Cell Biology

Stressful Lipids

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Science  22 Mar 2013:
Vol. 339, Issue 6126, pp. 1360
DOI: 10.1126/science.339.6126.1360-c

Lipid perturbations activate the endoplasmic reticulum (ER) unfolded protein response (UPR), and UPR activity modifies cellular and organismal responses to changes in dietary lipids. The physiological ramifications of the lipid-UPR axis affect diseases of aging such as diabetes, atherosclerosis, and cirrhosis, but its molecular basis has remained obscure. It is unclear if the sensors of the UPR respond to altered membrane lipid composition because of its indirect effects on the protein-folding environment in the ER lumen or if direct sensing of lipids contributes to UPR activation. Working in mammalian tissue culture cells, Volmer et al. found that the mammalian UPR sensors PERK and IRE1 lacking their lumenal stress-sensing domains selectively lost the ability to respond to unfolded protein stress, but retained sensitivity to changes in membrane lipids. This sensitivity to changes in lipid composition was reconstituted in vitro in liposomes with defined acyl-chain saturation, which suggests that a UPR transducer can directly sense and respond to its lipid environment.

Proc. Natl. Acad. Sci. U.S.A. 110, 10.1073/pnas.1217611110 (2013).

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