1. Cell Biology

Regulated Ire1-dependent mRNA decay requires no-go mRNA degradation to maintain endoplasmic reticulum homeostasis in S. pombe

  1. Nicholas R Guydosh
  2. Phillip Kimmig
  3. Peter Walter  Is a corresponding author
  4. Rachel Green  Is a corresponding author
  1. Johns Hopkins School of Medicine, United States
  2. University of California, San Francisco, United States
https://doi.org/10.7554/eLife.29216
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  1. Nicholas R Guydosh
  2. Phillip Kimmig
  3. Peter Walter
  4. Rachel Green
(2017)
Regulated Ire1-dependent mRNA decay requires no-go mRNA degradation to maintain endoplasmic reticulum homeostasis in S. pombe
eLife 6:e29216.
https://doi.org/10.7554/eLife.29216
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Abstract

The unfolded protein response (UPR) monitors and adjusts the protein folding capacity of the endoplasmic reticulum (ER). In S. pombe, the ER membrane-resident kinase/endoribonuclease Ire1 utilizes a mechanism of selective degradation of ER-bound mRNAs (RIDD) to maintain homeostasis. We used a genetic screen to identify factors critical to the Ire1-mediated UPR and found several proteins, Dom34, Hbs1 and Ski complex subunits, previously implicated in ribosome rescue and mRNA no-go-decay (NGD). Ribosome profiling in ER-stressed cells lacking these factors revealed that Ire1-mediated cleavage of ER-associated mRNAs results in ribosome stalling and mRNA degradation. Stalled ribosomes iteratively served as a ruler to template precise, regularly spaced upstream mRNA cleavage events. This clear signature uncovered hundreds of novel target mRNAs. Our results reveal that the UPR in S. pombe executes RIDD in an intricate interplay between Ire1, translation, and the NGD pathway, and establish a critical role for NGD in maintaining ER homeostasis.

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Article and author information

Author details

  1. Nicholas R Guydosh

    Department of Molecular Biology and Genetics, Howard Hughes Medical Institute, Johns Hopkins School of Medicine, Baltimore, United States
    Competing interests
    No competing interests declared.

  2. Phillip Kimmig

    Department of Biochemistry and Biophysics, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.

  3. Peter Walter

    Department of Biochemistry and Biophysics, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States
    For correspondence
    peter@walterlab.ucsf.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6849-708X

  4. Rachel Green

    Department of Molecular Biology and Genetics, Howard Hughes Medical Institute, Johns Hopkins School of Medicine, Baltimore, United States
    For correspondence
    ragreen@jhmi.edu
    Competing interests
    Rachel Green, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9337-2003

Funding

Howard Hughes Medical Institute

  • Peter Walter
  • Rachel Green

National Institute of General Medical Sciences (GM 059425)

  • Rachel Green

National Institutes of Health

  • Peter Walter

National Institute of Diabetes and Digestive and Kidney Diseases

  • Nicholas R Guydosh

Human Frontier Science Program

  • Phillip Kimmig

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

Version history

  1. Received: June 1, 2017
  2. Accepted: September 12, 2017
  3. Accepted Manuscript published: September 25, 2017 (version 1)
  4. Accepted Manuscript updated: September 26, 2017 (version 2)
  5. Version of Record published: October 20, 2017 (version 3)

Copyright

© 2017, Guydosh 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. Nicholas R Guydosh
  2. Phillip Kimmig
  3. Peter Walter
  4. Rachel Green
(2017)
Regulated Ire1-dependent mRNA decay requires no-go mRNA degradation to maintain endoplasmic reticulum homeostasis in S. pombe
eLife 6:e29216.
https://doi.org/10.7554/eLife.29216

Share this article

https://doi.org/10.7554/eLife.29216

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