1. Cancer Biology
  2. Cell Biology

The mTORC1-mediated activation of ATF4 promotes protein and glutathione synthesis downstream of growth signals

  1. Margaret E Torrence
  2. Michael R MacArthur
  3. Aaron M Hosios
  4. Alexander J Valvezan
  5. John M Asara
  6. James R Mitchell
  7. Brendan D Manning  Is a corresponding author
  1. Harvard T H Chan School of Public Health, United States
  2. Rutgers Robert Wood Johnson Medical School, United States
  3. Beth Israel Deaconess Medical Center, United States
  4. Swiss Federal Institute of Technology (ETH) Zurich, United States
https://doi.org/10.7554/eLife.63326
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  1. Margaret E Torrence
  2. Michael R MacArthur
  3. Aaron M Hosios
  4. Alexander J Valvezan
  5. John M Asara
  6. James R Mitchell
  7. Brendan D Manning
(2021)
The mTORC1-mediated activation of ATF4 promotes protein and glutathione synthesis downstream of growth signals
eLife 10:e63326.
https://doi.org/10.7554/eLife.63326
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Abstract

The mechanistic target of rapamycin complex 1 (mTORC1) stimulates a coordinated anabolic program in response to growth-promoting signals. Paradoxically, recent studies indicate that mTORC1 can activate the transcription factor ATF4 through mechanisms distinct from its canonical induction by the integrated stress response (ISR). However, its broader roles as a downstream target of mTORC1 are unknown. Therefore, we directly compared ATF4-dependent transcriptional changes induced upon insulin-stimulated mTORC1 signaling to those activated by the ISR. In multiple mouse embryo fibroblast (MEF) and human cancer cell lines, the mTORC1-ATF4 pathway stimulated expression of only a subset of the ATF4 target genes induced by the ISR, including genes involved in amino acid uptake, synthesis, and tRNA charging. We demonstrate that ATF4 is a metabolic effector of mTORC1 involved in both its established role in promoting protein synthesis and in a previously unappreciated function for mTORC1 in stimulating cellular cystine uptake and glutathione synthesis.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files. Source data files have been provided as supplemental tables for Figures 1, 2, and 3. RNA-Seq data have been deposited in GEO under accession code GSE158605.

The following data sets were generated

Article and author information

Author details

  1. Margaret E Torrence

    Department of Molecular Metabolism, Harvard T H Chan School of Public Health, Boston, United States
    Competing interests
    No competing interests declared.

  2. Michael R MacArthur

    Department of Molecular Metabolism, Harvard T H Chan School of Public Health, Boston, United States
    Competing interests
    No competing interests declared.

  3. Aaron M Hosios

    Department of Molecular Metabolism, Harvard T H Chan School of Public Health, Boston, United States
    Competing interests
    No competing interests declared.

  4. Alexander J Valvezan

    Center for Advanced Biotechnology and Medicine, Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ, United States
    Competing interests
    No competing interests declared.

  5. John M Asara

    Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, United States
    Competing interests
    No competing interests declared.

  6. James R Mitchell

    Department of Health Sciences and Technology, Swiss Federal Institute of Technology (ETH) Zurich, Schwerzenbach, United States
    Competing interests
    No competing interests declared.

  7. Brendan D Manning

    Department of Molecular Metabolism, Harvard T H Chan School of Public Health, Boston, United States
    For correspondence
    bmanning@hsph.harvard.edu
    Competing interests
    Brendan D Manning, Brendan Manning is a scientific advisory board member and stockholder of Navitor Pharmaceuticals and LAM Therapeutics..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3895-5956

Funding

National Institutes of Health (R35-CA197459)

  • Brendan D Manning

National Institutes of Health (P01-CA120964)

  • Brendan D Manning

U.S. Department of Defense (W81XWH-18-1- 0659)

  • Brendan D Manning

National Institutes of Health (T32-ES016645)

  • Margaret E Torrence

National Institutes of Health (F31-CA228332)

  • Margaret E Torrence

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Roger J Davis, University of Massachusetts Medical School, United States

Ethics

Animal experimentation: All animal procedures were conducted under strict adherence to recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health and were approved by the Harvard Institutional Animal Care and Use Committee (#IS00000780).

Version history

  1. Received: September 22, 2020
  2. Accepted: February 26, 2021
  3. Accepted Manuscript published: March 1, 2021 (version 1)
  4. Version of Record published: March 26, 2021 (version 2)

Copyright

© 2021, Torrence et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Margaret E Torrence
  2. Michael R MacArthur
  3. Aaron M Hosios
  4. Alexander J Valvezan
  5. John M Asara
  6. James R Mitchell
  7. Brendan D Manning
(2021)
The mTORC1-mediated activation of ATF4 promotes protein and glutathione synthesis downstream of growth signals
eLife 10:e63326.
https://doi.org/10.7554/eLife.63326

Share this article

https://doi.org/10.7554/eLife.63326

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