Division of Cell Signaling and Immunology, School of Life Sciences, University of Dundee, Dundee, UK.
Department of Computer Science, Purdue University, West Lafayette, IN, USA.
Cell Rep. 2020 Dec 22;33(12):108545. doi: 10.1016/j.celrep.2020.108545.
Cytokines are highly pleiotropic ligands that regulate the immune response. Here, using interleukin-6 (IL-6) as a model system, we perform detailed phosphoproteomic and transcriptomic studies in human CD4 T helper 1 (Th-1) cells to address the molecular bases defining cytokine functional pleiotropy. We identify CDK8 as a negative regulator of STAT3 transcriptional activities, which interacts with STAT3 upon IL-6 stimulation. Inhibition of CDK8 activity, using specific small molecule inhibitors, reduces the IL-6-induced phosphoproteome by 23% in Th-1 cells, including STAT3 S727 phosphorylation. STAT3 binding to target DNA sites in the genome is increased upon CDK8 inhibition, which results in a concomitant increase in STAT3-mediated transcriptional activity. Importantly, inhibition of CDK8 activity under Th-17 polarizing conditions results in an enhancement of Th-17 differentiation. Our results support a model where CDK8 regulates STAT3 transcriptional processivity by modulation of its gene loci resident time, critically contributing to diversification of IL-6 responses.
细胞因子是高度多功能的配体，可调节免疫反应。在这里，我们以白细胞介素 6（IL-6）作为模型系统，在人类 CD4 辅助性 T 细胞 1（Th-1）细胞中进行详细的磷酸化蛋白质组学和转录组学研究，以解决定义细胞因子功能多样性的分子基础。我们确定 CDK8 是 STAT3 转录活性的负调节剂，其在 IL-6 刺激下与 STAT3 相互作用。使用特异性小分子抑制剂抑制 CDK8 活性，可使 Th-1 细胞中的 IL-6 诱导的磷酸蛋白质组减少 23%，包括 STAT3 S727 磷酸化。CDK8 抑制后，STAT3 与基因组中靶 DNA 位点的结合增加，从而导致 STAT3 介导的转录活性增加。重要的是，在 Th-17 极化条件下抑制 CDK8 活性会增强 Th-17 分化。我们的结果支持这样一种模型，即 CDK8 通过调节其基因座驻留时间来调节 STAT3 转录过程性，这对 IL-6 反应的多样化有重要贡献。
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