Transcriptional regulation by O-GlcNAcylation in T lymphocytes

T 淋巴细胞中 O-GlcNAc 酰化的转录调节

• 批准号: 9251750
• 负责人: Parameswaran Ramakrishnan
• 金额: $ 39.63万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9251750
• 关键词: Adverse effects; Affect; Area; Arthritis; Autoimmune Diabetes; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Bacterial Artificial Chromosomes; Biological Assay; Blindness; Bone Marrow; C57BL/6 Mouse; CD4 Positive T Lymphocytes; Celiac Disease; Cell physiology; Cells; Child; Chronic; DNA Biochemistry; Data; Development; Diabetes Mellitus; Diagnosis; Disease; Disease model; FOXP3 gene; Foundations; Gene Expression; Gene Expression Profiling; Gene Targeting; Genes; Genetic Transcription; Granulocyte-Macrophage Colony-Stimulating Factor; Heart; Human; Hyperglycemia; Immune; Immunosuppression; Immunosuppressive Agents; Impairment; Inbred NOD Mice; Insulin-Dependent Diabetes Mellitus; Interferon Type II; Interleukin-2; Jurkat Cells; Kidney Failure; Knockout Mice; Lead; Lupus; Mediating; Molecular; Molecular Target; Monoclonal Antibodies; Mus; NF-kappa B; Nerve; Nuclear; Pathogenesis; Pathologic; Patients; Pharmaceutical Preparations; Physiological; Post-Translational Protein Processing; Process; Protein Biochemistry; Proteins; Reagent; Receptor Activation; Regulation; Research; Role; Serine; Specificity; T cell response; T-Cell Receptor; T-Lymphocyte; Therapeutic; Threonine; To autoantigen; Transcriptional Activation; Transcriptional Regulation; Transforming Growth Factor beta; Transgenic Mice; Transgenic Organisms; base; c new; chromatin immunoprecipitation; cytokine; experimental study; forkhead protein; glucose metabolism; in vivo; molecular drug target; mouse model; mutant; novel; public health relevance; reconstitution; sugar; therapeutic target; transcription factor

 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.

 描述（由申请人提供）：高血压是糖尿病的标志。高血糖症的不良病理学作用包括在称为O-GlcNAc酰化的过程中，糖N-乙酰葡糖胺在丝氨酸和苏氨酸残基处对细胞蛋白的翻译后修饰增加。我们发现转录因子核因子-κ B（NF-κB）亚单位c-Rel是这种病理性O-GlcNAc酰化的靶点。我们的初步数据表明，c-Rel是在T淋巴细胞的丝氨酸残基350 O-GlcNAc酰化。c-Rel是分别控制自身免疫和免疫抑制的T细胞功能和T调节（T reg）细胞发育的主要调节因子。我们发现c-Rel O-GlcNAc化增加其转录活性和促自身免疫细胞因子白介素-2（IL-2）和干扰素γ（IFNG）的表达，并降低T细胞中转录因子叉头盒P3（FOXP 3）的表达。基于此，我们假设c-Rel的O-GlcNAc化作为一个关键的调节开关，在控制T细胞和T reg细胞的转录中具有双重作用，从而促进1型糖尿病的自身免疫。在此，我们提出使用表达非GlcNAc酰化c-Rel的非肥胖糖尿病（NOD）小鼠模型来研究c-Rel O-GlcNAc酰化在（1）促自身免疫细胞因子和T细胞功能的转录调节（2）FOXP 3转录、T reg细胞发育和免疫抑制的调节和（3）T细胞介导的自身免疫中的作用。这项研究探讨了免疫代谢的新兴领域。它揭示了c-Rel O-GlcNAc酰化作为一种新的葡萄糖代谢依赖性分子机制，调节自身免疫。抑制总NF-κ B产生广泛的副作用，尽管经过数十年的研究，基于分子靶点的药物治疗1型糖尿病仍然难以捉摸。因此，了解独特的翻译后修饰，如O-GlcNAc酰化，NF-κ B经历，可以证明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-GlcNAc化在其他自身免疫性疾病如乳糜泻、狼疮和关节炎中的作用奠定了基础，其中c-Rel功能已经受到牵连。