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

通过翻译后修饰调节 RIG-I 介导的抗病毒先天免疫

• 批准号: 180789143
• 负责人: Dr. Effi Susanne Wies, Ph.D.
• 金额: --
• 依托单位: Lerner Research Institute
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2011-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/180789143?language=en
• 关键词: Regulation; RIG; mediated; anti; viral

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.

I 型干扰素，即干扰素α和干扰素β，赋予细胞抗病毒状态并限制病毒复制和传播。为了引发干扰素反应，哺乳动物宿主进化出了多种模式识别受体，这些受体能够感知入侵病原体的成分并触发下游信号级联，从而导致干扰素α/β的转录激活。其中包括 Toll 样受体和最近鉴定的胞质解旋酶 RIG-I 和 MDA5。与 TLR 不同，RIG-I 和 MDA5 普遍表达，并在各种细胞类型中的 RNA 病毒识别中发挥重要作用。免疫信号通路的严格调节对于成功抵抗病毒感染的免疫反应至关重要。 RIG-I 的抗病毒活性受到翻译后修饰的调节。 E3 泛素连接酶 TRIM25 对 RIG-I 的赖氨酸 63 连接泛素化对于 RIG-I 与 MAVS（该途径的下游信号分子）的相互作用至关重要，从而对于干扰素的产生至关重要。此外，进一步的数据表明 RIG-I 的磷酸化对于 RIG-I 的调节也可能很重要。拟议的研究旨在调查磷酸化和泛素化之间的相互作用，以严格调节 RIG-I 抗病毒干扰素反应。主要焦点在于参与这些过程的激酶和磷酸酶的表征。因此，这项研究有望确定针对病毒感染的细胞干扰素反应的新关键参与者。