1. Biochemistry and Chemical Biology
  2. Cell Biology
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EDF1 coordinates cellular responses to ribosome collisions

  1. Niladri K Sinha
  2. Alban Ordureau
  3. Katharina Best
  4. James A Saba
  5. Boris Zinshteyn
  6. Elayanambi Sundaramoorthy
  7. Amit Fulzele
  8. Danielle M Garshott
  9. Timo Denk
  10. Matthias Thoms
  11. Joao A Paulo
  12. Wade Harper
  13. Eric J Bennett
  14. Roland Beckmann  Is a corresponding author
  15. Rachel Green  Is a corresponding author
  1. Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, United States
  2. Harvard Medical School, United States
  3. Ludwig Maximilian University of Munich, Germany
  4. University of California, San Diego, United States
  5. Gene Center, Ludwig-Maximilians-Universität München, Germany
Research Article
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Cite this article as: eLife 2020;9:e58828 doi: 10.7554/eLife.58828

Abstract

Translation of aberrant mRNAs induces ribosomal collisions, thereby triggering pathways for mRNA and nascent peptide degradation and ribosomal rescue. Here we use sucrose gradient fractionation combined with quantitative proteomics to systematically identify proteins associated with collided ribosomes. This approach identified Endothelial differentiation-related factor 1 (EDF1) as a novel protein recruited to collided ribosomes during translational distress. Cryo-electron microscopic analyses of EDF1 and its yeast homolog Mbf1 revealed a conserved 40S ribosomal subunit binding site at the mRNA entry channel near the collision interface. EDF1 recruits the translational repressors GIGYF2 and EIF4E2 to collided ribosomes to initiate a negative-feedback loop that prevents new ribosomes from translating defective mRNAs. Further, EDF1 regulates an immediate-early transcriptional response to ribosomal collisions. Our results uncover mechanisms through which EDF1 coordinates multiple responses of the ribosome-mediated quality control pathway and provide novel insights into the intersection of ribosome-mediated quality control with global transcriptional regulation.

Article and author information

Author details

  1. Niladri K Sinha

    Department of Molecular Biology and Genetics, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9143-495X
  2. Alban Ordureau

    Department of Cell Biology, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4924-8520
  3. Katharina Best

    Gene Center, Department of Biochemistry, Ludwig Maximilian University of Munich, Munich, Germany
    Competing interests
    No competing interests declared.
  4. James A Saba

    Department of Molecular Biology and Genetics, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3453-8151
  5. Boris Zinshteyn

    Department of Molecular Biology and Genetics, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0103-3501
  6. Elayanambi Sundaramoorthy

    Section of Cell and Developmental Biology, University of California, San Diego, La Jolla, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1256-9758
  7. Amit Fulzele

    Section of Cell and Developmental Biology, University of California, San Diego, La Jolla, United States
    Competing interests
    No competing interests declared.
  8. Danielle M Garshott

    Section of Cell and Developmental Biology, University of California, San Diego, La Jolla, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4357-1781
  9. Timo Denk

    Department of Biochemistry, Gene Center, Ludwig-Maximilians-Universität München, Munich, Germany
    Competing interests
    No competing interests declared.
  10. Matthias Thoms

    Department of Biochemistry, Gene Center, Ludwig-Maximilians-Universität München, Munich, Germany
    Competing interests
    No competing interests declared.
  11. Joao A Paulo

    Department of Cell Biology, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  12. Wade Harper

    Cell Biology, Harvard Medical School, Boston, United States
    Competing interests
    Wade Harper, J.W.H. is a reviewing editor, eLife, a founder and advisory board member for Caraway Therapeutics, Inc, and an advisor for X-Chem Inc..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6944-7236
  13. Eric J Bennett

    Section of Cell and Developmental Biology, University of California, San Diego, La Jolla, United States
    Competing interests
    Eric J Bennett, E.J.B is an advisor and scientific advisory board member for Plexium.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1201-3314
  14. Roland Beckmann

    Gene Center, Department of Biochemistry, Ludwig Maximilian University of Munich, Munich, Germany
    For correspondence
    beckmann@genzentrum.lmu.de
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4291-3898
  15. Rachel Green

    Department of Molecular Biology and Genetics, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, United States
    For correspondence
    ragreen@jhmi.edu
    Competing interests
    Rachel Green, eLife, reviewing editor; advisory board member for Moderna, Inc., FL63, and the Cystic Fibrosis Foundation.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9337-2003

Funding

Howard Hughes Medical Institute

  • Rachel Green

Deutsche Forschungsgemeinschaft (GRK 1721)

  • Roland Beckmann

Deutsche Forschungsgemeinschaft (QBM (Quantitative Biosciences Munich) Graduate School Fellowships)

  • Katharina Best

Deutsche Forschungsgemeinschaft (QBM (Quantitative Biosciences Munich) Graduate School Fellowships)

  • Timo Denk

National Institute of General Medical Sciences (R37GM059425)

  • Rachel Green

National Institute of Neurological Disorders and Stroke (R37NS083524)

  • Wade Harper

National Institute on Aging (AG011085)

  • Wade Harper

National Institute of General Medical Sciences (DP2GM119132)

  • Eric J Bennett

National Institute of General Medical Sciences (5K99GM135450-02)

  • Boris Zinshteyn

Jane Coffin Childs Memorial Fund for Medical Research

  • Niladri K Sinha

National Institute of General Medical Sciences (T32GM007240)

  • Danielle M Garshott

National Science Foundation (DGE-1650112)

  • Danielle M Garshott

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

Reviewing Editor

  1. Nahum Sonenberg, McGill University, Canada

Publication history

  1. Received: May 12, 2020
  2. Accepted: August 2, 2020
  3. Accepted Manuscript published: August 3, 2020 (version 1)
  4. Version of Record published: September 11, 2020 (version 2)

Copyright

© 2020, Sinha 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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