Publication Date:
2015-08-01
Description:
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, IRE1alpha, which leads to a progressive decline in hepatic IRE1alpha-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 IRE1alpha deficiency, reconstitution of IRE1alpha expression with a nitrosylation-resistant variant restored IRE1alpha-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 IRE1alpha, which contributes to defective IRE1alpha activity, impaired ER function, and prolonged ER stress in obesity.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4573582/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4573582/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Yang, Ling -- Calay, Ediz S -- Fan, Jason -- Arduini, Alessandro -- Kunz, Ryan C -- Gygi, Steven P -- Yalcin, Abdullah -- Fu, Suneng -- Hotamisligil, Gokhan S -- DK052539/DK/NIDDK NIH HHS/ -- R01 DK052539/DK/NIDDK NIH HHS/ -- T32 GM007367/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2015 Jul 31;349(6247):500-6. doi: 10.1126/science.aaa0079.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics and Complex Diseases and Sabri Ulker Center, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA. ; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA. ; Department of Genetics and Complex Diseases and Sabri Ulker 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.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26228140" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
DNA-Binding Proteins/*genetics
;
Diet, High-Fat
;
Disease Models, Animal
;
Endoplasmic Reticulum/*metabolism
;
*Endoplasmic Reticulum Stress
;
Endoribonucleases/*metabolism
;
Glucose/metabolism
;
Homeostasis
;
Inflammation/metabolism
;
Liver/metabolism
;
Mice
;
Mice, Obese
;
Nitric Oxide Synthase Type II/metabolism
;
Nitrogen Oxides/*metabolism
;
Obesity/*metabolism/*pathology
;
Protein-Serine-Threonine Kinases/*metabolism
;
*RNA Splicing
;
RNA, Messenger/metabolism
;
Transcription Factors/*genetics
;
Unfolded Protein Response
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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