A Hybrid IRF9-STAT2 Protein Recapitulates Interferon-stimulated Gene Expression and Antiviral Response

Type I interferon (IFN) signaling induces the heterotrimeric transcription complex, IFN-stimulated gene factor (ISGF) 3, which contains STAT1, STAT2, and the DNA binding subunit, interferon regulatory factor (IRF) 9. Because IRF9 is targeted to the nucleus in the absence of IFN stimulation, the pote...

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Bibliographic Details
Published in:The Journal of biological chemistry 2003-04, Vol.278 (15), p.13033-13038
Main Authors: Kraus, Thomas A, Lau, Joe F, Parisien, Jean-Patrick, Horvath, Curt M
Format: Article
Language:English
Subjects:
Animals
Antiviral Agents
Base Sequence
Cell Line
Chlorocebus aethiops
DNA Primers
DNA-Binding Proteins - genetics
DNA-Binding Proteins - physiology
Gene Expression Regulation - drug effects
Gene Expression Regulation - immunology
Genes, Reporter
Humans
Interferon Type I - pharmacology
Interferon-Stimulated Gene Factor 3
Interferon-Stimulated Gene Factor 3, gamma Subunit
Luciferases - genetics
Open Reading Frames
Recombinant Fusion Proteins - biosynthesis
Saccharomyces cerevisiae Proteins - genetics
STAT2 Transcription Factor
Trans-Activators - genetics
Trans-Activators - physiology
Transcription Factors - genetics
Transcription Factors - physiology
Transcription, Genetic
Tumor Cells, Cultured
Vero Cells
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Summary:Type I interferon (IFN) signaling induces the heterotrimeric transcription complex, IFN-stimulated gene factor (ISGF) 3, which contains STAT1, STAT2, and the DNA binding subunit, interferon regulatory factor (IRF) 9. Because IRF9 is targeted to the nucleus in the absence of IFN stimulation, the potential of IRF9 protein for gene regulation was examined using a GAL4 DNA binding domain fusion system. GAL4-IRF9 was transcriptionally active in reporter gene assays but not in the absence of cellular STAT1 and STAT2. However, the inert IRF9 protein was readily converted to a constitutively active ISGF3-like activator by fusion with the C-terminal transcriptional activation domain of STAT2 or the acidic activation domain of herpesvirus VP16. The IRF9 hybrids are targeted to endogenous ISGF3 target loci and can activate their transcription. Moreover, expression of the IRF9-STAT2 fusion can recapitulate the type I IFN biological response, producing a cellular antiviral state that protects cells from virus-induced cytopathic effects and inhibits virus replication. The antiviral state generated by regulated IRF9-STAT2 hybrid protein expression is independent of autocrine IFN signaling and inhibits both RNA and DNA viruses.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M212972200