Graduate Institute of Immunology, National Taiwan University College of Medicine, Taipei 10051, Taiwan.
Proc Natl Acad Sci U S A. 2013 Sep 24;110(39):15776-81. doi: 10.1073/pnas.1304343110. Epub 2013 Sep 9.
E26 transformation-specific sequence 1 (Ets-1), the prototype of the ETS family of transcription factors, is critical for the expression of IL-2 by murine Th cells; however, its mechanism of action is still unclear. Here we show that Ets-1 is also essential for optimal production of IL-2 by primary human Th cells. Although Ets-1 negatively regulates the expression of Blimp1, a known suppressor of IL-2 expression, ablation of B lymphocyte-induced maturation protein 1 (Blimp1) does not rescue the expression of IL-2 by Ets-1-deficient Th cells. Instead, Ets-1 physically and functionally interacts with the nuclear factor of activated T-cells (NFAT) and is required for the recruitment of NFAT to the IL-2 promoter. In addition, Ets-1 is located in both the nucleus and cytoplasm of resting Th cells. Nuclear Ets-1 quickly exits the nucleus in response to calcium-dependent signals and competes with NFAT proteins for binding to protein components of noncoding RNA repressor of NFAT complex (NRON), which serves as a cytoplasmic trap for phosphorylated NFAT proteins. This nuclear exit of Ets-1 precedes rapid nuclear entry of NFAT and Ets-1 deficiency results in impaired nuclear entry, but not dephosphorylation, of NFAT proteins. Thus, Ets-1 promotes the expression of IL-2 by modulating the activity of NFAT.
E26 转化特异性序列 1（Ets-1）是 ETS 家族转录因子的原型，对于小鼠 Th 细胞中 IL-2 的表达至关重要；然而，其作用机制仍不清楚。在这里，我们表明 Ets-1 对于原代人 Th 细胞中 IL-2 的最佳产生也是必需的。尽管 Ets-1 负调控 Blimp1 的表达，Blimp1 是已知的 IL-2 表达抑制剂，但 Blimp1 缺失并不能挽救 Ets-1 缺陷型 Th 细胞中 IL-2 的表达。相反，Ets-1 与活化 T 细胞的核因子（NFAT）物理和功能相互作用，并且需要 NFAT 募集到 IL-2 启动子。此外，Ets-1 存在于静止 Th 细胞的细胞核和细胞质中。Ets-1 在响应钙依赖性信号时迅速从细胞核中输出，并与 NFAT 蛋白竞争结合非编码 RNA NFAT 复合物抑制物（NRON）的蛋白成分，NRON 作为磷酸化 NFAT 蛋白的细胞质陷阱。Ets-1 的这种核输出先于 NFAT 的快速核内进入，并且 Ets-1 缺陷导致 NFAT 蛋白的核内进入受损，但不导致去磷酸化。因此，Ets-1 通过调节 NFAT 的活性来促进 IL-2 的表达。
