Abstract
Abstract The NF-kappaB protein c-Rel plays a critical role in controlling autoimmunity through regulating T cell function and T regulatory cell development. Type 1 diabetes is a T cell-mediated autoimmune disease associated with hyperglycemia and chronic inflammatory complications. Previously, we discovered that hyperglycemia induces hyper O-GlcNAcylation of c-Rel at serine residue 350 and enhances the transcription of c-Rel-dependent pro-autoimmune cytokines interleukin-2 (IL-2), interferon gamma (IFNG) and granulocyte macrophage colony-stimulating factor (GM-CSF). In contrast, our recent results show that c-Rel O-GlcNAcylation decreases forkhead boxP3 (FOXP3) expression in T cells. Chemically enhancing cellular O-GlcNAcylation decreases the DNA binding ability of c-Rel at the FOXP3 promoter as demonstrated both by oligonucleotide pulldown and chromatin immunoprecipitation assays. Moreover, mutation of serine 350 in c-Rel to alanine augments T cell receptor-induced FOXP3 expression. O-GlcNAcylation-dependent suppression of FOXP3 was also found in vivo in streptozotocin-induced diabetic mouse model. This study reveals a novel molecular mechanism that regulates hyperglycemia-dependent c-Rel function in autoimmune diabetes, with potential to develop novel therapeutics targeting c-Rel O-GlcNAcylation.
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