常染色体显性遗传性多囊肾病（ADPKD）是最常见的遗传性多囊肾疾病，主要由PKD1或PKD2基因突变所致。目前对于PKD2乙酰化修饰及其功能尚无报道。我们发现PKD2能够被乙酰化酶KAT2A及去乙酰化酶SIRT2调控；且PKD2的乙酰化水平能够影响其与泛素化酶HERC4的结合，继而影响PKD2的表达和细胞膜电流的改变。据此推测：PKD2乙酰化通过改变HERC4对PKD2的靶向泛素化作用，继而调控其自身的表达及功能。本课题拟从以下3个方向进行研究：①细胞模型确定KAT2A/SIRT2对PKD2的乙酰化调控作用；②PKD2乙酰化通过HERC4调控其自身泛素化及功能的分子机制；③在斑马鱼模型中，验证PKD2乙酰化对斑马鱼肾囊肿表型的影响，进一步阐明PKD2乙酰化在ADPKD发生发展中的作用。本项目的研究不仅有助于完善ADPKD的信号调控网络及发病机制，更为临床上对ADPKD的治疗提供全新的思路。

Autosomal-dominant polycystic kidney disease (ADPKD) is the most common form of inherited polycystic kidney disease (PKD)and due to mutations in the PKD1 or PKD2 gene which encodes a membrane receptor and a Ca-permeable ion channel, respectively. Currently, it is unknown whether and how acetylation is involved in the regulation of PKD2. Our previous study showed that the level of PKD2 acetylation can be regulated by KAT2A or SIRT2. Additionally, the level of acetylated PKD2 modulated the binding of ubiquitination ligase HERC4 and PKD2, affecting its expression and function for membrane current. These data indicated that PKD2 acetylation regulated its expression and functions, which required PKD2 ubiquitinated by HERC4. Based on our preliminary results, in Aim 1 we propose to investigate how PKD2 acetylation sites K16 and K714 regulates its function via directly interaction of SIRT2-PKD2 or KAT2A-PKD2 in cell model. In Aim 2, we propose to investigate the molecular mechanisms the molecular mechanism by which PKD2 acetylation regulates its function through HERC4 mediated ubiquitination for PKD2 in cell model. In Aim 3, we propose to utilize zebrafish model to characterize the function of PKD2’s acetylation. Implementation of this study will enhance our understanding in the mechanism and additional pathway of ADPKD, and could provide novel therapeutic strategies and targets for ADPKD treatment.