GCRV hijacks TBK1 to evade IRF7-mediated antiviral immune responses in grass carp Ctenopharyngodon idella
GCRV hijacks TBK1 to evade IRF7-mediated antiviral immune responses in grass carp Ctenopharyngodon idella
复制标题
草鱼GCRV劫持TBK1逃避IRF7介导的抗病毒免疫反应
DOI：
10.1016/j.fsi.2019.08.005
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发表时间：
2019
影响因子：
4.7
通讯作者：
Su Jianguo
中科院分区：
文献类型：
--
作者：
Rao Youliang;Ji Jianfei;Liao Zhiwei;Su Hang;Su Jianguo
TANK-binding kinase 1（TBK 1）是一种重要的激酶，在抗病毒免疫应答中调节干扰素调节因子3/7（IRF 3/7）的活化以诱导I型干扰素（IFN-I）的产生。然而，在长期的病毒-宿主串扰中，病毒已经进化出复杂的策略来逃避宿主的免疫防御机制。在本研究中，我们发现草鱼呼肠孤病毒（GCRV）劫持TBK 1逃避IRF 7-IFN-Is信号转导激活。简而言之，GCRV通过抑制TBK 1的K63连接的泛素化并促进其K48连接的泛素化来抑制TBK 1的活化。这种调节导致在低滴度GCRV感染下，TBK 1过表达特异性地抑制启动子活性和IRF 7的磷酸化以及下游IFN 1和IFN 3的诱导。qRT-PCR数据揭示了TBK 1在低病毒滴度感染下负调控IRF 7、IFN 1和IFN 3的转录水平。随着GCRV滴度的增加，TBK 1沿着上调IRF 7、IFN 1和IFN 3的mRNA水平。因此，TBK 1在低感染滴度下促进GCRV复制，但在高感染滴度下抑制GCRV复制。这些结果揭示了GCRV利用TBK 1在鱼类体内阻断细胞内低滴度或早期IFN应答的病毒逃避策略，为进一步研究宿主-病毒相互作用和开发低等脊椎动物抗病毒新策略奠定了基础。
TANK-binding kinase 1 (TBK1) is an important kinase that regulates the activation of interferon regulatory factor 3/7 (IRF3/7) to induce type I interferon (IFN–I) production in antiviral immune responses. However, in long-term virus-host crosstalk, viruses have evolved elaborate strategies to evade host immune defense mechanisms. In the present study, we found that grass carp (Ctenopharyngodon idella) reovirus (GCRV) hijacks TBK1 to escape IRF7-IFN-Is signaling activation. In brief, GCRV inhibited TBK1 activation by restaining K63-linked ubiquitination of TBK1 and promoting its K48-linked ubiquitination. This regulation resulted in that under low titer of GCRV infection, TBK1 overexpression specifically supressed promoter activity and phosphorylation of IRF7 and induction of downstream IFN1and IFN3. qRT-PCR data uncovered that TBK1 negatively regulated IRF7, IFN1 and IFN3 transcription levels under low viral titer infection. Along with enhancement of GCRV titers, TBK1 swiched its function to up-regulate IRF7, IFN1 and IFN3 mRNA levels. Accordingly, TBK1 promoted GCRV replication at low infected titer, but inhibited GCRV replication at high infected titer. All these results revealed a viral evasion strategy that GCRV utilizes TBK1 to block cellular IFN responses at low titers or early stages in fish species, which will lay a foundation for further researching on host-virus interactions and developing novel antiviral strategies in lower vertebrates.