Negative regulation of FOXP3 expression by c-Rel O-GlcNAcylation
| Autor: | Tristan J de Jesus, Angela R Liu, Parameswaran Ramakrishnan, Franklin D Staback Rodriguez, Joshua Centore, Ruchira A Agarwal, Timothy S. Kern, Jeffrey Tomalka |
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| Rok vydání: | 2021 |
| Předmět: |
Biochemistry & Molecular Biology
type 1 diabetes T cell T-Lymphocytes Immunology Biochemistry T-Lymphocytes Regulatory Autoimmune Disease Medical and Health Sciences Diabetes Mellitus Experimental 03 medical and health sciences Mice Experimental 0302 clinical medicine Transcription (biology) Gene expression medicine Transcriptional regulation Diabetes Mellitus Genetics Animals 2.1 Biological and endogenous factors Interferon gamma NF-kappaB Aetiology Transcription factor Metabolic and endocrine 030304 developmental biology 0303 health sciences Chemistry autoimmunity Diabetes FOXP3 Forkhead Transcription Factors Biological Sciences Regulatory Proto-Oncogene Proteins c-rel Cell biology medicine.anatomical_structure Gene Expression Regulation 030220 oncology & carcinogenesis REL transcription Treg cells medicine.drug |
| Zdroj: | Glycobiology, vol 31, iss 7 Glycobiology |
| Popis: | O-GlcNAcylation is a reversible post-translational protein modification that regulates fundamental cellular processes including immune responses and autoimmunity. Previously, we showed that hyperglycemia increases O-GlcNAcylation of the transcription factor, nuclear factor kappaB c-Rel at serine residue 350 and enhances the transcription of the c-Rel-dependent proautoimmune cytokines interleukin-2, interferon gamma and granulocyte macrophage colony stimulating factor in T cells. c-Rel also plays a critical role in the transcriptional regulation of forkhead box P3 (FOXP3)—the master transcription factor that governs development and function of Treg cells. Here we show that the regulatory effect of c-Rel O-GlcNAcylation is gene-dependent, and in contrast to its role in enhancing the expression of proautoimmune cytokines, it suppresses the expression of FOXP3. Hyperglycemia-induced O-GlcNAcylation-dependent suppression of FOXP3 expression was found in vivo in two mouse models of autoimmune diabetes; streptozotocin-induced diabetes and spontaneous diabetes in nonobese diabetic mice. Mechanistically, we show that both hyperglycemia-induced and chemically enhanced cellular O-GlcNAcylation decreases c-Rel binding at the FOXP3 promoter and negatively regulates FOXP3 expression. Mutation of the O-GlcNAcylation site in c-Rel, (serine 350 to alanine), augments T cell receptor-induced FOXP3 expression and resists the O-GlcNAcylation-dependent repression of FOXP3 expression. This study reveals c-Rel S350 O-GlcNAcylation as a novel molecular mechanism inversely regulating immunosuppressive FOXP3 expression and proautoimmune gene expression in autoimmune diabetes with potential therapeutic implications. |
| Databáze: | OpenAIRE |
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