Department of Immunology, Basic Medical College, Tianjin Medical University, Heping District, Qixiangtai Road No. 22, Tianjin 300070, China.
J Biol Chem. 2011 Feb 4;286(5):3451-9. doi: 10.1074/jbc.M110.168377. Epub 2010 Nov 24.
Regulation of transcription requires cooperation between sequence-specific transcription factors and numerous coregulatory proteins. In IL-4/IL-13 signaling several coactivators for STAT6 have been identified, but the molecular mechanisms of STAT6-mediated gene transcription are still not fully understood. Here we identified by proteomic approach that the PTB-associated splicing factor (PSF) interacts with STAT6. In intact cells the interaction was observed only after IL-4 stimulation. The IL-4-induced tyrosine phosphorylation of both STAT6 and PSF is a prerequisite for the efficient association of the two proteins. Functional analysis demonstrated that ectopic expression of PSF resulted in inhibition of STAT6-mediated transcriptional activation and mRNA expression of the Igε germline heavy chain gene, whereas knockdown of PSF increased the STAT6-mediated responses. PSF recruited histone deacetylase 1 (HDAC1) to the STAT6 transcription complex, which resulted in reduction of H3 acetylation at the promoter regions of Ig heavy chain germline Igε and inhibition of STAT6-mediated transcription. In addition, the HDACs inhibitor trichostatin A (TSA) enhanced H3 acetylation, and reverted the PSF-mediated transcriptional repression of Igε gene transcription. In summary, these results identify PSF as a repressor of STAT6-mediated transcription that functions through recruitment of HDAC to the STAT6 transcription complex, and delineates a novel regulatory mechanism of IL-4 signaling that may have implications in the pathogenesis of allergic diseases and pharmacological HDAC inhibition in lymphomas.
转录调控需要序列特异性转录因子和众多共调节蛋白之间的合作。在 IL-4/IL-13 信号通路中，已经鉴定出了几种 STAT6 的共激活因子，但 STAT6 介导的基因转录的分子机制仍不完全清楚。在这里，我们通过蛋白质组学方法鉴定出 PTB 相关剪接因子（PSF）与 STAT6 相互作用。在完整的细胞中，只有在 IL-4 刺激后才观察到这种相互作用。STAT6 和 PSF 的 IL-4 诱导的酪氨酸磷酸化是两者有效结合的前提。功能分析表明，PSF 的异位表达导致 STAT6 介导的转录激活和 Igε 重链基因的 mRNA 表达受到抑制，而 PSF 的敲低增加了 STAT6 介导的反应。PSF 将组蛋白去乙酰化酶 1（HDAC1）募集到 STAT6 转录复合物中，导致启动子区域的 H3 乙酰化减少，从而抑制 STAT6 介导的转录。此外，HDAC 抑制剂曲古抑菌素 A（TSA）增强了 H3 乙酰化，并使 PSF 介导的 Igε 基因转录的转录抑制逆转。总之，这些结果表明 PSF 是 STAT6 介导的转录的抑制剂，通过将 HDAC 募集到 STAT6 转录复合物中来发挥作用，并描绘了 IL-4 信号的一种新的调节机制，这可能对过敏疾病的发病机制和淋巴瘤中的药理学 HDAC 抑制具有重要意义。
