Ctenopharyngodon idella TBK1 activates innate immune response via IRF7
Ctenopharyngodon idella TBK1 activates innate immune response via IRF7
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草鱼TBK1通过IRF7激活先天免疫反应
DOI：
10.1016/j.fsi.2018.06.045
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发表时间：
2018-09
影响因子：
4.7
通讯作者：
Hu Chengyu
中科院分区：
文献类型：
--
作者：
Yu Ningli;Xu Xiaowen;Qi Guoqin;Liu Dan;Chen Xin;Ran Xiaoqin;Jiang Zeyin;Li Yinping;Mao Huiling;Hu Chengyu
在哺乳动物中，IFN调节因子（IRF） 7是IFN-α表达的中心调节因子，以应对可变致病性感染。有几种病原传感器参与监测哺乳动物的病原体入侵。这些传感器通过不同的途径触发irf7介导的反应。TANK-binding kinase 1 （TBK1）是病原体感染时IRF7激活的关键介质。在鱼类中，关于TBK1、IRF3和IRF7的报道较多，特别是关于TBK1-IRF3信号通路的报道较多。然而，TBK1-IRF7在先天免疫信号通路中的作用机制尚不清楚。在本研究中，我们探讨了TBK1如何上调IFN、ISG的表达，以及TBK1如何在脂多糖（LPS）刺激下通过IRF7启动先天免疫反应。LPS刺激后，草鱼IRF3和IRF7转录上调，表明它们参与了tlr介导的抗病毒信号通路。有趣的是，草鱼IRF3对LPS的响应时间要早于IRF7。此外，在tenopharyngodon idellakidney细胞（CIKs）中，IRF7而不是IRF3对IFN和ISG转录的正向调节作用更强。提示IRF3和IRF7在LPS感染后可能存在功能分化。双荧光素酶实验也显示草鱼IRF7和TBK1的过表达上调了fifnandpkr的转录水平。然而，IRF7的敲低抑制了ISG的表达，这表明草鱼TBK1通过IRF7调控转录。共免疫沉淀和GST下拉实验证实草鱼IRF7与TBK1结合。草鱼TBK1可以促进IRF7的核易位。结果表明，草鱼TBK1可直接结合并激活IRF7。
In mammals, IFN regulatory factor (IRF) 7 is a central regulator of IFN-α expression in response to variable pathogenic infections. There are several pathogenic sensors involved in monitoring pathogen intrusion in mammals. These sensors trigger IRF7-mediated responses through different pathways. TANK-binding kinase 1 (TBK1) is a critical mediator of IRF7 activation upon pathogen infection. In fish, there are many reports on TBK1, IRF3 and IRF7, especially on TBK1-IRF3 signaling pathway. However, it is not very clear how TBK1-IRF7 works in innate immune signaling pathway. In this study, we explored how TBK1 up-regulates IFN, ISG expression, and how TBK1 initiates innate immune response through IRF7 in fish under lipopolysaccharides (LPS) stimulation. After stimulation with LPS, grass carp IRF3 and IRF7 transcriptions were up-regulated, indicating they participate in TLR-mediated antiviral signaling pathway. It is interesting that the response time of grass carp IRF3 to LPS was earlier than that of IRF7. In addition, IRF7 rather than IRF3 acted as a stronger positive regulator of IFN and ISG transcription inCtenopharyngodon idellakidney cells (CIKs). It is suggested the potential function differentiation between IRF3 and IRF7 upon LPS infection in fish. Dual luciferase assays also showed that overexpression of grass carp IRF7 and TBK1 up-regulated the transcription level ofIFNandPKR. However, knockdown of IRF7 inhibits ISG expression, suggesting that grass carp TBK1 regulates the transcription via IRF7. Co-immunoprecipitation and GST pull-down assays proved the binding of grass carp IRF7 to TBK1. Furthermore, grass carp TBK1 can promote the nuclear translocation of IRF7. The results indicated that grass carp TBK1 can bind directly to and activate IRF7.
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