title: METABOLISM. 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, 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.
authors.affiliation: Department of Genetics and Complex Diseases and Sabri Ülker Center, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
authors.affiliation: Department of Genetics and Complex Diseases and Sabri Ülker Center, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Ediz S
authors.initials: ES
authors.lastname: Calay
authors.affiliation: Department of Genetics and Complex Diseases and Sabri Ülker Center, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Fan
authors.affiliation: Department of Genetics and Complex Diseases and Sabri Ülker Center, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Arduini
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Ryan C
authors.initials: RC
authors.lastname: Kunz
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Steven P
authors.initials: SP
authors.lastname: Gygi
authors.affiliation: Department of Genetics and Complex Diseases and Sabri Ülker Center, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Abdullah
authors.initials: A
authors.lastname: Yalcin
authors.affiliation: Department of Genetics and Complex Diseases and Sabri Ülker Center, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
authors.forename: Suneng
authors.initials: S
authors.lastname: Fu
authors.affiliation: Department of Genetics and Complex Diseases and Sabri Ülker Center, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA. Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. ghotamis@hsph.harvard.edu.
authors.forename: Gökhan S
authors.initials: GS
authors.lastname: Hotamisligil
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics*; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress; D004722:Endoribonucleases / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis; D007249:Inflammation / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D008820:Mice, Obese; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009589:Nitrogen Oxides / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism* / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012326:RNA Splicing; D012333:RNA, Messenger / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000235:genetics*; D056811:Unfolded Protein Response; D000071717:X-Box Binding Protein 1
chemical_list: D004268:DNA-Binding Proteins; D009589:Nitrogen Oxides; D012333:RNA, Messenger; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C510185:Ern1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases; D005947:Glucose