泛素蛋白酶体系统的失调涉及许多人类疾病的发病机理，包括癌症、神经退行性和病毒性疾病。泛素是一种重要的调控成分在各种宿主过程，包括宿主对病毒感染的反应。泛素特异性蛋白酶（USP）是控制蛋白质泛素化循环的去泛素化酶（DUB）。在神经退行性疾病中，DUB的作用知之甚少。狂犬病病毒（RABV）作为严格的嗜神经性病毒，可导致中枢神经系统发生退行性疾病。然而，DUB如何调控RABV引起神经退行性疾病的发病机制还未可知。为了检测DUB在RABV感染期间的作用，我们使用了一种小分子DUB抑制剂PR-619，发现其可能是通过靶向USP3来抑制RABV的复制。我们将通过蛋白质组学与泛素化修饰蛋白质组学分析及鉴定差异表达的DUB，从而进一步研究USP3在病毒感染过程中的作用，对阐明RABV的复制机制及DUB在RABV引起的退行性疾病中的作用具有重要的意义，同时为开发狂犬病的治疗药物提供新的靶标。

Deregulation of the ubiquitin-proteasome system has been implicated in the pathogenesis of many human diseases, including cancer, neurodegenerative disorders and viral diseaes. Ubiquitin is a vital regulatory component in various cellular processes, including cellular responses to viral infection. Ubiquitin specific proteases (USP) are de-ubiquitinases (DUB) that control protein ubiquitination cycle. The role of DUB is poorly understood in neurodegenerative diseases. Rabies virus (RABV), a rigorous neurotropic virus, can cause neurodegenerative diseases in the central nervous system. However, how DUB modulate pathogenesis of RABV-induce neurodegenerative diseases is poorly understood. To examine the role of DUB during RABV infection, we used a small molecule DUB inhibitor PR-619, which was found to be likely to inhibit RABV replication by targeting USP3. We will analysis and identify differentially expressed DUB by proteomics and ubiquitination-modified proteomics , and further investigate the role of USP3 in viral infection, which is important to elucidate the replication mechanism of RABV and DUB in RABV-induced neurodegenerative diseases, and to provide new targets for the development of therapeutic drugs for rabies.