Multiple decay events target HAC1 mRNA during splicing to regulate the unfolded protein response

  1. Patrick D Cherry
  2. Sally E Peach
  3. Jay R Hesselberth  Is a corresponding author
  1. University of Colorado School of Medicine, United States

Abstract

In the unfolded protein response (UPR), stress in the endoplasmic reticulum (ER) activates a large transcriptional program to increase ER folding capacity. During the budding yeast UPR, Ire1 excises an intron from the HAC1 mRNA and the exon products of cleavage are ligated, and the translated protein induces hundreds of stress-response genes. Using cells with mutations in RNA repair and decay enzymes, we show that phosphorylation of two different HAC1 splicing intermediates is required for their degradation by the 5′→3′ exonuclease Xrn1 to enact opposing effects on the UPR. We also found that ligated but 2′-phosphorylated HAC1 mRNA is cleaved, yielding a decay intermediate with both 5′- and 2′-phosphates at its 5′-end that inhibit 5′→3′ decay and suggesting that Ire1 degrades incompletely processed HAC1. These decay events expand the scope of RNA-based regulation in the budding yeast UPR and have implications for the control of the metazoan UPR.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Patrick D Cherry

    Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6421-2035
  2. Sally E Peach

    Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Jay R Hesselberth

    Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, United States
    For correspondence
    jay.hesselberth@gmail.com
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6299-179X

Funding

National Institutes of Health (R35GM119550)

  • Jay R Hesselberth

University of Colorado School of Medicine (RNA Bioscience Initiative)

  • Patrick D Cherry

National Institutes of Health (T32GM008730)

  • Patrick D Cherry
  • Sally E Peach

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

Reviewing Editor

  1. Timothy W Nilsen, Case Western Reserve University, United States

Publication history

  1. Received: October 24, 2018
  2. Accepted: March 14, 2019
  3. Accepted Manuscript published: March 15, 2019 (version 1)
  4. Version of Record published: April 9, 2019 (version 2)

Copyright

© 2019, Cherry 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. Patrick D Cherry
  2. Sally E Peach
  3. Jay R Hesselberth
(2019)
Multiple decay events target HAC1 mRNA during splicing to regulate the unfolded protein response
eLife 8:e42262.
https://doi.org/10.7554/eLife.42262

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