Hyperglycemia is a hallmark of diabetes. Adverse pathological effects of hyperglycemia include the increased posttranslational modification of cellular proteins at serine and threonine residues by the sugar N- acetylglucosamine, in a process termed O-GlcNAcylation. We found that the transcription factor nuclear factor- kappaB (NF-?B) subunit, c-Rel, is a target for this pathologic O-GlcNAcylation. Our preliminary data shows that c-Rel is O-GlcNAcylated at serine residue 350 in T lymphocytes. c-Rel is the major regulator of T cell function and T regulatory (T reg) cell development that controls autoimmunity and immunosuppression, respectively. We found that c-Rel O-GlcNAcylation increases its transcriptional activity and the expression of pro- autoimmune cytokines interleukin-2 (IL-2) and interferon gamma (IFNG), and decreases the expression of the transcription factor, forkhead box P3 (FOXP3) in T cells. Based on this, we hypothesize that O-GlcNAcylation of c-Rel serves as a key regulatory switch with dual roles in controlling transcription in T cells and T reg cells promoting autoimmunity in type 1 diabetes. Here, we propose to study the role of c-Rel O-GlcNAcylation in (1) the transcriptional regulation of proautoimmune cytokines and T cell function (2) regulation of FOXP3 transcription, T reg cell development and immunosuppression and (3) T cell-mediated autoimmunity using non- GlcNAcylatable c-Rel expressing non obese diabetic (NOD) mouse model. This study explores the emerging area of immunometabolism. It reveals c-Rel O-GlcNAcylation as a novel glucose metabolism-dependent molecular mechanism that regulates autoimmunity. Inhibition of total NF-kappaB elicits broad side effects and despite decades of research, drugs based on molecular targets to treat type 1 diabetes have remained elusive. Therefore, understanding unique post-translational modifications such as O-GlcNAcylation, that NF-kappaB undergoes, could prove a potential therapeutic target and lead to develop drugs with higher specificity. Moreover, this study serves as the basis to explore the role of c-Rel O-GlcNAcylation in other autoimmune diseases such as celiac disease, lupus and arthritis, where c-Rel function has been implicated.
Type 1 diabetes or autoimmune diabetes is a chronic, lifelong disease with over 15000 children diagnosed every year and more than 370 million people affected worldwide. The proposed project will reveal a novel molecular mechanism promoting self-reactivity of immune cells (autoimmunity) in type 1 diabetes. This study will generate two new publicly available mouse models of this disease. It will also lay the foundation to develop potential therapeutic reagents to treat type 1 diabetes and ameliorate its secondary complications such as renal failure, blindness, heart problems and nerve damage.
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