Type 1 diabetes is an autoimmune disease associated with hyperglycemia. Increased glucose flux enhances the hexosamine biosynthetic pathway and intracellular posttranslational modification of proteins by the sugar N-acetyl glucosamine (GlcNAc) in a process called O-GlcNAcylation. We discovered that hyperglycemia increases the O-GlcNAcylation of the transcription factor, nuclear factor kappaB (NF-κB) c-Rel at serine 350. O-GlcNAcylation of c-Rel activates c-Rel-dependent transcription of proautoimmune cytokines in T cells and inhibits the expression of T regulatory cell specific transcription factor FOXP3. These reciprocal effects caused by c-Rel O-GlcNAcylation may act as positive feedback accelerator of autoimmunity under hyperglycemia. Hence, blocking the function of O-GlcNAcylated c-Rel will have dual benefits in controlling autoimmune diabetes by diminishing the T cell-mediated autoimmunity and enhancing the T regulatory cell function to suppress autoimmunity. We developed a novel peptoid, called peptoid3 that specifically blocks the function of O-GlcNAcylated c-Rel. 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. Peptoid3 treatment selectively affected autoimmunity-associated genes and did not exhibit toxicity on survival or proliferation of T cells. Broad inhibition of hexosamine biosynthetic pathway or NF-κB will cause many side effects due to their ubiquitous importance in multiple biological functions. Therefore, inhibitors of O-GlcNAcylated NF-κB c-Rel function may prove long-sought-after specific molecular therapeutic to diminish autoimmunity in type 1 diabetes.
P. Ramakrishnan: None. J. Pokorski: None. T.J. de Jesus: None. J. Centore: None.
National Institute of Allergy and Infectious Diseases (R01AI116730-01A1)