Membrane lipid saturation activates endoplasmic reticulum unfolded protein response transducers through their transmembrane domains.

Abstract:

:Endoplasmic reticulum (ER) stress sensors use a related luminal domain to monitor the unfolded protein load and convey the signal to downstream effectors, signaling an unfolded protein response (UPR) that maintains compartment-specific protein folding homeostasis. Surprisingly, perturbation of cellular lipid composition also activates the UPR, with important consequences in obesity and diabetes. However, it is unclear if direct sensing of the lipid perturbation contributes to UPR activation. We found that mutant mammalian ER stress sensors, IRE1α and PERK, lacking their luminal unfolded protein stress-sensing domain, nonetheless retained responsiveness to increased lipid saturation. Lipid saturation-mediated activation in cells required an ER-spanning transmembrane domain and was positively regulated in vitro by acyl-chain saturation in reconstituted liposomes. These observations suggest that direct sensing of the lipid composition of the ER membrane contributes to the UPR.

authors

Volmer R,van der Ploeg K,Ron D

doi

10.1073/pnas.1217611110

subject

Has Abstract

pub_date

2013-03-19 00:00:00

pages

4628-33

issue

12

eissn

0027-8424

issn

1091-6490

pii

1217611110

journal_volume

110

pub_type

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