Translational control of ERK signaling through miRNA/4EHP-directed silencing

  1. Seyed Mehdi Jafarnejad
  2. Clément Chapat
  3. Edna Matta-Camacho
  4. Idit Anna Gelbart
  5. Geoffrey G Hesketh
  6. Meztli Arguello
  7. Aitor Garzia
  8. Sung-Hoon Kim
  9. Jan Attig
  10. Maayan Shapiro
  11. Masahiro Morita
  12. Arkady Khoutorsky
  13. Tommy Alain
  14. Christos Gkogkas
  15. Noam Stern-Ginossar
  16. Thomas Tuschl
  17. Anne-Claude Gingras
  18. Thomas F Duchaine  Is a corresponding author
  19. Nahum Sonenberg  Is a corresponding author
  1. McGill University, Canada
  2. Weizmann Institute of Science, Israel
  3. Lunenfeld-Tanenbaum Research Institute, Canada
  4. The Rockefeller University, United States
  5. The Francis Crick Institute, United Kingdom
  6. University of Ottawa, Canada
  7. University of Edinburgh, United Kingdom

Abstract

MicroRNAs (miRNAs) exert a broad influence over gene expression by directing effector activities that impinge on translation and stability of mRNAs. We recently discovered that the cap-binding protein 4EHP is a key component of the mammalian miRNA-Induced Silencing Complex (miRISC), which mediates gene silencing. However, little is known about the mRNA repertoire that is controlled by the 4EHP/miRNA mechanism or its biological importance. Here, using ribosome profiling, we identify a subset of mRNAs that are translationally controlled by 4EHP. We show that the Dusp6 mRNA, which encodes an ERK1/2 phosphatase, is translationally repressed by 4EHP and a specific miRNA, miR-145. This promotes ERK1/2 phosphorylation, resulting in augmented cell growth and reduced apoptosis. Our findings thus empirically define the integral role of translational repression in miRNA-induced gene silencing and reveal a critical function for this process in the control of the ERK signalling cascade in mammalian cells.

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Article and author information

Author details

  1. Seyed Mehdi Jafarnejad

    Goodman Cancer Research Center, McGill University, Montreal, Canada
    Competing interests
    No competing interests declared.
  2. Clément Chapat

    Goodman Cancer Research Center, McGill University, Montreal, Canada
    Competing interests
    No competing interests declared.
  3. Edna Matta-Camacho

    Goodman Cancer Research Center, McGill University, Montreal, Canada
    Competing interests
    No competing interests declared.
  4. Idit Anna Gelbart

    Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
    Competing interests
    No competing interests declared.
  5. Geoffrey G Hesketh

    Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Toronto, Canada
    Competing interests
    No competing interests declared.
  6. Meztli Arguello

    Goodman Cancer Research Center, McGill University, Montreal, Canada
    Competing interests
    No competing interests declared.
  7. Aitor Garzia

    Laboratory for RNA Molecular Biology, The Rockefeller University, New York, United States
    Competing interests
    No competing interests declared.
  8. Sung-Hoon Kim

    Goodman Cancer Research Center, McGill University, Montreal, Canada
    Competing interests
    No competing interests declared.
  9. Jan Attig

    The Francis Crick Institute, London, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2159-2880
  10. Maayan Shapiro

    Goodman Cancer Research Center, McGill University, Montreal, Canada
    Competing interests
    No competing interests declared.
  11. Masahiro Morita

    Goodman Cancer Research Center, McGill University, Montreal, Canada
    Competing interests
    No competing interests declared.
  12. Arkady Khoutorsky

    Department of Anesthesia, McGill University, Montreal, Canada
    Competing interests
    No competing interests declared.
  13. Tommy Alain

    Department of Biochemistry, University of Ottawa, Ottawa, Canada
    Competing interests
    No competing interests declared.
  14. Christos Gkogkas

    Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6281-3419
  15. Noam Stern-Ginossar

    Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3583-5932
  16. Thomas Tuschl

    Laboratory for RNA Molecular Biology, The Rockefeller University, New York, United States
    Competing interests
    No competing interests declared.
  17. Anne-Claude Gingras

    Centre for Systems Biology, Lunenfeld-Tanenbaum Research Institute, Toronto, Canada
    Competing interests
    No competing interests declared.
  18. Thomas F Duchaine

    Goodman Cancer Research Center, McGill University, Montreal, Canada
    For correspondence
    thomas.duchaine@mcgill.ca
    Competing interests
    No competing interests declared.
  19. Nahum Sonenberg

    Goodman Cancer Research Center, McGill University, Montreal, Canada
    For correspondence
    nahum.sonenberg@mcgill.ca
    Competing interests
    Nahum Sonenberg, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4707-8759

Funding

Canadian Institutes of Health Research (FDN-148423)

  • Nahum Sonenberg

Fonds de la Recherche en Sante du Quebec

  • Thomas F Duchaine

Natural Sciences and Engineering Research Council of Canada (RGPIN-2014-06434)

  • Anne-Claude Gingras

Canadian Institutes of Health Research (FDN-143301)

  • Anne-Claude Gingras

Canadian Institutes of Health Research (MOP-123352)

  • Thomas F Duchaine

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

Reviewing Editor

  1. David Ron, University of Cambridge, United Kingdom

Publication history

  1. Received: January 12, 2018
  2. Accepted: February 1, 2018
  3. Accepted Manuscript published: February 7, 2018 (version 1)
  4. Version of Record published: February 20, 2018 (version 2)

Copyright

© 2018, Jafarnejad 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. Seyed Mehdi Jafarnejad
  2. Clément Chapat
  3. Edna Matta-Camacho
  4. Idit Anna Gelbart
  5. Geoffrey G Hesketh
  6. Meztli Arguello
  7. Aitor Garzia
  8. Sung-Hoon Kim
  9. Jan Attig
  10. Maayan Shapiro
  11. Masahiro Morita
  12. Arkady Khoutorsky
  13. Tommy Alain
  14. Christos Gkogkas
  15. Noam Stern-Ginossar
  16. Thomas Tuschl
  17. Anne-Claude Gingras
  18. Thomas F Duchaine
  19. Nahum Sonenberg
(2018)
Translational control of ERK signaling through miRNA/4EHP-directed silencing
eLife 7:e35034.
https://doi.org/10.7554/eLife.35034
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