PRRSV非结构蛋白NSP4和细胞蛋白SRCAP相互作用调控Notch-RBP-Jκ信号通路的机制

猪繁殖与呼吸综合征病毒（PRRSV）是危害养猪业首要病原之一。非结构蛋白NSP4是PRRSV最重要的病毒蛋白酶，可抑制NF-κB信号通路而抑制先天性免疫反应。我们前期研究发现NSP4与Notch信号通路转录激活因子SRCAP相互作用，二者相互作用可抑制转录因子RBP-Jκ转录，促进PRRSV感染，但是具体作用机制不清楚。本项目通过研究（1）SRCAP在PRRSV感染过程中作用机制；（2）NSP4和SRCAP相互作用调控RBP-Jκ转录机制；（3）NSP4调控RBP-Jκ转录抑制先天性免疫反应机制。解析NSP4和SRCAP相互作用激活Notch-RBP-Jκ信号通路的机制，明确激活该信号通路促进PRRSV的机制。研究结果将揭示NSP4调控基因转录的新功能和抑制先天性免疫反应的新机制，为以NSP4和Notch信号通路为靶标设计抗PRRSV感染药物提供理。

Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most economically important pathogens in the global swine industry. Currently, the mechanism of PRRSV pathogenesis has yet to be fully understood. PRRSV nonstructural protein 4 (NSP4) is a viral proteinase responsible for the proteolytic processing of NSP3-12 into individual non-structural proteins which are the main components of viral replication/transcription complex. In our previous study, we elucidated the interactome of NSP4 and identified Snf2-related CBP activator protein (SRCAP) as an interacting partner of NSP4. The interaction between NSP4 and SRCAP was found to reduce the transcription of the recombination signal binding protein for immunoglobulin kappa (RBP-Jκ), which results in the activation of the Notch signal pathway and enhanced PRRSV replication. In this project, we propose to investigate the mechanism of NSP4-SRCAP interaction in activating the Notch signaling pathway and enhancing PRRSV replication focusing on three specific aims. In Aim 1, we will determine the role of SRCAP in PRRSV infection. In Aim 2, we will study how the interaction between NSP4 and SRCAP regulates the transcriptional activity of RBP-Jκ. In Aim 3, we will explore how the RBP-Jκ affecting PRRSV infection by regulating NF-κB signaling pathway. The data generated in this study will provide information on the new function of PRRSV NSP4 in regulating gene transcription and suppressing the innate immune response, and also on the development of drugs against PRRSV infection.