Genes containing an
interferon (IFN)-stimulated response element (ISRE) can be divided into two groups according to their inducibility by IFN and
virus infection: one induced only by IFN and the other induced by both IFN and
virus infection. Although it is now clear that IFN regulatory
factor 7 (IRF7) is a multifunctional gene essential for induction of type I IFNs, regulation of the IRF7 promoter (IRF7p) is poorly understood. The IRF7 gene includes two IFN responsive elements, an IRF-binding
element (IRFE) in the promoter region and an ISRE in the first intron, and is induced by the IFN-triggered Jak-STAT pathway by binding of the IFN-stimulated gene factor 3 (ISGF3) complex to the ISRE. In this study, we demonstrate that IRF3 and IRF7, which with the coactivators
CREB-binding protein and P300 form the virus-activated factor (VAF) complex upon Sendai virus
infection, bind to the IRF7 ISRE and IRFE and can directly activate IRF7 transcription. Promoter reporter assays show that both the ISRE and IRFE are responsive to activation by IRF7 and IRF3. In cells transiently expressing IRF7 or/and IRF3, the VAF level and binding of VAF are clearly increased after Sendai virus
infection. Studies with
Jak1 kinase inactive 293 cells that were stably transfected with a
Jak1 kinase dead dominant negative construct, and the mutant cell lines SAN (IFNalpha-/beta-), U2A (IRF9-), U4A (Jak1-), and DKO (IRF1-/IRF2-) show that the IRF7 transcription activated directly by VAF is distinct from and independent of the IFN signaling pathway. Thus, IRF7 transcription is autoregulated by binding of the IRF7-containing VAF to its own ISRE and IRFE. The results show two distinct mechanisms for the activation of the IRF7 promoter, by IFN and by
virus infection. A regulatory network between type I IFNs and IRF7 is proposed. The distinct pathways may reflect special roles for an efficient
antiviral response at different stages of
virus infection.