Molecular Regulation of CIITA Function by GTP-Binding

描述(由申请人提供)：诱导第二类MHC基因是抗肿瘤细胞因子干扰素-伽马增强免疫反应的中心事件。第二类反式激活因子(CIITA)是第二类MHC、DM和不变链的主要转录开关，参与第一类MHC和β2-微球蛋白基因的转录。因此，CIITA是干扰素-γ和对抗原呈递和免疫反应调节重要的基因上调之间的联系。CIITA缺陷导致结构性和诱导性II类MHC表达的丧失，从而导致T细胞和抗体介导的免疫联合丧失。CIITA已成为研究第二类MHC GO调控的主要领域，也是许多控制第二类MHC表达和抗原提呈从而改变免疫反应的策略的靶点。参与抗原处理和提呈的基因调控改变是肿瘤细胞逃避免疫监视的一种机制，并与某些肿瘤的转移有关。改变第二类MHC表达的能力不仅在肿瘤生物学上有广泛的意义，而且在对感染性物质、自身免疫性疾病和移植的免疫反应中也有广泛的意义。对CIITA功能的清楚理解对于设计和实施旨在操纵免疫反应基因用于肿瘤免疫治疗的策略至关重要。尽管最近取得了进展，但我们对CIITA的行动模式的了解仍然有限。CIITA是一种非常规的、独特的非DNA结合的转录共激活因子，它利用GTP结合和富含亮氨酸的重复序列将一个有效的激活结构域传递给一系列相关的启动子。CIITA到达细胞核后，既能控制启动子的可及性，又能激活转录。本研究试图通过1)了解GTP结合在调控CIITA反式激活功能中的作用，2)探索CIITA的C末端在转录调控中的作用，以及3)研究如何操纵CIITA的调控来影响其所能影响的各种基因的表达，从而阐明CIITA功能调控的核心机制(S)。这些知识将有助于建立一个框架，最终可能不仅导致对CIITA在转录控制中的功能的准确看法，而且还可能导致改进免疫疗法的途径。

DESCRIPTION (provided by applicant): The induction of class II MHC genes is a central event in the augmentation of immune responses by the anti-tumor cytokine, IFN-gamma. The class II transactivator (CIITA) is a master transcriptional switch for class II MHC, DM, and invariant chain and participates in transcription of class I MHC and beta2-microglobulin genes. CIITA is thus a link between IFN-gamma and the upregulation of genes important for antigen presentation and modulation of immune responses. Defects in CIITA result in a loss of both constitutive and inducible class II MHC expression which leads to a combined loss of T-cell and antibody mediated immunity. CIITA has become the major area of interest in the study of class II MHC gone regulation and is the target of numerous strategies to control class II MHC expression and antigen presentation thereby altering immune responses. Altered regulation of genes involved in antigen processing and presentation is a mechanism by which tumors cells escape immune surveillance and correlates with metastasis in some tumors. The ability to alter class II MHC expression has broad implications not only in tumor biology but in immune responses to infectious agents, autoimmune disease, and transplantation as well. A clear understanding of CIITA function is crucial for devising and implementing strategies aimed at manipulation of immune response genes for tumor immunotherapy. Despite recent advances, our understanding of CIITA's mode-of-action remains limited. CIITA is an unconventional and unique non-DNA binding transcriptional coactivator that utilizes GTP-binding and leucine-rich repeats to deliver a potent activation domain to a broad set of related promoters. Arrival of CIITA in the nucleus commands both promoter accessibility and transcriptional activation. This proposal seeks to elucidate mechanism(s) central to regulating CIITA's function by 1) understanding the role of GTP-binding in regulating CIITA's transactivator function, 2) exploring the contributions of CIITA's C-terminus in regulating transcription, and 3) investigating how CIITA regualtion can be manipulated to impact the expression of the various genes it can influence. This knowledge will help establish a framework that may ultimately lead not only to an accurate view of CIITA's function in transcriptional control, but avenues for improved immunotherapies.