translation machinery.
雷帕霉素靶蛋白复合体1（mTORC1）是细胞生长的主要调节因子，在人类疾病中常常失调。我们发现，mTORC1通过一种也用于调节蛋白质合成的机制，控制着一个编码氨基酸转运体和代谢酶的转录程序。对mTORC1反应性mRNA的生物信息学分析确定了一个由激活转录因子4（ATF4）识别的启动子元件，ATF4是整合应激反应的关键效应因子。ATF4的翻译通常通过真核起始因子2α（eIF2α）的磷酸化诱导，该机制需要ATF4 5'非翻译区中的上游开放阅读框（uORF）。mTORC1也通过uORF控制ATF4的翻译，但独立于eIF2α磷酸化的变化。相反，mTORC1利用翻译抑制因子4E结合蛋白（4E-BP）家族。这些结果将mTORC1调节的蛋白质合成需求与ATF4调节的转录程序联系起来，该转录程序控制着向翻译机器供应氨基酸。
