Transcriptional regulation by O-GlcNAcylation in T lymphocytes

 描述(申请人提供)：高血糖是糖尿病的一个特征。高血糖的不良病理影响包括糖N-乙酰氨基葡萄糖增加细胞蛋白质丝氨酸和苏氨酸残基的翻译后修饰，这一过程称为O-GlcN酰化。我们发现，转录因子核因子-kappaB(NF-κB)亚单位c-Rel是这种病理性O-GlcN酰化的靶标。我们的初步数据显示，在T淋巴细胞中，c-Rel是在丝氨酸残基350位发生O-GlcN酰化的。C-Rel是T细胞功能和T细胞发育的主要调节因子，分别控制自身免疫和免疫抑制。我们发现，c-Rel O-GlcN酰化增加了其转录活性和自身免疫前细胞因子白介素2(IL-2)和干扰素γ(IFNG)的表达，并降低了转录因子叉头盒P3(FOXP3)的表达。在此基础上，我们推测c-Rel的O-GlcN酰化是一个关键的调节开关，在控制T细胞和T reg细胞的转录促进1型糖尿病自身免疫方面具有双重作用。在这里，我们建议研究c-relO-GlcN酰化在(1)原免疫细胞因子的转录调控和T细胞功能中的作用(2)FOXP3转录、T细胞发育和免疫抑制的调节以及(3)非GlcNacylatable c-rel表达的非肥胖糖尿病(NOD)小鼠模型的T细胞介导的自身免疫。这项研究探索了免疫新陈代谢的新兴领域。它揭示了c-relO-GlcN酰化是一种新的依赖于糖代谢的调节自身免疫的分子机制。抑制总的核因子-kappaB会引起广泛的副作用，尽管几十年的研究，基于分子靶点的药物治疗1型糖尿病仍然难以捉摸。因此，了解核因子-kappaB所经历的独特的翻译后修饰，如O-GlcN酰化，可能被证明是一个潜在的治疗靶点，并导致开发具有更高特异性的药物。此外，本研究还为探索c-rel O-GlcN酰化在其他自身免疫性疾病中的作用奠定了基础，如乳糜泻、狼疮和关节炎等与c-rel功能有关的疾病。

 DESCRIPTION (provided by applicant): 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-κB) 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.