RNF115调控抗病毒天然免疫信号转导的功能与机制研究

MAVS和MITA是介导抗病毒天然免疫的关键接头蛋白，其活性与稳定性受到泛素化修饰的严格调控。尽管有若干个蛋白被报道泛素化MAVS和MITA，但其在静息状态以及病毒感染后等不同时空内发生泛素化的精细调控机制仍不清楚。我们发现E3泛素连接酶RNF115与MAVS和MITA相互作用并介导其泛素化。RNF115与MAVS存在持续相互作用，VSV感染后减弱，而与MITA的相互作用受HSV-1的诱导。敲低RNF115分别促进RNA病毒和抑制DNA病毒感染诱导的信号转导，表明RNF115可能通过不同的机制在不同时空介导MAVS和MITA的泛素化，进而调控不同类型病毒感染诱导的信号转导。我们已经制备了Rnf115基因敲除小鼠，拟通过本项目深入研究RNF115调控抗病毒天然免疫应答的功能与机制。相关结果将推动对天然免疫应答精细调控机制的了解，并为相关疾病的治疗提供理论基础和分子靶标。

MAVS and MITA are two adaptor proteins critically involved in innate antiviral signaling. Their activity and stability are strictly controlled by posttranslational modifications such as ubiquitination. Although several E3s have been reported to catalyze ubiquitination of MAVS and MITA, the exact regulatory mechanisms in a temporal and spatial context are incompletely understood. In current study, we have found that RNF115 interacts with and catalyzes ubiquitination of MAVS and MITA. Interestingly, RNF115 interacts with MAVS constitutively and such a interaction is impaired by infection of SeV or VSV or by transfection of poly(I:C), whereas RNA115 interacts with MITA only after HSV-1 infection, indicating that RNF115 interacts with MAVS and MITA in a temporally dependent manner. In addition, we found that knockdown of RNF115 potentiates RNA virus-triggered signaling and inhibits DNA virus-triggered signaling, respectively. These preliminary data together indicate that RNF115 may regulate innate antiviral signaling in different temporal and spatial phases in response to viral infections by catalyzing distinct modes of ubiquitination of MAVS and MITA. We have generated Rnf115 knockout mice and plan to explore the functions and mechanisms of RNF115-mediated regulation of innate antiviral immunity. These findings will not only elucidate the exact temporal and spatial regulation of MAVS and MITA ubiquitination, but also provide potential strategies and therapeutic targets for future infection-related diseases.