Regulation of TCR Signaling by Sts-1 and Sts-2

Sts-1 和 Sts-2 对 TCR 信号传导的调节

• 批准号: 8197150
• 负责人: NICHOLAS A CARPINO
• 金额: $ 38.41万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-10 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8197150
• 关键词: Address; Amino Acid Sequence; Apoptosis; Autoimmune Diseases; Autoimmune Responses; Autoimmunity; Biochemical; Biological; Biological Models; C-terminal; CCL4 gene; Cells; Coupled; Cues; Employee Strikes; Ensure; Enzymes; Etiology; Goals; Immune System Diseases; Immune response; Immune system; Individual; Laboratories; Link; Modeling; Multiple Sclerosis; Mus; N-terminal; Outcome; Pathology; Peripheral; Phenotype; Phosphoglycerate Mutase; Phosphoric Monoester Hydrolases; Phosphorylation; Play; Predisposition; Production; Proliferating; Property; Protein Binding Domain; Protein Tyrosine Kinase; Protein Tyrosine Phosphatase; Proteins; Receptor Signaling; Regulation; Research; Role; SH3 Domains; Shapes; Signal Pathway; Signal Transduction; Stream; Structure; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; Testing; Tissues; UBA Domain; Ubiquitin; arm; cytokine; design; insight; mouse model; novel; pathogen; prevent; public health relevance; receptor; research study; response; therapy development

DESCRIPTION (provided by applicant): The same properties that allow T cells to mount an effective immune response can be turned against host tissue, provoking an autoimmune response. Intriguingly, T cell auto-reactivity is often the result of deregulated signaling pathways within T cells. Thus, understanding the etiology of different autoimmune diseases will require a thorough and integrated understanding of the mechanisms that control T cell activation. The long-term objective of my research is to understand the regulation of T cell activation. Currently, my laboratory is studying how two related proteins, Sts-1 and Sts-2, act in concert to negatively regulate T cell signaling pathways. The Sts proteins have a unique modular structure, with an N- terminal ubiquitin-interacting domain (UBA), a central protein-protein interaction domain (SH3), and a C- terminal region with homology to the enzyme phosphoglycerate mutase (PGM). The realization that the Sts proteins have a role in regulating TCR signaling pathways emerged from an analysis of mice lacking Sts-1 and -2. T cells from Sts-1/2-/- mice dramatically hyper-proliferate in response to TCR stimulation. This hyper- proliferative phenotype is accompanied by increased activation of signaling pathways downstream of the TCR, elevated levels of cytokine production, and increased susceptibility of Sts-1/2-/- mice to autoimmunity in a mouse model of multiple sclerosis. In our ongoing effort to characterize the functions of the Sts proteins, we recently discovered a novel protein tyrosine phosphatase activity associated with the Sts PGM domain. Intriguingly, the Sts phosphatase domain shows no similarity to classical PTPs in primary amino acid sequence and important catalytic features. Coupled with the fact that no known PTP contains a UBA or SH3 domain, our results suggest that the Sts proteins operate in an intracellular signaling niche within T cells that is separate and distinct from classical PTPs. The experiments outlined in this proposal are designed to address the underlying function(s) and mechanism(s) of action of the Sts-1 and Sts-2. Our Specific Aims are: 1. Determine how the Sts proteins regulate T cell activation thresholds via regulation of Zap-70. 2. Determine how the three Sts modular domains (UBA, SH3, PGM) cooperate to negatively regulate TCR signaling pathways. We will use a combination of biochemical, biophysical, and cell biological approaches to accomplish our goals. Completion of the studies described herein will help us build a model of how the Sts proteins cooperate to negatively regulate TCR signaling pathways. PUBLIC HEALTH RELEVANCE: Autoimmune diseases arise when normal regulatory mechanisms within the immune system fail. Developing therapies that will prevent or cure autoimmune diseases will require a thorough and integrated understanding of the mechanisms that control the immune response. This project focuses on understanding the function(s) and mechanism(s) of action of a closely related pair of negative regulators of T cell receptor signaling, Sts-1 and Sts-2.

描述（由申请人提供）：允许 T 细胞产生有效免疫反应的相同特性可以转化为针对宿主组织，引发自身免疫反应。有趣的是，T 细胞自身反应性通常是 T 细胞内信号通路失调的结果。因此，了解不同自身免疫性疾病的病因需要对控制 T 细胞激活的机制有全面、综合的了解。我研究的长期目标是了解 T 细胞激活的调节。 目前，我的实验室正在研究两种相关蛋白 Sts-1 和 Sts-2 如何协同作用来负向调节 T 细胞信号通路。 Sts 蛋白具有独特的模块化结构，具有 N 端泛素相互作用结构域 (UBA)、中心蛋白质-蛋白质相互作用结构域 (SH3) 和与磷酸甘油酸变位酶 (PGM) 同源的 C 端区域。通过对缺乏 Sts-1 和 -2 的小鼠进行分析，我们认识到 Sts 蛋白在调节 TCR 信号通路中发挥作用。 Sts-1/2-/- 小鼠的 T 细胞响应 TCR 刺激而急剧过度增殖。这种过度增殖表型伴随着TCR下游信号通路激活的增加、细胞因子产生水平的升高以及多发性硬化症小鼠模型中Sts-1/2-/-小鼠对自身免疫的易感性增加。 在我们不断研究 Sts 蛋白功能的过程中，我们最近发现了一种与 Sts PGM 结构域相关的新型蛋白酪氨酸磷酸酶活性。有趣的是，Sts 磷酸酶结构域在一级氨基酸序列和重要催化特征方面与经典 PTP 没有相似之处。再加上没有已知的 PTP 含有 UBA 或 SH3 结构域，我们的结果表明 Sts 蛋白在 T 细胞内的细胞内信号传导生态位中发挥作用，该生态位与经典 PTP 是独立且不同的。本提案中概述的实验旨在解决 Sts-1 和 Sts-2 的基本功能和作用机制。我们的具体目标是： 1. 确定 Sts 蛋白如何通过调节 Zap-70 来调节 T 细胞激活阈值。 2. 确定三个 Sts 模块结构域（UBA、SH3、PGM）如何协同负向调节 TCR 信号通路。我们将结合使用生物化学、生物物理和细胞生物学方法来实现我们的目标。完成本文描述的研究将帮助我们建立 Sts 蛋白如何合作负向调节 TCR 信号通路的模型。 公共卫生相关性：当免疫系统内的正常调节机制失效时，就会出现自身免疫性疾病。开发预防或治疗自身免疫性疾病的疗法需要对控制免疫反应的机制有全面、全面的了解。该项目的重点是了解一对密切相关的 T 细胞受体信号传导负调节因子 Sts-1 和 Sts-2 的功能和作用机制。