1. Biochemistry and Chemical Biology
  2. Cell Biology

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
https://doi.org/10.7554/eLife.07426
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  1. Rachel Plumb
  2. Zai-Rong Zhang
  3. Suhila Appathurai
  4. Malaiyalam Mariappan
(2015)
A functional link between the co-translational protein translocation pathway and the UPR
eLife 4:e07426.
https://doi.org/10.7554/eLife.07426
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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.

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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.

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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  1. Rachel Plumb
  2. Zai-Rong Zhang
  3. Suhila Appathurai
  4. Malaiyalam Mariappan
(2015)
A functional link between the co-translational protein translocation pathway and the UPR
eLife 4:e07426.
https://doi.org/10.7554/eLife.07426

Share this article

https://doi.org/10.7554/eLife.07426

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Further reading

    1. Cell Biology

    The Sec61 translocon limits IRE1α signaling during the unfolded protein response

    Arunkumar Sundaram, Rachel Plumb ... Malaiyalam Mariappan
    Research Advance Updated

    IRE1α is an endoplasmic reticulum (ER) localized endonuclease activated by misfolded proteins in the ER. Previously, we demonstrated that IRE1α forms a complex with the Sec61 translocon, to which its substrate XBP1u mRNA is recruited for cleavage during ER stress (Plumb et al., 2015). Here, we probe IRE1α complexes in cells with blue native PAGE immunoblotting. We find that IRE1α forms a hetero-oligomeric complex with the Sec61 translocon that is activated upon ER stress with little change in the complex. In addition, IRE1α oligomerization, activation, and inactivation during ER stress are regulated by Sec61. Loss of the IRE1α-Sec61 translocon interaction as well as severe ER stress conditions causes IRE1α to form higher-order oligomers that exhibit continuous activation and extended cleavage of XBP1u mRNA. Thus, we propose that the Sec61-IRE1α complex defines the extent of IRE1α activity and may determine cell fate decisions during ER stress conditions.