Molecular Regulation of CIITA Function by GTP-Binding

描述（由申请方提供）：II类MHC基因的诱导是抗肿瘤细胞因子IFN-γ增强免疫应答的中心事件。II类反式激活因子（CIITA）是II类MHC、DM和不变链的主要转录开关，并参与I类MHC和β 2-微球蛋白基因的转录。因此CIITA是IFN-γ和上调对抗原呈递和免疫应答调节重要的基因之间的联系。CIITA的缺陷导致组成型和诱导型II类MHC表达的丧失，这导致T细胞和抗体介导的免疫的组合丧失。CIITA已经成为研究II类MHC基因调控的主要领域，并且是控制II类MHC表达和抗原呈递从而改变免疫应答的许多策略的靶标。参与抗原加工和呈递的基因的调节改变是肿瘤细胞逃避免疫监视的机制，并与某些肿瘤的转移相关。改变II类MHC表达的能力不仅在肿瘤生物学中具有广泛的意义，而且在对感染因子、自身免疫性疾病和移植的免疫应答中也具有广泛的意义。清楚地了解CIITA功能对于设计和实施旨在操纵免疫应答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的行动方式的了解仍然有限。CIITA是一种非传统的和独特的非DNA结合转录辅激活因子，其利用GTP结合和富含亮氨酸的重复序列将有效的激活结构域递送到广泛的一组相关启动子。CIITA到达细胞核中命令启动子可及性和转录激活。该提议试图通过以下方式阐明调节CIITA功能的核心机制：1）理解GTP结合在调节CIITA的反式激活因子功能中的作用，2）探索CIITA的C-末端在调节转录中的贡献，以及3）研究如何操纵CIITA调节以影响其可以影响的各种基因的表达。这些知识将有助于建立一个框架，最终不仅可以准确地了解CIITA在转录控制中的功能，还可以改善免疫疗法。

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.