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

Ling Yang; Ediz S Calay; Jason Fan; Alessandro Arduini; Ryan C Kunz; Steven P Gygi; Abdullah Yalcin; Suneng Fu; Gökhan S Hotamisligil

doi:10.1126/science.aaa0079

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

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

Ling Yang, Ediz S Calay, Jason Fan, Alessandro Arduini, Ryan C Kunz, Steven P Gygi, Abdullah Yalcin, Suneng Fu and Gökhan S Hotamisligil

Science (American Association for the Advancement of Science), Vol.349(6247), pp.500-506

07/31/2015

DOI: 10.1126/science.aaa0079

PMCID: PMC4573582

PMID: 26228140

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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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Title: Subtitle: S-Nitrosylation links obesity-associated inflammation to endoplasmic reticulum dysfunction
Creators: Ling Yang - Department of Genetics and Complex Diseases and Sabri Ülker Center, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
Ediz S Calay - Department of Genetics and Complex Diseases and Sabri Ülker Center, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
Jason Fan - Department of Genetics and Complex Diseases and Sabri Ülker Center, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
Alessandro Arduini - Department of Genetics and Complex Diseases and Sabri Ülker Center, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
Ryan C Kunz - Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
Steven P Gygi - Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
Abdullah Yalcin - Department of Genetics and Complex Diseases and Sabri Ülker Center, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
Suneng Fu - Department of Genetics and Complex Diseases and Sabri Ülker Center, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
Gökhan S Hotamisligil - Department of Genetics and Complex Diseases and Sabri Ülker Center, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
Resource Type: Journal article
Publication Details: Science (American Association for the Advancement of Science), Vol.349(6247), pp.500-506
DOI: 10.1126/science.aaa0079
PMID: 26228140
PMCID: PMC4573582
NLM abbreviation: Science
ISSN: 0036-8075
eISSN: 1095-9203
Grant note: DOI: 10.13039/100000002, name: NIH, award: DK052539
Language: English
Date published: 07/31/2015
Academic Unit: Molecular Physiology and Biophysics; Anatomy and Cell Biology
Record Identifier: 9984025463702771

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