Tollip在RIG-I介导的抗病毒天然免疫信号通路中的作用及机制

RIG-I是细胞内感知病毒侵染的重要模式识别受体，该信号通路受到复杂而精细的调控以维持免疫系统的稳态平衡。Tollip是Toll样受体信号通路的负调节因子，但是它在RIG-I信号通路的作用尚不清楚。我们前期研究发现，过表达Tollip抑制RIG-I和下游接头蛋白MAVS诱导的干扰素表达，敲除Tollip增强poly(I:C)及RNA病毒如VSV和SeV诱导的RIG-I信号通路激活。本项目拟利用Tollip过表达和沉默细胞系以及Tollip敲除小鼠，结合荧光素酶报告基因、空斑实验等技术深入研究Tollip对RIG-I信号通路的调控并明确其在抗病毒天然免疫中的作用；使用免疫共沉淀、SDD-AGE和基因突变体阐明Tollip与信号转导蛋白的相互作用及其机制。本研究将揭示Tollip在RIG-I信号通路中的作用，增加对抗病毒天然免疫调控机制的认知，为相关疾病的治疗提供新的靶点和研究思路。

Retinoic acid-inducible gene-I (RIG-I) is an important cytoplasmic pattern recognition receptor for sensing viral infection. The signaling pathway is complicated and finely regulated to maintain the homeostasis of the immune system. The Toll-interacting protein (Tollip) is a negative regulator of Toll-like receptor signaling pathway. However, the role of Tollip in the RIG-I signaling pathway is unclear. Our preliminary studies found that overexpression of Tollip inhibits the interferon induction by RIG-I and downstream adaptor protein called mitochondrial antiviral signaling protein (MAVS); knocking out Tollip enhances the activation of RIG-I signaling pathway induced by poly(I:C) or RNA viruses such as VSV and SeV. This project aims to use Tollip overexpression or silencing cell lines and Tollip knockout mice, combined with luciferase reporter assays, viral plaque assays and other technologies to investigate the regulation of RIG-I signaling pathway by Tollip and clarify its role in antiviral innate immunity; the interactions between Tollip and signal transduction proteins and the corresponding mechanism will be explored using immunoprecipitation, SDD-AGE and gene mutations. This study will reveal the role of Tollip in the RIG-I signaling pathway, enrich the regulatory mechanism of antiviral innate immunity, and provide new targets and research ideas for the treatment of related diseases.