MAP4K1激酶负调控RIG-I/MAVS/TBK1抗病毒免疫应答机理研究

识别病毒成分的受体，包括RLRs、TLRs、和cGAS都利用TBK1磷酸化IRF3/IRF7，最终促进干扰素和细胞因子的产生，引发抗病毒先天免疫应答，任何过度干扰素和细胞因子的产生对机体都是有害的。RNA病毒被RIG-I识别后，TBK1被招募到RIG-I/MAVS复合物并被快速激活。在这个过程中，TBK1的活化状态必须受到严格监管以便维护机体内稳定的免疫状态。.我们发现MAP4K1与TBK1相互作用，促进TBK1的降解负调控RIG-I介导的抗病毒免疫应答。TBK1的降解一般由E3连接酶通过泛素化实现，但MAP4K1激酶没有连接酶活性。研究发现MAP4K1通过与E3连接酶DTX4相互作用，促进DTX4对TBK1的泛素化修饰，加速TBK1的降解。本项目拟对MAP4K1负调控RIG-I/MAVS/TBK1介导的抗病毒信号转导机理做深入研究，研究结果将使我们对TBK1介导的先天免疫应答有新的认识。

Receptors that recognize viral components, including RLRs, TLRs, and cGAS, use TBK1 to phosphorylate IRF3 / IRF7, which ultimately promotes the production of interferons and cytokines and triggers antiviral innate immune responses. Any excessive interferon and cytokine production is harmful. Upon recognition of viral RNA　by RIG-I, TBK1 was recruited to the RIG-I / MAVS complex and quickly activated. During this process, the activation state of TBK1 must be strictly regulated in order to maintain a stable immune state in the body..We found that MAP4K1 interacts with TBK1 and promotes the degradation of TBK1 to negatively regulate RIG-I-mediated antiviral immune responses. The degradation of TBK1 is generally achieved by ubiquitination by E3 ligase, but MAP4K1 kinase has no ligase activity. The study found that MAP4K1 interacts with the E3 ligase DTX4 to promote the ubiquitination modification of TBK1 by DTX4 and accelerate the degradation of TBK1. This project intends to make an in-depth study on the mechanism of MAP4K1 negative regulation RIG-I / MAVS / TBK1-mediated antiviral signal transduction. The results of the study will give us a new understanding of the innate immune response mediated by TBK1.