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Physiological Function of Virus-induced sigraing for Artivirall mate immunity

病毒诱导的信号传导对 Artivirall 配偶免疫的生理功能

基本信息

批准号：
18390156
负责人：
YONEYAMA Mitsutoshi
金额：
$ 10.77万
依托单位：
Kyoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18390156/
关键词：
Signal transduction Virus Immunology 自然免疫インターフェロン RNAヘリカーゼ

项目摘要

Type I interferon (IFN) plays a critical role in antiviral innate immunity. Virus-infected cells transiently express type I IFNs and confer strong antiviral activities on surrounding cells Via IFN receptor-mediated signaling. In this research, we focused on the function of virus sensor molecules, RIG-I family RNA helicases, which detect viral RNA in cytoplasm to induce IFN gene expression, and analyzed molecular mechanisms underlying activation of RIG-I family-mediated antiviral innate immunity.1. We analyzed virus-induced activation of type III IFNs. Our data clearly indicated that type III IFNs are regulated by RIG-I-mediated signaling as well as type I IFNs.2. In order to elucidate a physiological significance of another RIG-I family member, MDA5, we generated and analyzed knockout mice of MDA5 gene, as collaboration with Dr. Shizuo Akira's group in Osaka University. The results showed that MDA5 also plays an essential role in virus-induced activation of IFN genes. However, MDA5 were involved in the detection of different type of viruses including picorna viruses.3. We tried to generate a novel assay system for RIG-I-mediated signal transduction. The enforced oligomerization of N-terminal CARD of RIG-I clearly activated the identical signaling to natural virus-induced signal. Using this system, we are going to observe the physiological significance of RIG-I- mediated signaling in innate immunity.4. We analyzed substrate specificity of RIG-I using in vitro assay system. Finally, we identified RIG-I can detect not only 5ppp-dontaining singe stranded RNA but also monophosphate-containing double stranded RNAs. Furthermore, the C-terminal domain of RIG-I was essential for detection of these substrates to initiate antiviral signaling.

I型干扰素在抗病毒先天免疫中起着重要作用。病毒感染的细胞瞬时表达I型干扰素，并通过干扰素受体介导的信号对周围细胞产生强大的抗病毒活性。在本研究中，我们重点研究了病毒感受器分子RIG-I家族RNA解旋酶的功能，它检测细胞质中的病毒RNA以诱导干扰素基因的表达，并分析了RIG-I家族介导的抗病毒天然免疫激活的分子机制。我们分析了病毒诱导的III型IFN的激活。我们的数据清楚地表明，III型IFN既受RIG-I介导的信号调节，也受I型IFN的调控。为了阐明另一个RIG-I家族成员MDA5的生理意义，我们与大阪大学Akira博士的研究小组合作，建立并分析了MDA5基因敲除小鼠。结果表明，MDA5在病毒诱导的干扰素基因激活中也起着重要作用。然而，MDA5参与了包括短小核糖核酸病毒在内的不同类型病毒的检测。我们试图为Rig-I介导的信号转导建立一种新的检测系统。RIG-I N端的强制寡聚明显激活了与天然病毒诱导信号相同的信号。利用该系统，我们将观察RIG-I介导的信号在先天免疫中的生理意义。用体外检测系统分析RIG-I的底物特异性。最后，我们发现RIG-I不仅可以检测到含5ppp的单链RNA，还可以检测到含有单磷酸的双链RNA。此外，RIG-I的C-末端结构域对于检测这些底物以启动抗病毒信号是必不可少的。