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

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, IRE1a, which leads to a progressive decline in hepatic IRE1a-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 IRE1a deficiency, reconstitution of IRE1a expression with a nitrosylation-resistant variant restored IRE1a-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 IRE1a, which contributes to defective IRE1a activity, impaired ER function, and prolonged ER stress in obesity.