4 years ago

Activation of the Unfolded Protein Response by Lipid Bilayer Stress

Activation of the Unfolded Protein Response by Lipid Bilayer Stress
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.

Graphical abstract



The unfolded protein response (UPR) controls the secretory capacity of a cell and is activated by accumulating unfolded proteins in the lumen of the ER. More recently, it became obvious that aberrant membrane lipid compositions of the ER are equally potent in activating the UPR. Halbleib et al. identify a membrane-based mechanism of UPR activation and establish that Ire1, the most conserved transducer of ER stress, uses an amphipathic helix to sense and respond to aberrant physical properties of the ER membrane.

Publisher URL: www.sciencedirect.com/science

DOI: S1097276517304392

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