RUI: Control of CIITA Function and Immune System Gene Expression by Phosphorylation

RUI：通过磷酸化控制 CIITA 功能和免疫系统基因表达

• 批准号: 0212067
• 负责人: Drew Cressman
• 金额: $ 27.14万
• 依托单位: Sarah Lawrence College
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-10-01 至 2005-09-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0212067&HistoricalAwards=false
• 关键词: RUI; Control; CIITA; Function; Immune

When a body is threatened by foreign pathogens, expression of a variety of immune system genes allows cells to react to this threat and initiate an immune response. Central to inducing this immune response is the activation of the master regulator factor, the class II transactivator (CIITA). CIITA acts in the nucleus of cells to induce the expression of genes necessary for the presentation of foreign peptides on the cell surface. The CIITA protein is know to be present in both the cytoplasmic and nuclear compartments of cells, although the significance for this bimodal distribution and the factors that regulate it are unclear. It has been well established that the addition or subtraction of phosphate group moieties to a cellular protein can modify the activity and localization of that particular protein. Preliminary data indicates that CIITA is indeed subject to phosphorylation; however, the effect this phosphorylation has on regulating the function of the CIITA protein is unknown. One hypothesis is that phosphorylation of CIITA specifically present in the nucleus shuts down CIITA-regulated gene expression and subsequently induces the export of CIITA from the nucleus out to the cytoplasm. This may allow the organism to rapidly and precisely control the timing and extent of CIITA activity, and therefore mediate the magnitude of the immune response. This project will examine this hypothesis by: 1) identifying the cellular mechanisms and factors that mediate phosphorylation of CIITA; 2) determining the effect phosphorylation has on CIITA activity; and 3) identifying the protein domains that mediate the export of CIITA from the nucleus. Understanding the cellular and molecular mechanisms that control CIITA activity will be crucial to devising strategies to manipulate the immune system and alter immune responses.This project will identify the cellular mechanisms by which the immune system is regulated and signaled to respond to the presence of foreign pathogens. Laboratory experiments will determine how the central control protein, CIITA, is structurally modified and regulated and what effect these modifications have on the function of the protein within cells. This research will provide a basis for generating therapeutic strategies to modify and enhance the therapeutic abilities of the immune system at the molecular and cellular level. Additionally, during the three-year timeframe of this project, undergraduate students will participate in the program as summer or academic year interns, establishing the foundation for further curricular development and strengthening undergraduate scientific training at Sarah Lawrence College.

当身体受到外来病原体的威胁时，各种免疫系统基因的表达允许细胞对这种威胁做出反应并启动免疫反应。 诱导这种免疫应答的核心是主调节因子II类反式激活因子（CIITA）的激活。 CIITA在细胞核中起作用以诱导在细胞表面上呈递外源肽所必需的基因的表达。 已知CIITA蛋白存在于细胞的细胞质和细胞核区室中，尽管这种双峰分布的意义和调节它的因素尚不清楚。 已经充分确定，向细胞蛋白质添加或减去磷酸基团部分可以改变该特定蛋白质的活性和定位。 初步数据表明，CIITA确实受到磷酸化;然而，这种磷酸化对调节CIITA蛋白功能的影响尚不清楚。 一种假设是特异性存在于细胞核中的CIITA的磷酸化关闭CIITA调节的基因表达，随后诱导CIITA从细胞核输出到细胞质。 这可能允许生物体快速和精确地控制CIITA活性的时间和程度，并因此介导免疫应答的大小。 本项目将通过以下方式检验这一假设：1）确定介导CIITA磷酸化的细胞机制和因素; 2）确定磷酸化对CIITA活性的影响; 3）确定介导CIITA从细胞核输出的蛋白质结构域。 了解控制CIITA活性的细胞和分子机制对于设计操纵免疫系统和改变免疫反应的策略至关重要。本项目将确定免疫系统调节和响应外来病原体存在的细胞机制。 实验室实验将确定中央控制蛋白CIITA是如何在结构上进行修饰和调节的，以及这些修饰对细胞内蛋白质的功能有什么影响。 这项研究将为产生治疗策略提供基础，以在分子和细胞水平上修改和增强免疫系统的治疗能力。 此外，在该项目的三年时间内，本科生将作为暑期或学年实习生参加该项目，为进一步的课程开发奠定基础，并加强莎拉劳伦斯学院的本科科学培训。