1. Biochemistry and Chemical Biology
  2. Cell Biology
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A functional link between the co-translational protein translocation pathway and the UPR

  1. Rachel Plumb
  2. Zai-Rong Zhang
  3. Suhila Appathurai
  4. Malaiyalam Mariappan  Is a corresponding author
  1. Yale School of Medicine, United States
Research Article
  • Cited 49
  • Views 4,388
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Cite this article as: eLife 2015;4:e07426 doi: 10.7554/eLife.07426

Abstract

Upon endoplasmic reticulum (ER) stress, the transmembrane endoribonuclease Ire1α performs mRNA cleavage reactions to increase the ER folding capacity. It is unclear how the low abundant Ire1α efficiently finds and cleaves the majority of mRNAs at the ER membrane. Here, we reveal that Ire1α forms a complex with the Sec61 translocon to cleave its mRNA substrates. We show that Ire1α's key substrate, XBP1u mRNA, is recruited to the Ire1α-Sec61 translocon complex through its nascent chain, which contains a pseudo-transmembrane domain to utilize the signal recognition particle (SRP)-mediated pathway. Depletion of SRP, the SRP receptor or the Sec61 translocon in cells leads to reduced Ire1α-mediated splicing of XBP1u mRNA. Furthermore, mutations in Ire1α that disrupt the Ire1α-Sec61 complex causes reduced Ire1α-mediated cleavage of ER-targeted mRNAs. Thus, our data suggest that the UPR is coupled with the co-translational protein translocation pathway to maintain protein homeostasis in the ER during stress conditions.

Article and author information

Author details

  1. Rachel Plumb

    Department of Cell Biology, Nanobiology Institute, Yale School of Medicine, West Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Zai-Rong Zhang

    Department of Cell Biology, Nanobiology Institute, Yale School of Medicine, West Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Suhila Appathurai

    Department of Cell Biology, Nanobiology Institute, Yale School of Medicine, West Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Malaiyalam Mariappan

    Department of Cell Biology, Nanobiology Institute, Yale School of Medicine, West Haven, United States
    For correspondence
    malaiyalam.mariappan@yale.edu
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Reid Gilmore, University of Massachusetts Medical School, United States

Publication history

  1. Received: March 11, 2015
  2. Accepted: May 19, 2015
  3. Accepted Manuscript published: May 20, 2015 (version 1)
  4. Version of Record published: June 5, 2015 (version 2)

Copyright

© 2015, Plumb 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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