上游开放阅读框uORF防止MAVS自发聚集以维持天然免疫稳态的机制研究

RIG-I-MAVS信号转导通路是机体抗RNA病毒天然免疫的重要环节。当病毒侵染细胞后，线粒体抗病毒蛋白MAVS受RIG-I激活，以朊病毒样聚集体的形态激活下游信号转导通路，产生I型干扰素和促炎症因子来清除病毒。在静息细胞中，MAVS受到严格的调控而处于非聚集形态，以维持天然免疫系统的稳态。一旦调控出现差池MAVS将自发聚集，引发细胞因子风暴和慢性炎症反应等严重后果。目前，关于静息细胞如何防止MAVS自发聚集这一重要问题，领域内还没有展开过系统地研究。课题组前期工作显示，MAVS基因上游开放阅读框uORF的缺失会引起细胞内源MAVS的自发聚集。本项目以此为基础，旨在解析uORF防止MAVS自发聚集和天然免疫失调的开关调节机制，并建立MAVS基因uORF与系统性红斑狼疮的联系。本项目将拓展我们对于静息细胞中MAVS调控网络的认识，同时也为MAVS相关自身免疫性疾病的诊断提供新的依据。

RIG-I-MAVS signaling pathway plays critical roles in host innate immune response to RNA virus. On viral infection, RIG-I senses RNA signal and induces the adaptor protein MAVS to form prion-like aggregates (active), which stimulate the downstream signaling pathway and trigger the production of type I interferons to restrict virus proliferation. Although the MAVS prion-like aggregates are essential for antiviral signal transduction, endogenous MAVS in unstimulated cells is kept from aggregation (inactive) to maintain host immune homeostasis. However, the mechanism preventing cellular MAVS from spontaneous aggregation is poorly understood. Here we propose to study the regulatory mechanism of uORF in Mavs transcripts on Mavs gene function and spontaneous aggregation. Moreover, in vivo studies revealing the correlation between Mavs uORF and systemic lupus erythematosus (SLE) will be performed. This study will extend our understanding of the mechanism preventing cellular MAVS from spontaneous aggregation, and provide insight for medical diagnosis of systematic autoimmune diseases like SLE.