The fail-safe mechanism of post-transcriptional silencing of unspliced HAC1 mRNA

  1. Rachael Di Santo
  2. Soufiane Aboulhouda
  3. David E Weinberg  Is a corresponding author
  1. University of California, San Francisco, United States

Abstract

HAC1 encodes a transcription factor that is the central effector of the unfolded protein response (UPR) in budding yeast. When the UPR is inactive, HAC1 mRNA is stored as an unspliced isoform in the cytoplasm and no Hac1 protein is detectable. Intron removal is both necessary and sufficient to relieve the post-transcriptional silencing of HAC1 mRNA, yet the precise mechanism by which the intron prevents Hac1 protein accumulation has remained elusive. Here, we show that a combination of inhibited translation initiation and accelerated protein degradation-both dependent on the intron-prevents the accumulation of Hac1 protein when the UPR is inactive. Functionally, both components of this fail-safe silencing mechanism are required to prevent ectopic production of Hac1 protein and concomitant activation of the UPR. Our results provide a mechanistic understanding of HAC1 regulation and reveal a novel strategy for complete post-transcriptional silencing of a cytoplasmic mRNA.

Data availability

The following data sets were generated
    1. Di Santo R
    2. Weinberg DE
    (2016) Whole-genome sequencing of spontaneous mutants
    Publicly available at the NCBI Sequence Read Archive (accession no: SRP081128).
The following previously published data sets were used

Article and author information

Author details

  1. Rachael Di Santo

    Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Soufiane Aboulhouda

    Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. David E Weinberg

    Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, United States
    For correspondence
    david.weinberg@ucsf.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9348-1709

Funding

NIH Office of the Director (DP5OD017895)

  • Rachael Di Santo
  • Soufiane Aboulhouda
  • David E Weinberg

UCSF Program for Breakthrough Biomedical Research

  • Rachael Di Santo
  • Soufiane Aboulhouda
  • David E Weinberg

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

Reviewing Editor

  1. Rachel Green, Johns Hopkins School of Medicine, United States

Publication history

  1. Received: July 27, 2016
  2. Accepted: September 30, 2016
  3. Accepted Manuscript published: October 1, 2016 (version 1)
  4. Version of Record published: November 11, 2016 (version 2)
  5. Version of Record updated: October 26, 2017 (version 3)

Copyright

© 2016, Di Santo 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. Rachael Di Santo
  2. Soufiane Aboulhouda
  3. David E Weinberg
(2016)
The fail-safe mechanism of post-transcriptional silencing of unspliced HAC1 mRNA
eLife 5:e20069.
https://doi.org/10.7554/eLife.20069
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