TY - JOUR TI - A functional link between the co-translational protein translocation pathway and the UPR AU - Plumb, Rachel AU - Zhang, Zai-Rong AU - Appathurai, Suhila AU - Mariappan, Malaiyalam A2 - Gilmore, Reid VL - 4 PY - 2015 DA - 2015/05/20 SP - e07426 C1 - eLife 2015;4:e07426 DO - 10.7554/eLife.07426 UR - https://doi.org/10.7554/eLife.07426 AB - 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 Unfolded Protein Response is coupled with the co-translational protein translocation pathway to maintain protein homeostasis in the ER during stress conditions. KW - unfolded protein response KW - endoplasmic reticulum KW - protein translocation JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -