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 Unfolded Protein Response is coupled with the co-translational protein translocation pathway to maintain protein homeostasis in the ER during stress conditions.
Highlights
Secretory and transmembrane proteins are essential for linking intracellular trafficking and extracellular environments and, in metazoans, play broad roles in all aspects of intracellular communication
We were intrigued by the interaction between the Sec61 translocon and Ire1α since we reasoned that it could facilitate Ire1α access to regulated Ire1-dependent decay (RIDD) mRNA substrates (Hollien and Weissman, 2006) that are targeted to the Sec61 translocon via their nascent chains
Immunodepletion of the Sec61 translocon nearly quantitatively depleted the endogenous Ire1α, indicating that almost all Ire1α is in a complex with the Sec61 translocon in cells (Figure 1—figure supplement 2)
Summary
Secretory and transmembrane proteins are essential for linking intracellular trafficking and extracellular environments and, in metazoans, play broad roles in all aspects of intracellular communication. These proteins contain either a signal sequence or transmembrane domain (TMD) that is co-translationally captured by the SRP and targeted to the endoplasmic reticulum (ER) membrane (Akopian et al, 2013). When the influx of nascent polypeptides exceeds the ER protein folding capacity, misfolded proteins accumulate in the ER and lead to ER stress. Under ER stress, signaling pathways, collectively termed the Unfolded Protein Response (UPR), are activated to restore ER homeostasis (Walter and Ron, 2011). The UPR is constitutively activated as an adaptive response pathway for survival under adverse conditions, such as hypoxia (Wang and Kaufman, 2012)
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