Runx3調控丙型干擾素的探討

Abstract

Runx 家族蛋白皆含有一段與異二聚體Cbfβ鍵結的保守區塊，Runt 區域。Runx家族蛋白並有三個成員Runx1，Runx2 和Runx3。Runx3 是家族中分子量最小的蛋白質，主要表現於第一型輔助細胞及細胞毒殺細胞中，更與轉錄因子T-bet 共同參與活化第一型干擾素的表現。然而，Runx3 蛋白中與T-bet 相互作用的區域及其參與調控第一型干擾素表現的機制尚待進一步探討。 中研院基因突變鼠核心實驗室所建立的P054 突變鼠含有C 端105 個胺基酸缺失的Runx3 蛋白，初步研究發現P054 小鼠的週邊淋巴器官有異常的CD4/CD8 細胞族群表現。進一步研究顯示P054 突變鼠的第一型輔助細胞及細胞毒殺細胞的第一型干擾素表現皆有減少的趨勢。由此可知 C 端胺基酸缺失的Runx3 蛋白是調控淋巴細胞發育及功能的重要元素。然而，突變的Runx3 蛋白並未造成細胞分布及蛋白質穩定性的異常。此外，深入探討得知 NMTS 區域是與T-bet 作用共同驅動第一型干擾素活化的主要區塊。總結以上結果推論 Runx3 蛋白中的NMTS 區域可能是參與淋巴細胞發育及第一干擾素表現的重要元素。

Runx proteins, which contain a conserved Runt domain, are a heterodimer bound with cofactor, Cbfβ. Runx family contains three members, Runx1, Runx2, and Runx3. Runx3, the smallest protein of the family, mainly expressed in effector CD4+ Th1 cells and CD8+ T cells and cooperates with T-bet to activate IFN-γ gene expression. However, which domain(s) of Runx3 interacts/interact with T-bet to drive IFN-γ expression remains unknown. P054 mice, generated from ENU core in Academia Sinica, have a truncated Runx3 protein with 105 amino acid deletion in C-terminal. We observed abnormal profile of CD4/CD8 expression in P054 mice. Furthermore, decreased IFN-γ productions were identified in Th1 and CD8 of P054 mice. It indicates that the deleted C-terminal domain of Runx3 is important in T cell development and their effecor functions. However, loss of Runx3 C-terminal still maintains its cellular localization and protein stability. In addition, we observed that the NMTS domain of Runx3 is an important domain to cooperate with T-bet for the activation of IFN-γ. Take together, The NMTS domain of Runx3 might play a important role in lymphoid cell development and IFN-γ production.