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

维甲酸诱导基因I(RIG-I)属于胞质RNA解旋酶家族，识别病毒的RNA配体，在诱导天然抗病毒反应，尤其是I型干扰素(Interferon，IFN)的产生中起关键作用。RIG-I的激活和下游信号被严格调控，以避免过度的先天性免疫反应，这可能对宿主产生有害影响，同时确保充分控制病毒感染。通过免疫沉淀和质谱分析，我们已经鉴定出一种I型干扰素诱导的新型人RIG-I短型，具有负调节功能。这种短形式的RIG-I是由I型干扰素和晚期时间点的RIG-I激活诱导的，因此可能是在病毒感染后的正确时间点关闭RIG-I触发I型干扰素反应的关键分子。因此，本提议的目的是：1)阐明RIG-I短形蛋白的起源，它可能是由蛋白质降解或翻译另一个开放阅读框架产生的；2)研究RIG-I短形蛋白在暴露于RIG-I配体或病毒感染过程中在人原代细胞和小鼠体内的表达；以及3)研究这种新的RIG-I短型蛋白如何对RIG-I激活和信号转导起负调控作用。

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.