Neddylation介导的Nedd4-2激活在肾脏水电解质代谢中的作用机制

Neddylation是类泛素蛋白Nedd8共价结合靶蛋白的过程。目前研究多集中在Neddylation修饰Cullin-RING家族泛素E3调节泛素-蛋白质降解，而与非Cullin 的HECT家族泛素E3及其底物的研究鲜有报道。HECT家族泛素E3成员之一Nedd4-2是否被Neddylation修饰及其在调节水电解质代谢的生理作用和在高血压的病理生理机制仍未知。因此，本课题一方面将鉴定Neddylation修饰Nedd4-2及其活性位点，阐明其对肾脏离子通道和离子转运体的泛素化水平的调节机制。另一方面，根据前期研究结果，Nedd4-2和Nedd8在CYP4F2转基因小鼠肝和肾组织的差异性表达，将阐述20-HETE对Neddylation和Deneddylation修饰Nedd4-2在高血压发病机制中的调节作用，为治疗高血压提供新的治疗靶点。

Neddylation is a process of the covalent attachment of ubiquitin-like protein Nedd8 to target proteins. The relevant research has been focused on neddylation modification of Cullin-RING family ubiquitin ligases E3 and its substrates regulating degradation of proteins. However, regulation of non-Cullin HECT family ligases E3 by neddylation has been rarely reported to date. It is still unknown whether Nedd4-2, a member of HECT family ligases, is modified by neddylation, and what is role of its neddylation in water/electrolyte metabolism and in pathogenesis of hypertension. Therefore, the project, in one hand, is going to identify Nedd4-2 activation by neddylation and its active site, and to clarify the mechanism by which neddylation-mediated Nedd4-2 regulates ion channels and ion transporters through ubiquitin-proteasome pathway in kidney. On the other hand, according to our preliminary finding that the different expression of Nedd4-2 and Nedd8 appears in liver and kidney of the CYP4F2 transgenic mice, the project is going to verify the neddylation and deneddylation of Nedd4-2 regulated by 20-HETE play a role in pathogenesis of hypertension. The study will provide new therapeutic targets for the treatment of hypertension.