Dual regulatory role of c-Rel O-GlcNAcylation in T cell function and Type 1 Diabetes

Abstract

Abstract O-GlcNAcylation is a post-translational protein modification involving the addition of N-acetylglucosamine (GlcNAc) to serine and threonine residues on target proteins. Global O-GlcNAcylation levels rise under hyperglycemia such as that caused by Type 1 Diabetes (T1D). We found that hyperglycemia induces O-GlcNAcylation of the NF-kappaB protein c-Rel at a single serine residue, S350. O-GlcNAcylation of c-Rel enhances its DNA binding and the transcription of c-Rel-dependent pro-autoimmune Th1 cytokines in T cells. This direct link between hyperglycemia and augmented Th1 function imply a key regulatory role for c-Rel O-GlcNAcylation in the pathology of T1D. Interestingly, our recent results show that O-GlcNAcylation inhibits binding of c-Rel to the FOXP3 promoter, leading to reduced FOXP3 expression. Together, these data suggest that c-Rel O-GlcNAcylation has a novel, dual regulatory role in controlling T cell function by: 1) Enhancing pro-autoimmune T cell function and 2) Suppressing Treg function. This creates an immune environment prone to heightened inflammation and autoimmunity that may exacerbate the frequency of autoimmunity in Western countries. Our current work focuses on defining the molecular mechanisms by which c-Rel O-GlcNAcylation regulates transcriptional activation in T cells and Treg cells. We are studying the non-obese diabetic (NOD) mouse model of spontaneous diabetes to examine the pathophysiological role of c-Rel O-GlcNAcylation. Knowledge on the regulation of autoimmunity by c-Rel O-GlcNAcylation will enhance our understanding of the etiology immune-mediated pathologies in diabetes and reveal a new therapeutic target to treat autoimmune diabetes.