The Sec61 translocon limits IRE1α signaling during the unfolded protein response
- Yale School of Medicine, United States
Abstract
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.
Article and author information
Author details
Malaiyalam Mariappan
Funding
National Institutes of Health (NIH 1R01GM117386-01)
- Rachel Plumb
- Suhila Appathurai
- Malaiyalam Mariappan
Yale School of Medicine (Start-up)
- Arunkumar Sundaram
- Rachel Plumb
- Suhila Appathurai
- Malaiyalam Mariappan
Yale School of Medicine (Rudolph J Anderson Fellowship)
- Arunkumar Sundaram
National Institutes of Health (T32 GM007223)
- Rachel Plumb
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2017, Sundaram 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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The Sec61 translocon limits IRE1α signaling during the unfolded protein response
eLife 6:e27187.
https://doi.org/10.7554/eLife.27187
