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In mammals,interferon regulatory factor(IRF)1,IRF3 and IRF7 are three critical transcription factors pivotal for cooperative regulation of type Ⅰ IFN response.Herein,we explore the relative contribution of zebrafish Danio rerio IRF1,IRF3 and IRF7(DrIRF1/3/7)to zebrafish IFNΦ1 and IFNΦ3(DrIFNΦ1/3)activation.Following SVCV infection,DrIFNΦ1/3 and DrIRF1/3/7 transcripts are significantly induced in zebrafish tissues,which correlate with the replication of SVCV.DrIRF1,DrIRF3 and DrIRF7 selectively bind to the IRF-binding element(IRF-E)/IFN-stimulated regulatory element(ISRE)sites of DrIFNΦ1/3 promoters,with an exception that DrIRF3 has no preference for two IRF-E/ISRE motifs within DrIFNΦ3 promoter.Consistently,DrIRF3 alone activates DrIFNΦ1 but not DrIFNΦ3,DrIRF7 predominantly stimulates DrIFNΦ3,while 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 DrIFNΦ3 promoter.These binding properties correlate with differential response 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.