Regulation of RIG-I-mediated anti-viral innate immunity by post-translational modifications

I型干扰素，即干扰素α和干扰素β，赋予细胞抗病毒状态，限制病毒复制和传播。为了引发干扰素应答，哺乳动物宿主进化出了多种模式识别受体，它们感知入侵病原体的成分，并触发下游信号级联反应，导致干扰素α / β的转录激活。其中包括toll样受体和最近发现的胞质解旋酶RIG-I和MDA5。与TLRs不同，rig - 1和MDA5在各种细胞类型中普遍表达，在RNA病毒识别中发挥重要作用。免疫信号通路的严格调控对于成功的免疫应答病毒感染至关重要。rig - 1抗病毒活性受翻译后修饰调控。E3泛素连接酶TRIM25介导的赖氨酸63连接的rig - 1泛素化对于rig - 1与MAVS（该通路的下游信号分子）相互作用以及干扰素的产生至关重要。此外，进一步的数据表明，RIG-I的磷酸化可能对RIG-I的调控也很重要。该研究旨在研究磷酸化和泛素化之间的相互作用，以紧密调节rig - 1抗病毒干扰素反应。主要的重点将在于表征激酶(s)和磷酸酶(s)参与这些过程。因此，这项研究有望确定细胞干扰素对抗病毒感染反应的新关键参与者。

Type I Interferons, namely Interferon alpha and Interferon beta, confer an anti-viral state to cells and limit virus replication and dissemination. To elicit an Interferon response mammalian hosts have evolved a variety of pattern recognition receptors, which sense components of invading pathogens and trigger downstream signaling cascades that lead to the transcriptional activation of Interferon alpha/beta. Among these are the Toll-like receptors and the recently identified cytosolic helicases RIG-I and MDA5. Unlike TLRs, RIG-I and MDA5 are ubiquitously expressed and play essential roles in the recognition of RNA viruses in various cell types. Tight regulation of immune signaling pathways is essential for a successful immune response against viral infections. RIG-I anti-viral activity is regulated by post-translational modifications. Lysine 63-linked ubiquitination of RIG-I by the E3 ubiquitin ligase TRIM25 is essential for the interaction of RIG-I with MAVS, a downstream signaling molecule of the pathway, and thereby for Interferon production. Moreover, further data suggest that phosphorylation of RIG-I might as well be important for RIG-I regulation. The proposed study is directed toward investigating the interplay between phosphorylation and ubiquitination to tightly regulate the RIG-I anti-viral interferon response. The main focus will lie on the characterization of the kinase(s) and phosphatase(s) involved in these processes. This study thus promises to identify novel key players of the cellular interferon response against viral infection.