Presenter of 1 Presentation
O100 - NOVEL MOLECULAR TARGET AND THERAPEUTIC FOR THE TREATMENT OF AUTOIMMUNE DIABETES (ID 12)
Abstract
Background and Aims
Autoimmune diabetes involves T cell-mediated destruction of pancreatic beta cells resulting in hyperglycemia. Increased glucose flux enhances O-GlcNAcylation, an intracellular posttranslational modification of nucleo-cytoplasmic proteins. We found that hyperglycemia increases O-GlcNAcylation of NF-kappaB subunit c-Rel at serine residue 350 and enhances the transcription of pro-autoimmune cytokines, IL-2, IFNG and GM-CSF in T cells. 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) that controls Treg cell development and function. Hence, blocking the function of O-GlcNAcylated c-Rel will have benefits in controlling autoimmune diabetes by diminishing the T cell-mediated autoimmunity.
Methods
We developed a novel peptoid, called OGC350, by molecular modeling and de novo synthesis, and studied its potential to bind to O-GlcNAcylated c-Rel and block its function.
Results
We found that OGC350 treatment significantly decreased T cell receptor-induced, O-GlcNAcylation-dependent expression of proautoimmune cytokines and enhanced FOXP3 expression in T cells. OGC350 treatment selectively affected autoimmunity-associated genes and did not exhibit toxicity on survival or proliferation of T cells.
Conclusions
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 to treat type 1 diabetes. Broad inhibition of hexosamine biosynthetic pathway or NF-kappaB will cause many side effects due to their ubiquitous importance in multiple biological functions. Therefore, inhibitors of O-GlcNAcylated NF-kappaB c-Rel function may prove long-sought-after specific molecular therapeutic to diminish autoimmunity in type 1 diabetes.