The NF-kappaB protein c-Rel is essential for the expression of forkhead box P3 (FOXP3), the master transcription factor that governs development and function of T regulatory cells. We found that O-GlcNAcylation of c-Rel at serine residue 350 suppresses the expression of FOXP3. Hyperglycemia-induced c-Rel O-GlcNAcylation-dependent suppression of FOXP3 expression was found in vivo in two mouse models of autoimmune diabetes; the streptozotocin (STZ)-induced diabetic mouse model and in the non-obese diabetic (NOD) mouse model. Mechanistically, we show that both hyperglycemia-induced and chemically enhanced cellular O-GlcNAcylation decreases the DNA binding ability of c-Rel at the FOXP3 promoter. 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 regulating immunosuppressive FOXP3 expression in autoimmune diabetes with potential therapeutic implications.
P. Ramakrishnan: None. T.J. de Jesus: None. J. Centore: None.
National Institutes of Health (R01AI116730, R21AI144264)