Elevated O-GlcNAcylation enhances pro-inflammatory Th17 function by altering the intracellular lipid microenvironment
| Autor: | Todd A. Lydic, Harmony Saunders, Patrick E. Fields, Ee Phie Tan, Gentry K. Cork, Jibiao Li, Maria T. Villar, Chad Slawson, Zhen Zhang, Miranda Machacek, Antonio Artigues, Tiangang Li |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Orphan receptor 030102 biochemistry & molecular biology Chemistry medicine.medical_treatment Inflammation Lipid metabolism Cell Biology Biochemistry Cell biology 03 medical and health sciences 030104 developmental biology Cytokine RAR-related orphan receptor gamma medicine Interleukin 17 medicine.symptom Molecular Biology Transcription factor Intracellular |
| Zdroj: | Journal of Biological Chemistry. 294:8973-8990 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.ra119.008373 |
| Popis: | Chronic, low-grade inflammation increases the risk for atherosclerosis, cancer, and autoimmunity in diseases such as obesity and diabetes. Levels of CD4+ T helper 17 (Th17) cells, which secrete interleukin 17A (IL-17A), are increased in obesity and contribute to the inflammatory milieu; however, the relationship between signaling events triggered by excess nutrient levels and IL-17A–mediated inflammation is unclear. Here, using cytokine, quantitative real-time PCR, immunoprecipitation, and ChIP assays, along with lipidomics and MS-based approaches, we show that increased levels of the nutrient-responsive, post-translational protein modification, O-GlcNAc, are present in naive CD4+ T cells from a diet-induced obesity murine model and that elevated O-GlcNAc levels increase IL-17A production. We also found that increased binding of the Th17 master transcription factor RAR-related orphan receptor γ t variant (RORγt) at the IL-17 gene promoter and enhancer, as well as significant alterations in the intracellular lipid microenvironment, elevates the production of ligands capable of increasing RORγt transcriptional activity. Importantly, the rate-limiting enzyme of fatty acid biosynthesis, acetyl-CoA carboxylase 1 (ACC1), is O-GlcNAcylated and necessary for production of these RORγt-activating ligands. Our results suggest that increased O-GlcNAcylation of cellular proteins may be a potential link between excess nutrient levels and pathological inflammation. |
| Databáze: | OpenAIRE |
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