Zebrafish IRF1, IRF3, and IRF7 Differentially Regulate IFNΦ1 and IFNΦ3 Expression through Assembly of Homo- or Heteroprotein Complexes
Zebrafish IRF1, IRF3, and IRF7 Differentially Regulate IFNΦ1 and IFNΦ3 Expression through Assembly of Homo- or Heteroprotein Complexes
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斑马鱼 IRF1、IRF3 和 IRF7 通过同源或异源蛋白复合物的组装差异调节 IFN Phi 1 和 IFN Phi 3 表达
DOI：
10.4049/jimmunol.1600159
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发表时间：
2016-09-01
影响因子：
4.4
通讯作者：
Gui, Jian-Fang
中科院分区：
文献类型：
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作者：
Feng, Hui;Zhang, Qi-Min;Gui, Jian-Fang
在哺乳动物中，IFN调节因子（IRF）1、IRF 3和IRF 7是协同调节I型IFN应答的关键的三个关键转录因子。在这项研究中，我们探讨了斑马鱼（Danio rerio）IRF 1（DrIRF 1）、IRF 3（DrIRF 3）和IRF 7（DrIRF 7）（DrIRF 1/3/7）对斑马鱼IFN Phi 1（DrIFN Phi 1）和IFN Phi 3（DrIFN Phi 3）（DrIFN Phi 1/3）激活的相对贡献。感染鲤鱼病毒后，斑马鱼组织中DrIFN Phi 1/3和DrIRF 1/3/7转录子被显著诱导，这与鲤鱼病毒的复制有关。DrIRF 1/3/7选择性地结合到DrIFN Phi 1/3启动子的IRF结合元件/IFN刺激的调节元件位点，除了DrIRF 3对DrIFN Phi 3启动子内的两个IRF结合元件/IFN刺激的调节元件基序没有偏好。一致地，DrIRF 3单独激活DrIFN Phi 1，但不激活DrIFN Phi 3; DrIRF 7主要刺激DrIFN Phi 3;并且DrIRF 1具有与DrIFN Phi 1和DrIFN Phi 3相似的潜力。引人注目的是，DrIRF 3促进了DrIRF 1和DrIRF 7与斑马鱼IFN启动子的结合，DrIRF 7也促进了DrIRF 1的结合，特别是与DrIFN Phi 3启动子的结合。这些结合特性与DrIFN Phi 1和DrIFN Phi 3对DrIRF 1/3/7的组合刺激的差异反应相关，这取决于它们的相对量。类似于人IRF 3在调节IRF 7激活的IFN α基因中的双重作用，DrIRF 3对DrIRF 1介导的DrIFN Phi 3基因表达发挥双重作用：在较低浓度下的抑制作用和在较高浓度下的协同作用。这些数据提供的证据表明，鱼类和哺乳动物已经进化出一个类似的IRF依赖的调控机制微调IFN基因的激活。
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 IFN Phi 1 (DrIFN Phi 1) and IFN Phi 3 (DrIFN Phi 3) (DrIFN Phi 1/3) activation. Following spring viremia of carp virus infection, DrIFN Phi 1/3 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 DrIFN Phi 1/3 promoters, with the exception that DrIRF3 has no preference for two IRF-binding element/IFN-stimulated regulatory element motifs within the DrIFN Phi 3 promoter. Consistently, DrIRF3 alone activates DrIFN Phi 1, but not DrIFN Phi 3; DrIRF7 predominantly stimulates DrIFN Phi 3; and DrIRF1 has similar potential to DrIFN Phi 1 and DrIFN Phi 3. 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 DrIFN Phi 3 promoter. These binding properties correlate with differential responses of DrIFN Phi 1 and DrIFN Phi 3 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 IFN alpha genes, DrIRF3 exerts dual effects on DrIRF1-mediated DrIFN Phi 3 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.