Feng Hui, Zhang Qi-Min, Zhang Yi-Bing, Li Zhi, Zhang Jun, Xiong Ya-Wei, Wu Min, Gui Jian-Fang
State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Wuhan 430072, China.
State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Wuhan 430072, China
J Immunol. 2016 Sep 1;197(5):1893-904. doi: 10.4049/jimmunol.1600159. Epub 2016 Aug 5.
In mammals, IFN regulatory factor (IRF)1, IRF3, and IRF7 are three critical transcription factors that are pivotal for cooperative regulation of the type I IFN response. In this study, we explored the relative contribution of zebrafish (Danio rerio) IRF1 (DrIRF1), IRF3 (DrIRF3), and IRF7 (DrIRF7) (DrIRF1/3/7) to zebrafish IFNΦ1 (DrIFNΦ1) and IFNΦ3 (DrIFNΦ3) (DrIFNΦ1/3) activation. Following spring viremia of carp virus infection, DrIFNΦ1/3 and DrIRF1/3/7 transcripts are significantly induced in zebrafish tissues, which correlates with the replication of spring viremia of carp virus. DrIRF1/3/7 selectively bind to the IRF-binding element/IFN-stimulated regulatory element sites of DrIFNΦ1/3 promoters, with the exception that DrIRF3 has no preference for two IRF-binding element/IFN-stimulated regulatory element motifs within the DrIFNΦ3 promoter. Consistently, DrIRF3 alone activates DrIFNΦ1, but not DrIFNΦ3; DrIRF7 predominantly stimulates DrIFNΦ3; and DrIRF1 has similar potential to DrIFNΦ1 and DrIFNΦ3. Strikingly, DrIRF3 facilitates the binding of DrIRF1 and DrIRF7 to both zebrafish IFN promoters, and so does DrIRF7 for the binding of DrIRF1, particularly to the DrIFNΦ3 promoter. These binding properties correlate with differential responses of DrIFNΦ1 and DrIFNΦ3 to the combinatory stimulation of DrIRF1/3/7, depending on their relative amounts. Similar to the dual roles of human IRF3 in regulating IRF7-activated IFNα genes, DrIRF3 exerts dual effects on DrIRF1-mediated DrIFNΦ3 gene expression: an inhibitory effect at lower concentrations and a synergistic effect at higher concentrations. These data provide evidence that fish and mammals have evolved a similar IRF-dependent regulatory mechanism fine-tuning IFN gene activation.
在哺乳动物中，干扰素调节因子（IRF）1、IRF3和IRF7是三种关键转录因子，对I型干扰素反应的协同调节至关重要。在本研究中，我们探究了斑马鱼（Danio rerio）IRF1（DrIRF1）、IRF3（DrIRF3）和IRF7（DrIRF7）（DrIRF1/3/7）对斑马鱼干扰素Φ1（DrIFNΦ1）和干扰素Φ3（DrIFNΦ3）（DrIFNΦ1/3）激活的相对贡献。在鲤春病毒血症病毒感染后，DrIFNΦ1/3和DrIRF1/3/7转录本在斑马鱼组织中显著诱导，这与鲤春病毒血症病毒的复制相关。DrIRF1/3/7选择性地结合到DrIFNΦ1/3启动子的IRF结合元件/干扰素刺激调节元件位点，但DrIRF3对DrIFNΦ3启动子内的两个IRF结合元件/干扰素刺激调节元件基序没有偏好。一致地，单独的DrIRF3激活DrIFNΦ1，但不激活DrIFNΦ3；DrIRF7主要刺激DrIFNΦ3；而DrIRF1对DrIFNΦ1和DrIFNΦ3具有相似的激活潜力。令人惊讶的是，DrIRF3促进DrIRF1和DrIRF7与两个斑马鱼干扰素启动子的结合，DrIRF7对DrIRF1的结合也有促进作用，特别是对DrIFNΦ3启动子。这些结合特性与DrIFNΦ1和DrIFNΦ3对DrIRF1/3/7组合刺激的不同反应相关，这取决于它们的相对量。与人类IRF3在调节IRF7激活的IFNα基因中的双重作用类似，DrIRF3对DrIRF1介导的DrIFNΦ3基因表达发挥双重作用：在较低浓度下具有抑制作用，在较高浓度下具有协同作用。这些数据提供了证据，表明鱼类和哺乳动物已经进化出类似的依赖IRF的调节机制来微调干扰素基因的激活。
