去泛素化酶USP19在炎症反应中的功能及作用机制研究

NF-kB是介导炎症反应的核心转录因子，其激活调控的紊乱与非可控炎症及炎癌转化密切相关。在本项目前期研究中，申请人通过NF-kB报告基因实验筛选了1.3万个cDNA表达克隆，发现去泛素化酶USP19能抑制促炎症因子TNFa和IL-1b诱导的NF-kB激活，反之，USP19的敲低或敲除则在细胞水平促进这一过程，而且其潜在靶点可能是激酶TAK1。申请人还发现USP19抑制Toll样受体3/4而非其它TLRs介导的NF-kB激活，这暗示USP19通过不同的机理调控多条NF-kB活化途径。基于此，本项目计划在细胞及动物水平深入研究USP19在IL-1R、TNFR和TLRs介导的NF-kB激活过程中的精细调控作用及机制。并利用炎症性结直肠癌小鼠模型探讨USP19在炎癌转化中的潜在作用。该项目的完成不仅解析了一种NF-kB激活调控的新机制，同时也为炎性疾病的治疗和药物开发提供指导。

The transcription factor NF-kB is a central mediator of inflammatory response, its activation and regulations are greatly associated with the chronic inflammation and cancer. Here, we screened 13,000 expression clones by NF-kB reporter assays, and identified USP19 as a negative regulator of TNFa- and IL-1b-triggered signaling. In overexpression experiments, USP19 interacted with TAK1 and inhibited TNFa- and IL-1b-triggered NF-kB activation, whereas knockdown or knockout of USP19 had opposite effects. Beyond that, knockout of Usp19 potentiated TLR3/4- but not TLR2/7-mediated NF-kB activation. Based on these findings, our current project will use Usp19 knockout mice and aims to reveal the physiological functions of USP19 in different receptors (including IL-1R, TNFR, and TLRs)-mediated NF-kB activation, and its potential roles in tumorigenesis, especially the AOM/DSS-induced colon cancer. In addition, we will further elucidate the exact molecular mechanisms of USP19 in the regulation of NF-kB activation. Our research will enrich the basic research of regulations of NF-kB signaling, and contribute to the therapies and medicine explorations to the inflammatory diseases.