Journal
GLYCOBIOLOGY
Volume 31, Issue 7, Pages 812-826Publisher
OXFORD UNIV PRESS INC
DOI: 10.1093/glycob/cwab001
Keywords
autoimmunity; NF-kappaB; transcription; Treg cells; type 1 diabetes
Categories
Funding
- National Institute of Health, NIH/The National Institute of Allergy and Infectious Diseases [R01 AI116730, R21 AI144264]
- NIH/National Cancer Institute [R21 CA246194]
- National Institute of Health NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases T32 predoctoral training grant through the Department of Dermatology, CaseWestern Reserve University [T32AR007569]
- National Institute of Health NIH/National Eye Institute T32 through the Department of Ophthalmology, CaseWestern Reserve University [T32EY007157]
- AAI Careers in Immunology Fellowship
- National Institute of Health NIH/NEI T32 postdoctoral training grant through the Department of Ophthalmology, Case Western Reserve University [T32EY007157]
Ask authors/readers for more resources
The study reveals that high glucose-induced O-GlcNAcylation negatively regulates FOXP3 expression through modulating c-Rel binding at the FOXP3 promoter, impacting immunosuppression and proautoimmune gene expression in autoimmune diabetes.
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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available