Ets-1在調控介白素二中所扮演之角色

Abstract

E26轉型特異性序列1(Ets-1)是ETS轉錄因子家族蛋白之原型，也是第一個被發現的ETS家族成員，其對於小鼠體內輔助型T細胞(Th cells)的介白素二(Interleukin-2, IL-2)表現非常重要，然而目前對於Ets-1如何促進介白素二的表現，其機制仍然不明。 我們的研究顯示，Ets-1不僅對小鼠的介白素二表現重要，它也是人類介白素二重要的調控因子。雖然Ets-1可負調控一已知的介白素二抑制者Blimp-1，但在Ets-1基因剔除的輔助型T細胞中再剔除Blimp-1並無法讓介白素二的生成恢復正常。 另一方面，Ets-1可以和NFAT蛋白產生交互作用，除了促進NFAT蛋白的功能之外，也是NFAT聚集並活化至介白素二之啟動子所必須。除此之外，在未活化的輔助型T細胞中，Ets-1同時分布於細胞核和細胞中，當受到鈣離子的訊號刺激之後，核中的Ets-1會快速的離開細胞核並和細胞質中的NFAT蛋白競爭與NRON 複合體的結合，讓NFAT蛋白離開NRON 複合體。這個Ets-1在細胞受到刺激後從細胞核進入細胞質的過程是發生在NFAT蛋白進入核之前，所以當細胞缺少Ets-1時，NFAT蛋白進入核的能力就會受到影響，但其被去磷酸化的能力則沒有變化。 因此，我們認為Ets-1調控介白素二的主要機制乃是透過控制NFAT蛋白的活性而達成的。這篇論文不只增進了我們對於介白素二轉錄機制的了解，另一方面更指出了Ets-1控制下游基因的特殊機制。

Ets-1, the prototype of the ETS family of transcription factors, is critical for the expression of IL-2 in murine and human T cells. Although IL-2 is a well characterized cytokine, how Ets-1 regulates the expression of IL-2 remains unclear. Here we show that Ets-1 is also essential for optimal production of IL-2 by murine CD8+ T cells and primary human T helper (Th) cells. We also observed an elevated Blimp-1 expression in Ets-1 KO T cells. Although Blimp-1 plays as a suppressor for IL-2, our data indicated that Blimp-1 is not responsible for the impaired IL-2 production in Ets-1 KO cells. The defects we observed in Ets-1-deficient cells cannot be rescued by Blimp-1 deficiency in Ets-1 KO cells. Instead, Ets-1 physically and functionally interacts with the nuclear factor of activated T-cells (NFAT) through multiple domains and is required for the recruitment of NFAT to the IL-2 promoter. In resting Th cells, Ets-1 is located both in nucleus and cytoplasm. When receiving calcium dependent signals from T cell receptors (TCR), nuclear Ets-1 starts to exit the nucleus and competes with NFAT proteins for binding to protein components of NRON (non-coding RNA repressor of NFAT) complex. NRON complex serves as a cytoplasmic trap for phosphorylated NFAT proteins in cytoplasm and this competition results in the release of NFAT from the complex. Ets-1 deficiency results in impaired nuclear entry, but not dephosphorylation, of NFAT proteins. We also found that the nuclear resident Ets-1 can interact with NFAT proteins to facilitate the transcription activity of NFAT in nucleus. Thus, Ets-1 promotes the expression of IL-2 by modulating the activity of NFAT. To the best of our knowledge, Ets-1 is the first transcription factor that is known to interact with NRON complex and facilitate nuclear entry of NFAT proteins.