去泛素化酶USP19调控多聚谷氨酰胺蛋白积聚的分子机制

The degradation and aggregation of polyglutamine (PolyQ) proteins are finely modulated by cellular quality-control system. We previously found that ubiquitin-specific protease 19 (USP19), a deubiquitinating enzyme, regulates the aggregation of PolyQ proteins (Huntingtin，Ataxin-3) through heat shock protein 90 (HSP90). In this project, we will study the molecular mechanism underlying regulation of PolyQ-protein aggregation by USP19, focusing on the structure, molecular recognition and regulatory function of its harboring CS1 and CS2 domains. We will investigate how USP19 interplays with PolyQ client protein mediated by HSP90 and then regulates the degradation and aggregation of the PolyQ protein; and how USP19 modulates its deubiquitination activity through self-inhibition of the catalytic domain (USPD) for exerting its regulatory function. By study of USP19 in molecular and cellular levels, we will understand the function of USP19 in regulating the degradation and aggregation of PolyQ proteins and its underlying molecular mechanism. The research will provide fundamental information for further deciphering pathologies of PolyQ diseases and discovering drug targets and therapeutic strategies.

细胞中多聚谷氨酰胺(PolyQ)蛋白的降解和积聚的稳态平衡受到质量控制系统所调控。我们以往的研究表明去泛素化酶USP19通过分子伴侣HSP90调控PolyQ蛋白(Huntingtin、Ataxin-3)的积聚水平。本申请项目拟研究USP19调控PolyQ蛋白的积聚过程及分子机制，重点是两个结构域CS1和CS2的结构、分子识别和调控功能。我们将研究USP19如何通过HSP90的介导与PolyQ客户蛋白形成复合物，进而调控PolyQ蛋白的降解和积聚；USP19如何通过催化结构域(USPD)的自抑制结构调节自身的酶活性进而发挥调控功能。通过研究，我们将更清晰地认识USP19在调控PolyQ蛋白降解和积聚过程中的功能，并揭示这一过程的分子机制，为理解PolyQ疾病的致病机理以及寻找相应的药物靶点或治疗方案提供理论依据。

去泛素化酶USP19通过分子伴侣HSP90能够调控PolyQ蛋白(如Huntingtin、Ataxin-3)的降解和积聚水平。本项目研究了USP19调控PolyQ蛋白的积聚过程及其分子机制，重点是两个结构域CS1和CS2的结构、分子识别和调控功能。我们揭示了USP19的N-端CS结构域与C-端插入结构域的识别和酶的自抑制效应；USP19通过与HSP90的相互作用调节Huntingtin蛋白的降解和积聚过程。 另外，我们还对 USP19调控致癌相关融合蛋白EWS-FLI1的蛋白质水平和凝聚进行了初步探索。研究成果对于认识USP19在调控PolyQ蛋白的功能作用和分子机制中具有重要意义，为理解PolyQ疾病的致病机理以及寻找相应的药物靶点或治疗方案提供了理论依据。