RIPK1蛋白的泛素化修饰调节炎症免疫反应的分子机制研究

RIPK1是调控细胞程序性死亡和炎症等免疫反应的一个关键分子。近期临床研究发现病人中RIPK1表达缺失或突变与炎性肠炎、反复感染和多发性关节炎等病症密切相关。蛋白质的翻译后修饰精密调控其功能发挥，其中泛素化修饰近年来倍受研究者关注。然而，RIPK1作为一个关键蛋白如何被泛素化修饰调控并最终影响机体免疫反应和炎性疾病的进程仍需深入探究。.我们课题组多年致力于炎症和免疫反应信号通路调节的分子机制研究。本项目拟系统研究RIPK1蛋白的泛素化修饰调节细胞程序性死亡和炎症反应的分子机制，利用条件敲除和酶活性位点突变小鼠模型，分析RNF31调控RIPK1泛素化的机制，解析RIPK1线性泛素化影响细胞程序性死亡和炎性疾病的机理，同时探索CBM复合体参与RIPK1泛素化过程的具体机制。为深入理解线性泛素化修饰和RIPK1的生理功能提供新思路，也为相关炎性疾病的治疗提供新的分子靶标和干预策略。

RIPK1 is a key protein functioning to regulate programmed cell death and inflammation-related innate immune responses. Recently, several clinical studies showed that RIPK1 deletions or mutations are closely correlated with a few kinds of inflammatory diseases, such as colon inflammation, reciprocating infection and polyarticular arthritis. Post-translational modification of proteins precisely regulates their function, and ubiquitin modification has attracted much attention in recent years. However, it is still not clear how ubiquitin modification regulates the RIPK1 activation and the downstream function, which affect the immune response and progress of inflammatory diseases..Our group has been focusing on signal transduction pathways mediated innate immune and inflammation in response to microbial infection for more than eighteen years. This project is to investigate the molecular mechanisms that RIPK1 ubiquitination regulate the inflammation and innate immune responses. By using conditional knockout and enzymatic site-specific mutation knock-in animal models, we will identify and characterize the E3 ligase, especially RNF31, that regulates RIPK1 activation, determine how RIPK1 linear ubiquitination affects the programmed cell death (including apoptosis, necrosis and pyroptosis) and inflammatory disease. Moreover, we will analyze how CBM complex regulates RIPK1 ubiquitination process and their physiological function. Results from these lines of investigation will help better understanding of the physiological function of linear ubiquitination and RIPK1, and importantly, provide the molecular insight for designing therapeutic targets and agents against inflammatory diseases.