Casein Kinase II Controls TBK1/IRF3 Activation in IFN Response against Viral Infection
Casein Kinase II Controls TBK1/IRF3 Activation in IFN Response against Viral Infection
复制标题
酪蛋白激酶 II 在针对病毒感染的 IFN 反应中控制 TBK1/IRF3 激活
DOI：
10.4049/jimmunol.1402777
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发表时间：
2015-05-01
影响因子：
4.4
通讯作者：
Xiao, Hui
中科院分区：
文献类型：
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作者：
Du, Min;Liu, Jinghua;Xiao, Hui
宿主先天性受体通过感受病毒核酸，引发聚集在TBK 1-IFN调节因子（IRF）3轴上的信号通路，介导IFN-α β诱导和防御机制。相反，病毒已经进化出多种免疫逃避/干扰机制，以破坏先天受体信号传导和IFN应答。在这方面，迫切需要使宿主能够克服这种免疫逃避/干扰机制的方法来对抗流行/大流行病毒的感染。在这项研究中，我们报告说，蛋白激酶CK 2作为一个关键组成部分控制TBK 1和IRF 3激活IFN诱导TLR，RIG-I样受体，和cGAS/STING信号通路。因此，CK 2表达的敲低或其激酶活性的遗传消除导致响应于DNA和RNA病毒感染的IFN-α β应答升高。此外，PP 2A被鉴定为负责CK 2调节IFN应答的中间磷酸酶之一，表明CK 2可能间接调节TBK 1和IRF 3活化。重要的是，通过小分子抑制剂阻断CK 2活性能够激活TBK 1，从而引发针对丙型肝炎病毒感染的有效宿主防御机制。总而言之，我们的结果确定CK 2是TBK 1和IRF 3的新型调节剂，并表明通过小分子抑制剂靶向CK 2可能是预防和治疗病毒感染的可行方法。
By sensing viral nucleic acids, host innate receptors elicit signaling pathways converging on TBK1-IFN regulatory factor (IRF) 3 axis in mediating IFN-alpha beta induction and defense mechanisms. In contrast, viruses have evolved with diverse immune evasion/interference mechanisms to undermine innate receptor signaling and IFN response. In this regard, approaches enabling host to overcome such immune evasion/interference mechanisms are urgently needed to combat infections by epidemic/pandemic viruses. In this study, we report that protein kinase CK2 serves as a key component controlling TBK1 and IRF3 activation in IFN-inducing TLR, RIG-I-like receptors, and cGAS/STING signaling pathways. Accordingly, knocking down of CK2 expression or genetic ablation of its kinase activity resulted in elevated IFN-alpha beta response in response to infection by DNA and RNA viruses. Moreover, PP2A was identified as one of the intermediate phosphatases responsible for CK2-regulated IFN response, suggesting that CK2 may regulate TBK1 and IRF3 activation indirectly. Importantly, blockade of CK2 activity by small molecule inhibitor was able to activate TBK1, whereby eliciting effective host defense mechanisms against hepatitis C virus infection. Taken together, our results identify CK2 as a novel regulator of TBK1 and IRF3 and suggest that targeting CK2 by small molecular inhibitor may be a viable approach to prevent and treat viral infections.