PRMT1调控CIITA转录活性的机制研究及其生物学意义

MHC II molecules play a key role in the adaptive immune response of the host by selectively activating T lymphocyte. Class II transactivator (CIITA) is the master regulator of MHC II transactivation. The transcriptional activity of CIITA is modulated by a host of factors, among which post-translational modification (PTM, including methylation, phosphorylation, and acetylation) has gained tremendous attention in recent years. Our preliminary data indicate that CIITA interacts with a type I protein arginine methyltransferase (PRMT1). Silencing PRMT1 significantly dampens CIITA-dependent activation of MHC II transcription. More importantly, PRMT1 increases asymmetric methylation of CIITA. Of note, three stress stimuli known to suppress MHC II expression, namely chronic hypoxia, excessive oxidized low-density lipoprotein (oxLDL), and replicative senescence, down-regulate PRMT1 expression in cells indicating that PRMT1 might serve as a prime target for stress cues to impair the adaptive immune response. We hypothesize that PRMT1 potentiates MHC II transcription by methylating and thus potentiating CIITA. Our goals are to investigate the mechanism underlying which PRMT1 regulates CIITA activity and to assess the possibility that enhanced PRMT1 expression may overcome diminished MHC II expression and antigen presentation in cells confronted with stress. Our investigation will likely yield novel strategies for combating immune diseases.

MHC II在适应性免疫应答及T细胞的选择活化过程中具有重要作用。MHC II 反式激活蛋白(CIITA)是调控其表达的关键分子。CIITA的转录活性受到多种因素影响，其中翻译后修饰（PTM，包括甲基化、磷酸化、乙酰化等）调控是近年来的一个研究热点。蛋白精氨酸甲基化是一种非常重要的蛋白翻译后修饰。申请者在研究中发现，CIITA与I型精氨酸甲基转移酶PRMT1在细胞内存在互相作用；干扰内源PRMT1后，依赖于CIITA的MHC II启动子转录活性下降50%左右。本项目研究目的是观察PRMT1对CIITA 转录活性调控的机制以及对巨噬细胞抗原呈递功能的影响。并且在此基础上，使用不同的应激因素(缺氧、oxLDL、复制衰老等)作用下，检测PRMT1稳定细胞是否在MHC II分子的表达、CIITA的精氨酸甲基化、抗原呈递能力等方面有明显改善。此项目研究为研制新一代的治疗免疫系统疾病药物提供靶点。

MHC II在适应性免疫应答及T细胞的选择活化过程中具有重要作用。MHC II 反式激活蛋白(CIITA)是调控其表达的关键分子。CIITA的转录活性受到多种因素影响，其中翻译后修饰（PTM，包括甲基化、磷酸化、乙酰化等）调控是近年来的一个研究热点。蛋白精氨酸甲基化是一种非常重要的蛋白翻译后修饰。申请者在研究中发现，CIITA与I型精氨酸甲基转移酶PRMT1在细胞内存在互相作用；干扰内源PRMT1后，依赖于CIITA的启动子转录活性下降50%左右。本项目研究目的是观察PRMT1对CIITA 转录活性调控的机制以及对巨噬细胞抗原呈递功能的影响。并且在此基础上，使用不同的应激因素(缺氧、oxLDL、复制衰老等)作用下，检测PRMT1稳定细胞是否在MHC II分子的表达、CIITA的精氨酸甲基化、抗原呈递能力等方面有明显改善。此项目研究为研制新一代的治疗免疫系统疾病药物提供靶点。