MAP4K3介导的Hippo-YAP通路与IFN-I通路crosstalk的研究

Innate immunity serves as the first line of defense against pathogen infection. Type I Interferon (IFN-I)-mediated antiviral responses play crucial roles in resisting viral infection and maintaining homeostasis in body. The Hippo pathway senses cellular conditions and controls cellular and tissue homeostasis, organ size via regulation of YAP/TAZ. Crosstalk between Hippo-YAP pathway and IFN-I pathway was proven in our previous work. MAP4K3, an important protein kinase in the Hippo-YAP pathway, was identified to have a significant inhibitory effect on IFN-I expression. Knock down of MAP4K3 significantly enhanced the expression of IFN-I and reduced the replication of viruses. However, the molecular mechanism for the inhibitory role of MAP4K3 is still unclear. This project is designed to investigate the molecular mechanisms by which MAP4K3 inhibits the IFN-I expression and IFN-I-mediated the antiviral response via molecular biology and immunology techniques. The regulatory roles of MAP4K3 on the expression of IFN-I, viral proliferation and pathogenicity will be further studied in vivo. Upon successful conclusion of this work, we will clarify the new regulatory mechanisms of innate immunity, and make the crosstalk between IFN-I and Hippo-YAP pathway more comprehensive. This project will provide new ideas for the prevention and treatment of viral infection and autoimmune diseases.

天然免疫是机体防御病原体感染的第一道防线，其中I型干扰素（IFN-I）介导的抗病毒反应在抵抗病毒感染，维持自身稳定的过程中发挥重要作用。Hippo-YAP信号通路在组织平衡和器官大小调控中发挥重要作用。在之前的工作中我们发现，Hippo通路与IFN-I通路之间存在密切的crosstalk。我们发现Hippo通路中的重要蛋白激酶MAP4K3对病毒诱导的IFN-I表达具有显著的抑制作用，然而其作用的分子机制尚不清楚。本课题拟研究MAP4K3抑制IFN-I表达的分子机制，并检测MAP4K3在小鼠IFN-I表达、病毒增殖、致病过程中的作用，阐明蛋白激酶MAP4K3调控抗病毒天然免疫的机制，及其在IFN-I与Hippo-YAP通路crosstalk中发挥的作用。本项目将为开发抗病毒感染、自身免疫性疾病的防治策略提供新思路。

天然免疫是机体防御病原体感染的第一道防线，其中I型干扰素（IFN-I）介导的抗病毒反应在抵抗病毒感染，维持自身稳定的过程中发挥重要作用。Hippo-YAP信号通路在组织平衡和器官大小调控中发挥重要作用。我们在之前的工作中发现，Hippo通路与IFN-I通路之间存在密切的crosstalk。本项目发现Hippo通路核心组分MAP4K3可显著增强RNA病毒感染诱导的抗病毒天然免疫，而干扰MAP4K3具有相反的作用。MAP4K3敲除小鼠感染病毒后其抗病毒天然免疫反应显著降低，而病毒增殖、致病能力和小鼠的死亡率升高。进一步的研究发现，MAP4K3可直接结合MAVS，并磷酸化其S249位点，促进其结合E3泛素连接酶TRIM31，进而促进MAVS的K63连接的多聚泛素化、寡聚化，以及对下游信号分子TRAF3、IKKε的募集。另外，细胞的营养状态，如氨基酸浓度，可通过MAP4K3调控宿主抗病毒天然免疫。本研究阐明Hippo与抗病毒天然免疫互作的新机制，为开发新型抗病毒药物、抗病毒治疗手段提供靶点。在本项目的支持下，共发表论文9篇，其中包括Nature Cell Biology（2021）、Nature Immunology（2022）、Cell Reports（2022）、Signal transduction and targeted therapy（2020）等，受理国家发明专利1项。