Caillaud Alexandre, Prakash Arun, Smith Eric, Masumi Atsuko, Hovanessian Ara G, Levy David E, Marié Isabelle
Unité de Virologie et Immunologie Cellulaire, Institut Pasteur, 75724 Paris, France.
J Biol Chem. 2002 Dec 20;277(51):49417-21. doi: 10.1074/jbc.M207484200. Epub 2002 Oct 8.
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.
干扰素调节因子7（IRF7）是一种干扰素诱导型转录因子，是诱导延迟早期干扰素α基因和强效抗病毒状态起始所必需的。在自分泌干扰素诱导IRF7后，潜伏的IRF7通过病毒诱导的C末端调节域内丝氨酸残基磷酸化而被激活。尽管IRF7可能经历一系列负责调节其生物学活性的事件，但迄今为止，除了磷酸化之外，尚未有其他机制被报道可调节IRF7活性。在此，我们报道IRF7在体内被组蛋白乙酰转移酶p300/CBP相关因子（PCAF）和GCN5乙酰化。乙酰化的单个赖氨酸残基靶点，即赖氨酸92，位于DNA结合域，并且在整个IRF家族中保守。赖氨酸92的突变导致DNA结合能力完全丧失。然而，由于赖氨酸92周围氨基酸环境的改变而不能被PCAF乙酰化的突变体与野生型IRF7相比，显示出增强的DNA结合和活性。相反，我们表明乙酰化的IRF7显示出受损的DNA结合能力，并且PCAF的过表达导致IRF7活性降低。总之，我们的结果强烈表明赖氨酸92的乙酰化负向调节IRF7的DNA结合。
