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

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.

Keywords: ATF4; amino acid uptake; mTOR; mTORC1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5' Untranslated Regions
  • Activating Transcription Factor 4 / genetics
  • Activating Transcription Factor 4 / metabolism*
  • Amino Acid Transport Systems / metabolism*
  • Animals
  • Eukaryotic Initiation Factor-2 / metabolism
  • HEK293 Cells
  • Humans
  • Mechanistic Target of Rapamycin Complex 1 / metabolism*
  • Mice
  • Open Reading Frames
  • RNA Processing, Post-Transcriptional*
  • RNA Stability
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism


  • 5' Untranslated Regions
  • ATF4 protein, human
  • Amino Acid Transport Systems
  • Eukaryotic Initiation Factor-2
  • RNA, Messenger
  • Activating Transcription Factor 4
  • Mechanistic Target of Rapamycin Complex 1