Max F. Perutz Laboratories, University of Vienna, Dr. Bohr-Gasse 9, A-1030 Vienna, Austria.
Immunity. 2013 Feb 21;38(2):250-62. doi: 10.1016/j.immuni.2012.10.017. Epub 2013 Jan 24.
Gene regulation by cytokine-activated transcription factors of the signal transducer and activator of transcription (STAT) family requires serine phosphorylation within the transactivation domain (TAD). STAT1 and STAT3 TAD phosphorylation occurs upon promoter binding by an unknown kinase. Here, we show that the cyclin-dependent kinase 8 (CDK8) module of the Mediator complex phosphorylated regulatory sites within the TADs of STAT1, STAT3, and STAT5, including S727 within the STAT1 TAD in the interferon (IFN) signaling pathway. We also observed a CDK8 requirement for IFN-γ-inducible antiviral responses. Microarray analyses revealed that CDK8-mediated STAT1 phosphorylation positively or negatively regulated over 40% of IFN-γ-responsive genes, and RNA polymerase II occupancy correlated with gene expression changes. This divergent regulation occurred despite similar CDK8 occupancy at both S727 phosphorylation-dependent and -independent genes. These data identify CDK8 as a key regulator of STAT1 and antiviral responses and suggest a general role for CDK8 in STAT-mediated transcription. As such, CDK8 represents a promising target for therapeutic manipulation of cytokine responses.
细胞因子激活的转录因子信号转导和转录激活因子（STAT）家族通过丝氨酸磷酸化调节基因转录，该家族的转录激活域（TAD）需要磷酸化。STAT1 和 STAT3 的 TAD 磷酸化发生在启动子结合未知激酶之后。在这里，我们发现中介体复合物的细胞周期蛋白依赖性激酶 8（CDK8）模块磷酸化了 STAT1、STAT3 和 STAT5 的 TAD 中的调节位点，包括干扰素（IFN）信号通路中 STAT1 TAD 中的 S727。我们还观察到 CDK8 对 IFN-γ 诱导的抗病毒反应的需求。微阵列分析显示，CDK8 介导的 STAT1 磷酸化正向或负向调节了超过 40%的 IFN-γ 反应基因，RNA 聚合酶 II 占据与基因表达变化相关。尽管在 S727 磷酸化依赖性和非依赖性基因上 CDK8 占据相似，但这种差异调节仍然存在。这些数据表明 CDK8 是 STAT1 和抗病毒反应的关键调节剂，并表明 CDK8 在 STAT 介导的转录中具有普遍作用。因此，CDK8 代表了细胞因子反应治疗干预的有希望的靶点。
