Transcriptional regulation of Foxp3 expression by protein ubiquitination

蛋白质泛素化对 Foxp3 表达的转录调控

基本信息

批准号：
8860293
负责人：
YUN-CAI LIU
金额：
$ 46.59万
依托单位：
LA JOLLA INSTITUTE FOR IMMUNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至 2016-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8860293
关键词：
Adaptor Signaling Protein Affect Allergic Disease Autoantigens Autoimmune Diseases Autoimmunity Binding Binding Proteins Biochemical Biochemical Reaction Biological Biological Process C-terminal CD28 gene CD4 Positive T Lymphocytes Colitis Collaborations Defect Development Epigenetic Process Fingers Gene Expression Genes Genetic Genetic Transcription Goals Hypersensitivity IL2RA gene Immune Immune System Diseases Immune Tolerance Immune response Immune system Immunosuppression Instruction Interleukin-2 Invaded Investigation Knowledge Ligase Link Lymphocyte Maintenance Malignant Neoplasms Mediating Molecular Mus N-terminal Pathway interactions Phospholipase Phosphorylation Phosphotransferases Play Process Production Proline Protein Family Protein Tyrosine Kinase Proteins Regulation Regulatory T-Lymphocyte Research Personnel Role Signal Pathway Signal Transduction Signaling Molecule Solid T cell anergy T-Cell Activation T-Cell Proliferation T-Lymphocyte Techniques Testing Time Tissues Transcriptional Regulation Tretinoin Ubiquitination airway inflammation allergic response base design genome-wide genome-wide analysis in vivo innovation killer T cell link protein member mouse model novel novel therapeutic intervention pathogen programs promoter protein expression response transcription factor ubiquitin-protein ligase

项目摘要

PROJECT SUIVIIVIARY (See instructions): Our long-term goal is to study the regulation of immune responses under normal and diseased conditions, particularly the involvement of protein ubiquitination pathway in lymphocyte development, activation, and tolerance induction. Cbl-b is composed of an N-terminal tyrosine kinase binding domain, a RING finger, and C-terminal proline-rich sequences. Genetic studies using Cbl-b deficient mice have shown that Cbl-b is critical in T cell activation, and loss of Cbl-b results in increased autoimmunity. Cbl-b functions as RING-type E3 ubiquitin ligase to promote ubiquitin conjugation to critical signaling molelcules and affects their biological functions. More importantly, we showed that Cbl-b is upregulated during T cell anergy induction and controls the tolerigenic process, thus linking protein ubiquitination pathway to the T cell tolerance. We have recently obtained some unexpected and novel observations. Particularly, we found that Cbl-b is involved in the regulation of Foxp3 expression in inducible regulatory T cells (iTregs) via modulating a novel signaling pathway directly acting at the transcriptional regulation of Foxp3 gene. The new findings form a strong basis for us to hypothesize that Cbl-b plays an essential role in controlling immune responses via promoting protein ubiquitination. In this proposal, we will plan: 1) to investigate the molecular mechanisms by which Cblb E3 ubiquitn ligase regulates Foxp3 gene transcription via modulating Foxo3a-directed gene transcription and to perform genome-wide gene profiling of Tregs to understand the molecular regulation of epigenetic control in Tregs; 2) to examine the in vivo function of iTregs in mouse models of autoimmunity and airway inflammation. These studies will significantly advance our understanding ofthe molecular mechanisms governing Foxp3 gene transcription and ITreg-mediated immune regulation. Such knowledge will eventually facilitate the design of novel therapeutic approaches for cancer, autoimmune and allergic diseases.

项目 SUIVIIVIARY（参见说明）：我们的长期目标是研究正常和患病条件下免疫反应的调节，特别是蛋白质泛素化途径参与淋巴细胞的发育、激活和耐受诱导。 Cbl-b 由 N 端酪氨酸激酶结合结构域、环指和 C 端富含脯氨酸的序列。使用 Cbl-b 缺陷小鼠进行的遗传学研究表明，Cbl-b Cbl-b 对 T 细胞激活至关重要，Cbl-b 的缺失会导致自身免疫增强。 Cbl-b 用作 RING 型 E3 泛素连接酶促进泛素与关键信号分子缀合并影响其生物学功能。更重要的是，我们发现 Cbl-b 在 T 细胞无反应性诱导和控制过程中上调耐受性过程，从而将蛋白质泛素化途径与 T 细胞耐受性联系起来。我们最近有获得了一些意想不到的、新颖的观察结果。特别是，我们发现 Cbl-b 参与通过调节新的信号传导来调节诱导性调节 T 细胞 (iTreg) 中的 Foxp3 表达途径直接作用于Foxp3基因的转录调控。新发现奠定了坚实的基础让我们假设 Cbl-b 通过促进免疫反应在控制免疫反应中发挥重要作用蛋白质泛素化。在这个提案中，我们将计划：1）研究Cblb的分子机制 E3泛素连接酶通过调节Foxo3a指导的基因转录来调节Foxp3基因转录并对 Tregs 进行全基因组基因分析，以了解表观遗传的分子调控 Tregs 的控制； 2) 检查iTregs在小鼠自身免疫和气道模型中的体内功能炎。这些研究将显着增进我们对分子机制的理解控制 Foxp3 基因转录和 ITreg 介导的免疫调节。这些知识最终将促进癌症、自身免疫性疾病和过敏性疾病的新型治疗方法的设计。