1. Cell Biology
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Ribosome collisions trigger cis-acting feedback inhibition of translation initiation

  1. Szymon Juszkiewicz
  2. Greg Slodkowicz
  3. Zhewang Lin
  4. Paula Freire-Pritchett
  5. Sew-Yeu Peak-Chew
  6. Ramanujan S Hegde  Is a corresponding author
  1. MRC Laboratory of Molecular Biology, United Kingdom
  2. MRC-Laboratory of Molecular Biology, United Kingdom
Research Article
  • Cited 24
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Cite this article as: eLife 2020;9:e60038 doi: 10.7554/eLife.60038

Abstract

Translation of aberrant mRNAs can cause ribosomes to stall, leading to collisions with trailing ribosomes. Collided ribosomes are specifically recognized by ZNF598 to initiate protein and mRNA quality control pathways. Here we found using quantitative proteomics of collided ribosomes that EDF1 is a ZNF598-independent sensor of ribosome collisions. EDF1 stabilizes GIGYF2 at collisions to inhibit translation initiation in cis via 4EHP. The GIGYF2 axis acts independently of the ZNF598 axis, but each pathway's output is more pronounced without the other. We propose that the widely conserved and highly abundant EDF1 monitors the transcriptome for excessive ribosome density, then triggers a GIGYF2-mediated response to locally and temporarily reduce ribosome loading. Only when collisions persist is translation abandoned to initiate ZNF598-dependent quality control. This tiered response to ribosome collisions would allow cells to dynamically tune translation rates while ensuring fidelity of the resulting protein products.

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All data generated or analyzed during this study are included in the manuscript and supporting files. Source data have been provided for Figure 1.

The following data sets were generated

Article and author information

Author details

  1. Szymon Juszkiewicz

    Cell Biology Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3361-7264
  2. Greg Slodkowicz

    Division of Protein and Nucleic Acid Chemistry, MRC-Laboratory of Molecular Biology, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6918-0386
  3. Zhewang Lin

    Cell Biology Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
  4. Paula Freire-Pritchett

    Cell Biology Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
  5. Sew-Yeu Peak-Chew

    Cell Biology Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom
    Competing interests
    No competing interests declared.
  6. Ramanujan S Hegde

    Cell Biology Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom
    For correspondence
    rhegde@mrc-lmb.cam.ac.uk
    Competing interests
    Ramanujan S Hegde, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8338-852X

Funding

Medical Research Council (MC_UP_A022_1007)

  • Ramanujan S Hegde

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

Reviewing Editor

  1. Ivan Topisirovic, Jewish General Hospital, Canada

Publication history

  1. Received: June 15, 2020
  2. Accepted: July 10, 2020
  3. Accepted Manuscript published: July 13, 2020 (version 1)
  4. Version of Record published: July 24, 2020 (version 2)

Copyright

© 2020, Juszkiewicz 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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