Interferon regulatory factor-7 synergizes with other transcription factors through multiple interactions with p300/CBP coactivators.
Interferon regulatory factor (IRF)-7 is activated in response to virus infection and stimulates the transcription of a set of cellular genes involved in host antiviral defense. The mechanism by which IRF-7 is activated and cooperates with other transcription factors is not fully elucidated. Activation of IRF-7 results from a conformational change triggered by the virus-dependent phosphorylation of its C terminus. This conformational change leads to dimerization, nuclear accumulation, DNA-binding, and transcriptional transactivation. Here we show that activation of IRF-7, like that of IRF-3, is dependent on modifications of two distinct sets of Ser/Thr residues. Moreover, we show that different virus-inducible cis-acting elements display requirements for specific IRFs. In particular, the virus-responsive element of the ISG15 gene promoter can be activated by either IRF-3 or IRF-7 alone, whereas the P31 element of the interferon-beta gene is robustly activated only when IRF-3, IRF-7, and the p300/CBP coactivators are all present. Furthermore, we find that IRF-7 interacts with four distinct regions of p300/CBP. These interactions not only stimulate the intrinsic transcriptional activity of IRF-7, but they are also indispensable for its ability to strongly synergize with other transcription factors, including c-Jun and IRF-3.
Yang
Hongmei
H
Department of Molecular and Cellular Physiology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0576, USA.
Lin
Charles H
CH
Ma
Gang
G
Baffi
Michael O
MO
Wathelet
Marc G
MG
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000502:physiology*; D006801:Humans; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000502:physiology*; D011487:Protein Conformation; D016755:Proto-Oncogene Proteins c-jun / Q000502:physiology; D011817:Rabbits; D013329:Structure-Activity Relationship; D015534:Trans-Activators / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D015533:Transcriptional Activation; D014775:Virus Activation
D004268:DNA-Binding Proteins; C494232:IRF3 protein, human; C494234:IRF7 protein, human; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D009687:Nuclear Proteins; D016755:Proto-Oncogene Proteins c-jun; D015534:Trans-Activators; D014157:Transcription Factors; D004247:DNA