Analysis of virus-induced signaling leading to IRF-3 activation

先天免疫对于根除感染的病毒起着至关重要的作用。在这项工作中，我们分析了导致病毒诱导的抗病毒天然免疫激活的信号机制。我们鉴定了RNA解旋酶，维甲酸诱导基因(RIG)-I，作为病毒诱导I型干扰素基因激活的信号分子，而I型干扰素基因是抗病毒天然免疫的关键。RIG-I的解旋酶结构域负责识别病毒双链RNA，其完整的ATPase活性是信号转导所必需的。RIG-I的caspase募集结构域(CARD)传递下游信号，导致转录因子、IRF-3和I型干扰素基因的激活。此外，对Rig-I缺陷小鼠的分析清楚地表明了Rig-I在启动抗病毒天然免疫中的重要作用。我们还测定了其他RIG-I家族解旋酶MDA5和LGP2的功能。结果表明，MDA5是病毒诱导信号的正向调节因子，LGP2是RIG-I/MDA5介导的信号传导的主要负调节因子。我们将研究这些解旋酶在病毒诱导的信号转导中的分子机制(S)和生理意义。

Innate immunity plays an essential role for eradication of infected viruses. In this work, we analyzed signaling machinery that leads to virus-induced activation of antiviral innate immunity. We identified RNA helicase, retinoic acid inducible gene (RIG)-I, as signaling molecule for virus-induced activation of type I interferon genes, which are known to be critical for antiviral innate immunity. The helicase domain of RIG-I was responsible for recognition of viral double stranded RNA and its intact ATPase activity was essential for signaling. The caspase recruitment domain (CARD) of RIG-I transmitted downstream signals, resulting in the activation of transcription factor, IRF-3, and type I interferon genes. Furthermore, analysis of RIG-I-deficient mice clearly showed the essential role of RIG-I for initiation of antiviral innate immunity. We also determined the function of other RIG-I family helicases, MDA5 and LGP2. Our data indicated that MDA5 acts as positive regulator for virus-induced signal and LGP2 functions as a dominant negative regulator of RIG-I/MDA5-mediated signaling. We are going to examine a molecular mechanism(s) and physiological significance of these helicases in virus-induced signaling.