A functional link between the co-translational protein translocation pathway and the UPR

• Published in: eLife Vol. 4
• Main Authors: Plumb, Rachel, Zhang, Zai-Rong, Appathurai, Suhila, Mariappan, Malaiyalam
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 20.05.2015; eLife Sciences Publications, Ltd
• Subjects: Biochemistry; Cell Biology; CRISPR-Cas Systems; Endoplasmic reticulum; Endoplasmic Reticulum Stress - physiology; Endoribonucleases - metabolism; HEK293 Cells; HeLa Cells; Homeostasis; Homeostasis - physiology; Humans; Immunoglobulins; Immunoprecipitation; Membrane Proteins - metabolism; mRNA; Oligonucleotides - genetics; Phosphorylation; Polypeptides; Protein folding; protein translocation; Protein Translocation Systems - physiology; Protein transport; Protein-Serine-Threonine Kinases - metabolism; Proteins; Real-Time Polymerase Chain Reaction; RNA, Messenger - metabolism; RNA, Small Interfering - genetics; SEC Translocation Channels; Signal recognition particle; Signal Recognition Particle - physiology; Splicing; Translation; unfolded protein response; Unfolded Protein Response - physiology; unfolded protein response; cell biology; human; endoplasmic reticulum; biochemistry; protein translocation
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/elife.07426

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.