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
Reviewing Editor
- Reid Gilmore, University of Massachusetts Medical School, United States
Publication history
- Received: March 11, 2015
- Accepted: May 19, 2015
- Accepted Manuscript published: May 20, 2015 (version 1)
- 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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