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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI116730-01A1
Application #
9028299
Study Section
Cellular Signaling and Regulatory Systems Study Section (CSRS)
Program Officer
Bourcier, Katarzyna
Project Start
2016-04-01
Project End
2021-03-31
Budget Start
2016-04-01
Budget End
2017-03-31
Support Year
1
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Pathology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Tomalka, Jeffrey A; de Jesus, Tristan J; Ramakrishnan, Parameswaran (2017) Sam68 is a regulator of Toll-like receptor signaling. Cell Mol Immunol 14:107-117
Ramakrishnan, Parameswaran; Yui, Mary A; Tomalka, Jeffrey A et al. (2016) Deficiency of Nuclear Factor-?B c-Rel Accelerates the Development of Autoimmune Diabetes in NOD Mice. Diabetes 65:2367-79