Zebrafish foxo3b Negatively Regulates Antiviral Response through Suppressing the Transactivity of irf3 and irf7
Zebrafish foxo3b Negatively Regulates Antiviral Response through Suppressing the Transactivity of irf3 and irf7
复制标题
斑马鱼foxo3b通过抑制irf3和irf7的反式活性负调节抗病毒反应
DOI：
10.4049/jimmunol.1601187
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发表时间：
2016-12-15
影响因子：
4.4
通讯作者：
Xiao, Wuhan
中科院分区：
文献类型：
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作者：
Liu, Xing;Cai, Xiaolian;Xiao, Wuhan
叉头盒O（FOXO）3是FOXO转录因子家族的成员，在包括发育、寿命、生殖和代谢在内的各种细胞过程中起关键作用。最近，FOXO 3也被证明参与调节免疫反应。然而，FOXO 3如何调节免疫力及其潜在机制在很大程度上仍然未知。在这项研究中，我们表明，斑马鱼（Danio rerio）foxo 3b，哺乳动物FOXO 3的直向同源物，是由聚肌胞刺激和鲤鱼春季病毒血症病毒（SVCV）感染诱导的。我们发现，foxo 3b与irf 3和irf 7相互作用，抑制ifr 3/irf 7的转录活性，从而导致抑制SVCV或聚肌胞诱导的IFN激活。通过抑制关键的抗病毒基因的表达，foxo 3b负调控细胞的抗病毒反应。此外，SVCV感染后，关键的抗病毒基因的表达显着增强foxo 3b-null斑马鱼幼虫相比，野生型幼虫。此外，SVCV的复制在foxo 3b缺失的斑马鱼幼虫中被抑制，导致更高的存活率。我们的研究结果表明，通过抑制irf 3/irf 7活性，斑马鱼foxo 3b负调节抗病毒反应，暗示FOXO基因家族在先天免疫中的重要作用。
Forkhead box O (FOXO)3, a member of the FOXO family of transcription factors, plays key roles in various cellular processes, including development, longevity, reproduction, and metabolism. Recently, FOXO3 has also been shown to be involved in modulating the immune response. However, how FOXO3 regulates immunity and the underlying mechanisms are still largely unknown. In this study, we show that zebrafish (Danio rerio) foxo3b, an ortholog of mammalian FOXO3, is induced by polyinosinic-polycytidylic acid stimulation and spring viremia of carp virus (SVCV) infection. We found that foxo3b interacted with irf3 and irf7 to inhibit ifr3/irf7 transcriptional activity, thus resulting in suppression of SVCV or polyinosinic-polycytidylic acid-induced IFN activation. By suppressing expression of key antiviral genes, foxo3b negatively regulated the cellular antiviral response. Furthermore, upon SVCV infection, the expression of the key antiviral genes was significantly enhanced in foxo3b-null zebrafish larvae compared with wild-type larvae. Additionally, the replication of SVCV was inhibited in foxo3b-null zebrafish larvae, leading to a higher survival rate. Our findings suggest that by suppressing irf3/irf7 activity, zebrafish foxo3b negatively regulates the antiviral response, implicating the vital role of the FOXO gene family in innate immunity.