STAT1 pathway is involved in activation of caprine arthritis-encephalitis virus long terminal repeat in monocytes.
The caprine arthritis-encephalitis virus (CAEV) long terminal repeat (LTR) is activated by gamma interferon (IFN-gamma) in promonocytic cells. We have previously shown that a 70-bp element is necessary and sufficient for the response of the CAEV LTR to this cytokine. At the 5' end, this 70-bp IFN-gamma response element contains sequence similarity to the gamma activated site (GAS). Here we demonstrate that the putative GAS element in the CAEV LTR binds specifically to a cellular factor induced by IFN-gamma in promonocytic cells. Substitution mutations in this consensus sequence eliminate binding of the inducible factor. The GAS element from the 70-bp motif is sufficient to confer responsiveness to IFN-gamma using a heterologous minimal promoter. Consistent with the binding data, the same mutations in the GAS element eliminate responsiveness to IFN-gamma in the context of both a functional CAEV LTR and a heterologous promoter. The cellular factor that binds to the GAS element is present from 5 min to 14 h after stimulation with IFN-gamma. Binding of the nuclear factor to the GAS element in the CAEV LTR is inhibited by antibody directed against STAT1 (p91/84). Thus, the GAS sequence in the CAEV LTR is essential for the response to IFN-gamma and a STAT1-like factor binds to this site. The STAT-1 signaling pathway provides at least one mechanism for activation of the CAEV LTR by IFN-gamma in monocytes. These data are the first demonstration of a role for a STAT family member in the regulation of a viral promoter.
Sepp
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Department of Medicine, University of California-San Francisco, 94121, USA.
Tong-Starksen
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D016088:Arthritis-Encephalitis Virus, Caprine / Q000235:genetics*; D001483:Base Sequence; D004279:DNA, Viral; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D016898:Interferon-alpha / Q000494:pharmacology*; D008969:Molecular Sequence Data; D009000:Monocytes / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D012091:Repetitive Sequences, Nucleic Acid; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000502:physiology*; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D004279:DNA, Viral; D004268:DNA-Binding Proteins; D016898:Interferon-alpha; D009687:Nuclear Proteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D018799:Intercellular Adhesion Molecule-1