title: Acetylation of interferon regulatory factor-7 by p300/CREB-binding protein (CBP)-associated factor (PCAF) impairs its DNA binding.
abstract: Interferon regulatory factor 7 (IRF7) is an interferon-inducible transcription factor required for induction of delayed early interferon alpha genes and the onset of a potent antiviral state. After induction of IRF7 by autocrine interferon, latent IRF7 is activated by virus-induced phosphorylation on serine residues within the C-terminal regulatory domain. Although it is likely that IRF7 is subjected to a cascade of events responsible for regulating its biological activity, to date no mechanism other than phosphorylation has been reported to modulate IRF7 activity. Here, we report that IRF7 is acetylated in vivo by the histone acetyltransferases p300/CBP-associated factor (PCAF) and GCN5. The single lysine residue target for acetylation, lysine 92, is located in the DNA-binding domain and is conserved throughout the entire IRF family. Mutation of lysine 92 resulted in complete abolition of DNA binding ability. However, a mutant that cannot be acetylated by PCAF due to a change in the surrounding amino acid context of lysine 92 showed increased DNA binding and activity compared with wild type IRF7. Conversely, we showed that acetylated IRF7 displayed impaired DNA binding capability and that over-expression of PCAF led to decreased IRF7 activity. Together, our results strongly suggest that acetylation of lysine 92 negatively modulates IRF7 DNA binding.
authors.affiliation: Unité de Virologie et Immunologie Cellulaire, Institut Pasteur, 75724 Paris, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Caillaud
authors.forename: Arun
authors.initials: A
authors.lastname: Prakash
authors.forename: Eric
authors.initials: E
authors.lastname: Smith
authors.forename: Atsuko
authors.initials: A
authors.lastname: Masumi
authors.forename: Ara G
authors.initials: AG
authors.lastname: Hovanessian
authors.forename: David E
authors.initials: DE
authors.lastname: Levy
authors.forename: Isabelle
authors.initials: I
authors.lastname: Marié
mesh_terms: D000107:Acetylation; D000123:Acetyltransferases / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D019921:Biotinylation; D015153:Blotting, Western; D019556:COS Cells; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D017930:Genes, Reporter; D051548:Histone Acetyltransferases; D006801:Humans; D050839:Interferon Regulatory Factor-7; D007700:Kinetics; D008156:Luciferases / Q000378:metabolism; D008239:Lysine / Q000737:chemistry; D008969:Molecular Sequence Data; D009154:Mutation; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D029701:Saccharomyces cerevisiae Proteins / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D013997:Time Factors; D014162:Transfection; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D016207:Cytokines; D004268:DNA-Binding Proteins; C494234:IRF7 protein, human; D050839:Interferon Regulatory Factor-7; D029701:Saccharomyces cerevisiae Proteins; D004247:DNA; D008156:Luciferases; D000123:Acetyltransferases; D051548:Histone Acetyltransferases; D001616:beta-Galactosidase; D008239:Lysine