Activation of the Unfolded Protein Response by Lipid Bilayer Stress

• DOI: 10.1016/j.molcel.2017.06.012
• Publication Date: 2017-07-06T17:31:43Z
• Authors: Kristina Halbleib; Kristina Pesek; Roberto Covino; Harald F. Hofbauer; Dorith Wunnicke; Inga Hänelt; Gerhard Hummer; Robert Ernst
• Keywords: Protein Conformation, alpha-Helical; 0301 basic medicine; Protein Folding; Membrane Glycoproteins; Saccharomyces cerevisiae Proteins; Time Factors; Lipid Bilayers; Intracellular Membranes; Saccharomyces cerevisiae; Molecular Dynamics Simulation; Protein Serine-Threonine Kinases; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Structure-Activity Relationship; 03 medical and health sciences; Mutation; Unfolded Protein Response; Signal Transduction

The unfolded protein response (UPR) is a conserved homeostatic program that is activated by misfolded proteins in the lumen of the endoplasmic reticulum (ER). Recently, it became evident that aberrant lipid compositions of the ER membrane, referred to as lipid bilayer stress, are equally potent in activating the UPR. The underlying molecular mechanism, however, remained unclear. We show that the most conserved transducer of ER stress, Ire1, uses an amphipathic helix (AH) to sense membrane aberrancies and control UPR activity. In vivo and in vitro experiments, together with molecular dynamics (MD) simulations, identify the physicochemical properties of the membrane environment that control Ire1 oligomerization. This work establishes the molecular mechanism of UPR activation by lipid bilayer stress.