Targeting c-Rel O-GlcNAcylation to control hyperglycemia-dependent transcription in T lymphocytes

Abstract

Abstract The NF-kappaB protein c-Rel plays a critical role in controlling regulating T cell function and T regulatory cell development. We found that hyperglycemia increases O-GlcNAcylation of c-Rel at serine residue 350 and enhances the transcription of c-Rel-induced CD28RE-dependent pro-autoimmune cytokines, interleukin-2 (IL-2), interferon gamma (IFNG) and granulocyte macrophage colony stimulating factor (GM-CSF). Our recent results show that the regulatory effect of c-Rel O-GlcNAcylation is gene dependent and it suppresses the transcription of forkhead box P3 (FOXP3) expression in T cells. Mechanistically, we found that O-GlcNAcylation enhances the DNA binding of c-Rel at CD28RE and decreases it’s binding at the FOXP3 promoter. To specifically block O-GlcNAcylated c-Rel function, we developed a peptoid, called peptoid3 that specifically binds to O-GlcNAcylated c-Rel by molecular modeling and de novo synthesis. We found that peptoid3 treatment significantly decreased T cell receptor-induced, O-GlcNAcylation-dependent expression of proautoimmune cytokines and enhanced FOXP3 expression in T cells. This study reveals c-Rel S350 O-GlcNAcylation as a novel molecular mechanism inversely regulating proautoimmune gene expression and immunosuppressive FOXP3 expression in T cells with potential therapeutic implications in conditions such as type 1 diabetes.