The unfolded protein response and endoplasmic reticulum protein targeting machineries converge on the stress sensor IRE1

  1. Diego Acosta-Alvear  Is a corresponding author
  2. Gülsün Elif Karagöz  Is a corresponding author
  3. Florian Fröhlich
  4. Han Li
  5. Tobias C Walther
  6. Peter Walter  Is a corresponding author
  1. Howard Hughes Medical Institute, University of California, San Francisco, United States
  2. Harvard Medical School, United States

Abstract

The protein folding capacity of the endoplasmic reticulum (ER) is tightly regulated by a network of signaling pathways, known as the unfolded protein response (UPR). UPR sensors monitor the ER folding status to adjust ER folding capacity according to need. To understand how the UPR sensor IRE1 maintains ER homeostasis, we identified zero-length crosslinks of RNA to IRE1 with single nucleotide precision in vivo. We found that IRE1 specifically crosslinks to a subset of ER-targeted mRNAs, SRP RNA, ribosomal and transfer RNAs. Crosslink sites cluster in a discrete region of the ribosome surface spanning from the A-site to the polypeptide exit tunnel. Moreover, IRE1 binds to purified 80S ribosomes with high affinity, indicating association with ER-bound ribosomes. Our results suggest that the ER protein translocation and targeting machineries work together with the UPR to tune the ER's protein folding load.

Data availability

All data analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Diego Acosta-Alvear

    Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States
    For correspondence
    daa@lifesci.ucsb.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1139-8486
  2. Gülsün Elif Karagöz

    Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States
    For correspondence
    elif@walterlab.ucsf.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3392-2250
  3. Florian Fröhlich

    Harvard School of Public Health, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8307-2189
  4. Han Li

    Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Tobias C Walther

    Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Peter Walter

    Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States
    For correspondence
    peter@walterlab.ucsf.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6849-708X

Funding

Howard Hughes Medical Institute (Investigator)

  • Peter Walter

Cancer Research Institute (Postdoctoral fellowship)

  • Diego Acosta-Alvear

Howard Hughes Medical Institute (Investigator)

  • Tobias C Walther

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

Publication history

  1. Received: October 21, 2018
  2. Accepted: December 23, 2018
  3. Accepted Manuscript published: December 24, 2018 (version 1)
  4. Version of Record published: January 17, 2019 (version 2)

Copyright

© 2018, Acosta-Alvear 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. Diego Acosta-Alvear
  2. Gülsün Elif Karagöz
  3. Florian Fröhlich
  4. Han Li
  5. Tobias C Walther
  6. Peter Walter
(2018)
The unfolded protein response and endoplasmic reticulum protein targeting machineries converge on the stress sensor IRE1
eLife 7:e43036.
https://doi.org/10.7554/eLife.43036

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