Regulation of type I interferon gene expression by interferon regulatory factor-3.
The genes of the family of interferon (IFN) regulatory factors (IRF) encode DNA binding transcriptional factors that are involved in modulation of transcription of IFN and interferon-induced genes (ISG). The presence of IRF binding sites in the promoter region of IFNA and IFNB genes indicates that IRF factors recognizing these sites play an important role in the virus-mediated induction of these genes. We have described a novel human gene of this family, IRF-3, that is constitutively expressed in a variety of cell types. IRF-3 binds to the interferon-sensitive response element (ISRE) present in the ISG15 gene promoter and activates its transcriptional activity. In the present study, we examined whether IRF-3 can modulate transcriptional activity of IFNA and IFNB promoter regions. Our results demonstrate that IRF-3 can bind to the IRF-like binding sites present in the virus-inducible region of the IFNA4 promoter and to the PRDIII region of the IFNB promoter but cannot alone stimulate their transcriptional activity in the human cell line, 293. However, the fusion protein generated from the IRF-3 binding domain and the RelA(p65) activation domain effectively activates both IFNA4 and IFNB promoters. Cotransfection of IRF-3 and RelA(p65) expression plasmids activates the IFNB gene promoter but not the promoter of IFNA4 gene that does not contain the NF-kB binding site. Surprisingly, activation of the IFNA4 gene promoter by virus and IRF-1 in these cells was inhibited by IRF-3. These data indicate that in 293 cells IRF-3 does not stimulate expression of IFN genes but can cooperate with RelA(p65) to stimulate the IFNB promoter.
Schafer
S L
SL
Oncology Center, The Johns Hopkins University, Baltimore, Maryland 21231, USA.
Lin
R
R
Moore
P A
PA
Hiscott
J
J
Pitha
P M
PM
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D050856:Interferon Regulatory Factor-1; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I / Q000096:biosynthesis* / Q000235:genetics; D016898:Interferon-alpha / Q000096:biosynthesis / Q000235:genetics; D016899:Interferon-beta / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014780:Viruses / Q000254:growth & development
D004268:DNA-Binding Proteins; C494257:IRF1 protein, human; C494232:IRF3 protein, human; D050856:Interferon Regulatory Factor-1; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D016898:Interferon-alpha; C494258:Irf1 protein, mouse; C494233:Irf3 protein, mouse; D010446:Peptide Fragments; D010750:Phosphoproteins; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; D016899:Interferon-beta