Research Article

S-Nitrosylation links obesity-associated inflammation to endoplasmic reticulum dysfunction

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Science  31 Jul 2015:
Vol. 349, Issue 6247, pp. 500-506
DOI: 10.1126/science.aaa0079

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S-nitrosylation links obesity and cell stress

Obesity and other diseases are somehow linked to malfunction of the protein-protecting functions of the endoplasmic reticulum (ER). Yang et al. propose a mechanism by which obesity and associated chronic inflammation may be linked to the accumulation of unfolded proteins in the ER. Such stress would normally trigger the process known as the unfolded protein response (UPR). However, obese mice had increased S-nitrosylation of inositol-requiring protein-1 (IRE1α), a ribonuclease that regulates the UPR. The modified IRE1α had decreased RNAse activity. The authors expressed an IRE1α mutant protein that could not be nitrosylated in the liver of obese mice. This approach improved the UPR and helped restore glucose homeostasis.

Science, this issue p. 500

Abstract

The association between inflammation and endoplasmic reticulum (ER) stress has been observed in many diseases. However, if and how chronic inflammation regulates the unfolded protein response (UPR) and alters ER homeostasis in general, or in the context of chronic disease, remains unknown. Here, we show that, in the setting of obesity, inflammatory input through increased inducible nitric oxide synthase (iNOS) activity causes S-nitrosylation of a key UPR regulator, IRE1α, which leads to a progressive decline in hepatic IRE1α-mediated XBP1 splicing activity in both genetic (ob/ob) and dietary (high-fat diet–induced) models of obesity. Finally, in obese mice with liver-specific IRE1α deficiency, reconstitution of IRE1α expression with a nitrosylation-resistant variant restored IRE1α-mediated XBP1 splicing and improved glucose homeostasis in vivo. Taken together, these data describe a mechanism by which inflammatory pathways compromise UPR function through iNOS-mediated S-nitrosylation of IRE1α, which contributes to defective IRE1α activity, impaired ER function, and prolonged ER stress in obesity.

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