title: Limited specificity of IRF3 and ISGF3 in the transcriptional innate-immune response to double-stranded RNA.
abstract: The innate immune response is largely initiated by pathogen-responsive activation of the transcription factor IRF3. Among other target genes, IRF3 controls the expression of IFN-β, which triggers the activation of the transcription factor ISGF3 via the IFNAR. IRF3 and ISGF3 have been reported to control many of the same target genes and together, control the antimicrobial innate-immune program; however, their respective contributions and specificities remain unclear. Here, we used genomic technologies to characterize their specificity in terms of their physical DNA-binding and genetic function. With the use of ChiP-seq and transcriptomic measurements in WT versus ifnar(-/-) versus ifnar(-/-)irf3(-/-) macrophages responding to intracellular dsRNA, we confirmed the known ISGF3 DNA-binding motif and further specified a distinct IRF3 consensus sequence. The functional specificity of IRF3 is particularly pronounced in cytokine/chemokine regulation; yet, even in the control of IFN-β, that specificity is not absolute. By mathematically modeling IFN-β production within an abstracted tissue layer, we find that IRF3 versus ISGF3 specificity may be critical to limiting IFN-β production and ISGF3 activation, temporally and spatially, but that partial overlap in their specificity is tolerable and may enhance the effectiveness of the innate-immune response.
authors.affiliation: *Signaling Systems Laboratory and Department of Chemistry and Biochemistry and San Diego Center for Systems Biology, University of California, San Diego, La Jolla, California, USA; and Institute for Quantitative and Computational Biosciences, Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, California, USA.
authors.forename: Diana R
authors.initials: DR
authors.lastname: Ourthiague
authors.affiliation: *Signaling Systems Laboratory and Department of Chemistry and Biochemistry and San Diego Center for Systems Biology, University of California, San Diego, La Jolla, California, USA; and Institute for Quantitative and Computational Biosciences, Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, California, USA.
authors.forename: Harry
authors.initials: H
authors.lastname: Birnbaum
authors.affiliation: *Signaling Systems Laboratory and Department of Chemistry and Biochemistry and San Diego Center for Systems Biology, University of California, San Diego, La Jolla, California, USA; and Institute for Quantitative and Computational Biosciences, Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, California, USA.
authors.forename: Niklas
authors.initials: N
authors.lastname: Ortenlöf
authors.affiliation: *Signaling Systems Laboratory and Department of Chemistry and Biochemistry and San Diego Center for Systems Biology, University of California, San Diego, La Jolla, California, USA; and Institute for Quantitative and Computational Biosciences, Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, California, USA.
authors.forename: Jesse D
authors.initials: JD
authors.lastname: Vargas
authors.affiliation: *Signaling Systems Laboratory and Department of Chemistry and Biochemistry and San Diego Center for Systems Biology, University of California, San Diego, La Jolla, California, USA; and Institute for Quantitative and Computational Biosciences, Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, California, USA.
authors.forename: Roy
authors.initials: R
authors.lastname: Wollman
authors.affiliation: *Signaling Systems Laboratory and Department of Chemistry and Biochemistry and San Diego Center for Systems Biology, University of California, San Diego, La Jolla, California, USA; and Institute for Quantitative and Computational Biosciences, Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, California, USA ahoffmann@ucla.edu.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoffmann
mesh_terms: D000818:Animals; D047369:Chromatin Immunoprecipitation; D007113:Immunity, Innate / Q000502:physiology*; D050838:Interferon Regulatory Factor-3 / Q000502:physiology*; D050832:Interferon-Stimulated Gene Factor 3 / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D012330:RNA, Double-Stranded / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000502:physiology*
chemical_list: D050838:Interferon Regulatory Factor-3; D050832:Interferon-Stimulated Gene Factor 3; C494233:Irf3 protein, mouse; D012330:RNA, Double-Stranded
keywords: feed-forward loop; gene expression; interferon; mathematical modeling; pathogen response