An intact IRE1 transmembrane domain is necessary for UPR activation upon lipid bilayer stress in S. cerevisiae

Abstract

Membrane integrity at the endoplasmic reticulum (ER) is compromised in metabolic diseases. Recently, it became evident that such ER lipid aberrations activate the unfolded protein response (UPRLBS). Using a truncated form of the UPR sensor Ire1 that is responsive solely to changes in lipid bilayer composition, we identified pathways, beyond lipid metabolism, required to maintain ER integrity. A lipid sensing switch within the amphipathic helix of Ire1 revealed the importance of the transmembrane domain as a sensor to lipid bilayer stress (LBS). An exciting outcome of our transcriptomic and ChIP-qPCR data confirm novel genes upregulated solely by UPRLBS suggesting an alternative transcriptional programme activated for the adaptation of cells during LBS. This work establishes the broad extent of the UPR, providing insights for future therapeutic interventions.