IFNα诱导ADAR1泛素化降解的机制及其抗病毒效应研究

The interferons act as an important component in innate immunity, which are also the most important cytokines in the first line of defense against virus infection. Among various molecules involved in the regulation of IFNs antiviral signaling, the adenosine deaminase acting on RNA1 (ADAR1) has recently been found to inhibit the IFNs-mediated antiviral function. However, it remains to be explored that how did the IFNs signaling overcome the inhibitory effect of ADAR1 and finally play an effective role in antiviral function. Our preliminary data revealed that the antiviral effect of IFNα against VSV was significantly enhanced after ADAR1 knockdown, and IFNα could induce ADAR1 protein expression level decline and increase its ubiquitination level. Our preliminary data also implied that the E3 ligase Beta-Trcp is probably involved in the ubiquitination event of ADAR1. Thus, this project intends to explore the signaling mechanism of a negative regulatory factor ADAR1 whose ubiquitination and degradation was induced by IFNα, identify the potential ubiquitin E3 ligase, and finally investigate how ADAR1 interacts with its E3 ligase and its effects on IFNα antiviral function. Investigating the ubiquitin regulations of inhibitory molecules in IFNα signaling pathway would help to understand the new mechanism of IFNα antiviral signaling and provide a potential new target for clinical antiviral therapy.

干扰素（IFNs）是固有免疫的重要组成部分以及机体抵御病毒感染第一道防线中最重要的细胞因子。在调控IFNs抗病毒信号的各类分子中，腺苷脱氨酶（ADAR1）近年来被发现能抑制IFNs介导的抗病毒功能。然而，有关IFNs信号如何克服ADAR1的负性调控作用从而发挥有效抗病毒功能仍有待研究。我们前期工作发现ADAR1敲降后IFNα抗VSV病毒作用显著增强，并且发现IFNα能诱导ADAR1蛋白水平下降和泛素化水平增加，预研结果提示参与ADAR1泛素化的E3连接酶很可能是Beta-Trcp。因此，本项目拟探讨IFNα诱导负调控因子ADAR1泛素化和降解的信号机制，明确调控ADAR1泛素化的E3连接酶，并进一步探讨该E3与ADAR1相互作用及其对IFNα抗病毒功能的影响。通过探索IFNα抗病毒信号中抑制性分子的泛素化调控，有助于人们理解IFNα抗病毒信号的新机制，并为临床抗病毒治疗提供潜在的新靶点。

腺苷脱氨酶ADAR1（Adenosine deaminase acting on RNA1）主要催化细胞和病毒中RNA的编辑和修饰，且ADAR1在维持机体平衡包括组织稳态、器官发育以及自身免疫调节等方面均发挥重要的调控作用。不仅如此，ADAR1还抑制I型干扰素（IFNs）的产生以及IFNs下游的信号转导。因此，本项目对机体中IFNs信号如何克服ADAR1（ADAR1-P110）的抑制作用从而发挥有效抗病毒功能这一科学问题展开研究。通过本项目的实施，我们发现IFNs信号能促进ADAR1-P110发生K48位泛素化修饰，并且IFNs能诱导ADAR1泛素化水平升高和蛋白表达量的下调。此外，我们发现E3泛素连接酶SCFβ-Trcp调控ADAR1泛素化；证实IFNs信号能促进SCFβ-Trcp与ADAR1-P110相互作用；揭示SCFβ-Trcp调控ADAR1-P110泛素化修饰的位点是第574位和第576位赖氨酸。此外，我们发现机体在遭受病毒感染后，诱导产生的IFNs能够下调ADAR1-P110的蛋白表达以解除其对IFNs信号的抑制作用，最终使得机体发挥有效的抗病毒功能。因此，以上研究拓展了IFNs信号新的调控机制，并可能为基于IFNs的抗病毒治疗提供潜在的新靶点。

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