Pyrrothiogatain acts as an inhibitor of GATA family proteins and inhibits Th2 cell differentiation in vitro
Pyrrothiogatain acts as an inhibitor of GATA family proteins and inhibits Th2 cell differentiation in vitro
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DOI：
10.1038/s41598-019-53856-1
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发表时间：
2019-11-22
影响因子：
4.6
通讯作者：
Sawasaki, Tatsuya
中科院分区：
文献类型：
--
作者：
Nomura, Shunsuke;Takahashi, Hirotaka;Sawasaki, Tatsuya
转录因子 GATA3 是调节 T 辅助细胞 2 (Th2) 细胞分化并诱导 Th2 细胞因子（例如 IL-4、IL-5 和 IL-13）表达的主调节因子。 Th2 细胞因子参与针对外来病原体（例如寄生虫）的保护性免疫反应。然而，Th2 细胞因子的过量产生会导致 2 型过敏性炎症。因此，GATA3抑制剂的应用为调节Th2细胞因子的产生提供了新的治疗策略。在这里，我们建立了一种新型的 DNA 结合蛋白（例如转录因子）抑制剂的高通量筛选系统，并鉴定了吡咯硫加坦作为 GATA3 DNA 结合活性的新型抑制剂。 Pyrothiogatain 抑制 GATA3 和 GATA 家族其他成员的 DNA 结合活性。 Pyrothiogatain 还抑制 GATA3 和 SOX4 之间的相互作用，表明它与 GATA3 的 DNA 结合区相互作用。此外，pyrothiogatain 显着抑制 Th2 细胞分化，而不损害 Th1 细胞分化，并抑制 Th2 细胞因子的表达和产生。我们的结果表明，吡咯硫加坦通过抑制 GATA3 DNA 结合活性来调节 Th2 细胞的分化和功能，这证明了我们的药物筛选系统在开发抑制转录因子 DNA 结合活性的新型小化合物方面的效率。
The transcription factor GATA3 is a master regulator that modulates T helper 2 (Th2) cell differentiation and induces expression of Th2 cytokines, such as IL-4, IL-5, and IL-13. Th2 cytokines are involved in the protective immune response against foreign pathogens, such as parasites. However, excessive production of Th2 cytokines results in type-2 allergic inflammation. Therefore, the application of a GATA3 inhibitor provides a new therapeutic strategy to regulate Th2 cytokine production. Here, we established a novel high-throughput screening system for an inhibitor of a DNA-binding protein, such as a transcription factor, and identified pyrrothiogatain as a novel inhibitor of GATA3 DNA-binding activity. Pyrrothiogatain inhibited the DNA-binding activity of GATA3 and other members of the GATA family. Pyrrothiogatain also inhibited the interaction between GATA3 and SOX4, suggesting that it interacts with the DNA-binding region of GATA3. Furthermore, pyrrothiogatain significantly suppressed Th2 cell differentiation, without impairing Th1 cell differentiation, and inhibited the expression and production of Th2 cytokines. Our results suggest that pyrrothiogatain regulates the differentiation and function of Th2 cells via inhibition of GATA3 DNA binding activity, which demonstrates the efficiency of our drug screening system for the development of novel small compounds that inhibit the DNA-binding activity of transcription factors.