mTORC1 Balances Cellular Amino Acid Supply with Demand for Protein Synthesis through Post-transcriptional Control of ATF4

• DOI: 10.1016/j.celrep.2017.04.042
• Publication Date: 2017-05-09T19:01:34Z
• Authors: Yeonwoo Park; Andrea Reyna-Neyra; Lucas Philippe; Carson C. Thoreen
• Keywords: 0303 health sciences; Amino Acid Transport Systems; QH301-705.5; RNA Stability; amino acid uptake; Eukaryotic Initiation Factor-2; Mechanistic Target of Rapamycin Complex 1; Activating Transcription Factor 4; Article; Mice; Open Reading Frames; 03 medical and health sciences; HEK293 Cells; mTOR; Animals; Humans; ATF4; RNA, Messenger; Biology (General); RNA Processing, Post-Transcriptional; 5' Untranslated Regions; mTORC1

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.