Initiation and Regulation of Antiviral Innate Immunity

描述(由申请人提供)：这项提案采用了一种创新的方法来解决先天免疫和细胞生物学中的一个关键问题：在受感染的细胞中在哪里检测到病毒？我们最近发现，除了线粒体外，过氧化物酶体还是抗病毒天然免疫信号的信号平台。过氧化物酶体介导的信号传递通过MAVS的作用发生，MAVS是一种适配器蛋白，它接收来自RIG-I的信号，RIG-I是一种RNA解旋酶，用于检测细胞质中含有RNA基因组的病毒。来自过氧化物酶体的MAVS信号诱导了一条不寻常的干扰素非依赖性信号通路，激活了抗病毒因子的快速表达。该信号通路被流感病毒、水泡性口炎病毒和哺乳动物呼肠孤病毒等多种病毒激活，并能够限制病毒的复制。基于这一发现，我们现在试图(1)确定来自过氧体的信号如何导致抗病毒免疫的启动，(2)确定过氧体信号对于控制干扰I型干扰素表达的病毒是否至关重要，以及如何完成病毒限制，以及(3)表征一种新的RIG-I信号的负调控因子，该信号由过氧酶体和线粒体发挥作用。我们提出的研究有可能深刻改变我们对哺乳动物细胞中抗病毒免疫组织方式的看法。这项工作可能有助于设计新的疗法来操纵先天免疫信号分子的亚细胞定位，帮助触发或干扰免疫反应。)

DESCRIPTION (provided by applicant): This proposal takes an innovative approach to address a critical question in innate immunity and cell biology: Where within infected cells are viruses detected? We have recently discovered that in addition to mitochondria, peroxisomes are signaling platforms for antiviral innate immune signaling. Peroxisome-mediated signaling occurs through the actions MAVS, an adaptor protein that receives signals from RIG-I, an RNA helicase that surveys the cytosol for viruses containing RNA genomes. MAVS signaling from peroxisomes induces an unusual interferon-independent signaling pathway that activates the rapid expression of antiviral factors. This signaling pathway is activated by diverse viruses such as influenza virus, vesicular stomatitis virus and mammalian reovirus, and is capable of restricting viral replication. Based on this discovery, we now seek to (1) determine how signaling from peroxisomes leads to the initiation of antiviral immunity, (2) determine if peroxisomal signaling is critical for the control of viruses that disrupt type I interferon expression, and how viral restriction is accomplished, and (3) characterize a novel negative regulator of RIG-I signaling that functions from peroxisomes and mitochondria. Our proposed studies have the potential to profoundly change our view of how antiviral immunity is organized within mammalian cells. This work may facilitate the design of novel therapeutics to manipulate the subcellular positioning of innate immune signaling molecules, helping to either trigger or interfere with an immune reaction.)