精氨酸甲基化修饰对细胞运动关键蛋白HDAC6的调控

组蛋白去乙酰化酶6（HDAC6）是细胞运动的重要调节因子，能够依赖其去乙酰化酶活性或者与其他蛋白质分子的相互作用调控细胞运动的多个方面，包括细胞迁移、纤毛解聚、上皮-间充质转化以及肿瘤的迁移和侵袭等。HDAC6功能异常会导致纤毛病及癌症等疾病的发生。然而，调控HDAC6在细胞运动中发挥功能的上游蛋白或信号通路尚不清楚。本项目前期研究发现，精氨酸甲基转移酶PRMT5能够催化HDAC6发生精氨酸甲基化修饰，HDAC6精氨酸甲基化修饰降低了HDAC6的蛋白稳定性。在此基础上，本项目将深度解析HDAC6发生精氨酸甲基化修饰后其蛋白稳定性、活性及亚细胞定位的改变，揭示HDAC6精氨酸甲基化在细胞迁移和纤毛解聚中的功能和相应分子机制，并探讨PRMT5在细胞迁移和纤毛解聚中发挥的作用。这一研究将丰富HDAC6功能调控的分子信号网络，并为靶向HDAC6用于一系列疾病的治疗提供一个新的科学视角。

Accumulating evidence has revealed that Histone deacetylase 6 (HDAC6) is an important regulator of cell motility. HDAC6 regulates many important cell motility processes, including cell migration, ciliary disassembly, epithelial-mesenchymal transition, and tumor migration and invasion, through its deacetylase activity and interaction with other proteins. Emerging evidence shows that abnormal function of HDAC6 could result in ciliopathies as well as tumor formation. However, the upstream proteins or signaling pathways that regulate the biological actions of HDAC6 in cell motility remain unknown. In our previous studies, we identified that arginine methyltransferase PRMT5 could catalyze HDAC6 arginine methylation, and HDAC6 arginine methylation reduced its protein stability. In the proposed study, we will dissect deeply the changes of protein stability, activity and subcellular localization of HDAC6 after arginine methylation, reveal the function and molecular mechanisms of HDAC6 arginine methylation in cell migration and ciliary disassembly and explore the role of PRMT5 in cell migration and ciliary disassembly. This study will provide novel insights into the signaling network which participates in HDAC6 function regulation and provide a new scientific perspective for targeting HDAC6 in the treatment of a series of diseases.