1. Biochemistry and Chemical Biology
  2. Cell Biology
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Proteotoxicity from aberrant ribosome biogenesis compromises cell fitness

  1. Blake W Tye
  2. Nicoletta Commins
  3. Lillia V Ryazanova
  4. Martin Wühr
  5. Michael Springer
  6. David Pincus
  7. L Stirling Churchman  Is a corresponding author
  1. Harvard Medical School, United States
  2. Princeton University, United States
  3. Whitehead Institute for Biomedical Research, United States
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Cite this article as: eLife 2019;8:e43002 doi: 10.7554/eLife.43002

Abstract

To achieve maximal growth, cells must manage a massive economy of ribosomal proteins (r-proteins) and RNAs (rRNAs) to produce thousands of ribosomes every minute. Although ribosomes are essential in all cells, natural disruptions to ribosome biogenesis lead to heterogeneous phenotypes. Here, we model these perturbations in Saccharomyces cerevisiae and show that challenges to ribosome biogenesis result in acute loss of proteostasis. Imbalances in the synthesis of r-proteins and rRNAs lead to the rapid aggregation of newly synthesized orphan r-proteins and compromise essential cellular processes, which cells alleviate by activating proteostasis genes. Exogenously bolstering the proteostasis network increases cellular fitness in the face of challenges to ribosome assembly, demonstrating the direct contribution of orphan r-proteins to cellular phenotypes. We propose that ribosome assembly is a key vulnerability of proteostasis maintenance in proliferating cells that may be compromised by diverse genetic, environmental, and xenobiotic perturbations that generate orphan r-proteins.

Article and author information

Author details

  1. Blake W Tye

    Department of Genetics, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Nicoletta Commins

    Department of Systems Biology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Lillia V Ryazanova

    Department of Molecular Biology, Princeton University, Princeton, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Martin Wühr

    Department of Molecular Biology, Princeton University, Princeton, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0244-8947
  5. Michael Springer

    Department of Systems Biology, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. David Pincus

    Whitehead Institute for Biomedical Research, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9651-6858
  7. L Stirling Churchman

    Department of Genetics, Harvard Medical School, Boston, United States
    For correspondence
    churchman@genetics.med.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3888-2574

Funding

National Institutes of Health (R01-HG007173)

  • L Stirling Churchman

National Science Foundation (2013171680)

  • Blake W Tye

National Institutes of Health (R01-GM117333)

  • L Stirling Churchman

National Institutes of Health (R01-GM120122)

  • Michael Springer

National Institutes of Health (R35-GM128813)

  • Martin Wühr

Department of Energy, Labor and Economic Growth (DE-SC0018420)

  • Martin Wühr

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

Reviewing Editor

  1. Alan G Hinnebusch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, United States

Publication history

  1. Received: October 19, 2018
  2. Accepted: March 6, 2019
  3. Accepted Manuscript published: March 7, 2019 (version 1)

Copyright

© 2019, Tye 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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