Zebrafish IRF1, IRF3, and IRF7 Differentially Regulate IFN{Phi}1 and IFN{Phi}3 Expression through Assembly of Homo- or Heteroprotein Complexes [INNATE IMMUNITY AND INFLAMMATION]

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 IFN1 (DrIFN1) and IFN3 (DrIFN3) (DrIFN1/3) activation. Following spring viremia of carp virus infection, DrIFN1/3 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 DrIFN1/3 promoters, with the exception that DrIRF3 has no preference for two IRF-binding element/IFN-stimulated regulatory element motifs within the DrIFN3 promoter. Consistently, DrIRF3 alone activates DrIFN1, but not DrIFN3; DrIRF7 predominantly stimulates DrIFN3; and DrIRF1 has similar potential to DrIFN1 and DrIFN3. 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 DrIFN3 promoter. These binding properties correlate with differential responses of DrIFN1 and DrIFN3 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 DrIFN3 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.

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