Regulation of RIG-I signaling by a a novel interferon-inducible short form of RIG-I

视黄酸诱导基因I（Retinoic acid inducible gene I，RIG-I）属于胞质RNA解旋酶家族，识别病毒RNA配体，在诱导天然抗病毒反应尤其是I型干扰素（IFN）产生中起关键作用。RIG-I激活和下游信号传导受到严格调控，以避免可能对宿主产生有害影响的过度先天免疫应答，同时确保充分控制病毒感染。通过免疫沉淀和质谱分析，我们鉴定了一种I型IFN诱导的新型短型人RIG-I，具有负调控功能。这种短形式的RIG-I由I型IFN和在晚期时间点的RIG-I活化诱导，因此可能是在病毒感染后的正确时间点关闭RIG-I触发的I型IFN应答的关键分子。因此，本提案的目的是：i）阐明RIG-I短型的起源，其可能通过蛋白水解降解或翻译替代开放阅读框而产生，ii）研究RIG-I短型在人原代细胞中和暴露于RIG-I配体后或在病毒感染期间在小鼠体内的表达，和iii）研究这种新的短形式的RIG-I如何对RIG-I活化和信号传导发挥其负调节功能。

Retinoic acid inducible gene I (RIG-I) belongs to a family of cytosolic RNA helicases, which recognizes viral RNA ligands and is critical for the induction of innate antiviral responses especially type I Interferon (IFN) production. RIG-I activation and downstream signaling is tightly regulated to avoid excessive innate immune responses, which might have deleterious effects on the host, while ensuring sufficient control of viral infection. We have identified a type I IFN inducible novel short form of human RIG-I with negative regulatory function by immunoprecipitation and mass spectrometry analysis. This short form of RIG-I is induced by type I IFN and by RIG-I activation at late time points and might therefore be a critical molecule for shutting off the RIG-I triggered type I IFN response at the right time point after viral infection. The aims of this proposal are therefore: i) to elucidate the origin of RIG-I short form which might be generated by proteolytic degradation or translation of an alternative open reading frame, ii) to study the expression of RIG-I short form in human primary cells and in the mouse in vivo after exposure to RIG-I ligand or during viral infection, and iii) to investigate how this novel short form of RIG-I exerts its negative regulatory function on RIG-I activation and signaling.