近日,，國際學術期刊Journal of Biological Chemistry在線發(fā)表了中科院上海巴斯德研究所李斌課題組的研究論文,，題為TIP60 Positively Regulates ThPOK-Mediated Repression of Eomesodermin in Human CD4+ T Cells,。本研究揭示了一個抑制炎癥因子IFNg轉錄表達的TIP60-ThPOK-Eomes信號通路。在炎癥情況下該通路反向調控CD4+ T細胞表達I型促炎癥因子IFNg的功能。本發(fā)現(xiàn)對進一步深入理解炎癥微環(huán)境中人源CD4+ T細胞功能動態(tài)調節(jié)具有重要指導性意義。
本課題組研究人員前期研究發(fā)現(xiàn),，決定調節(jié)性T細胞(Treg)中FOXP3轉錄活性的關鍵性調控蛋白TIP60， 主要在CD4+ T細胞中表達,。作為蛋白乙酰轉移酶,，TIP60還與CD4+ T細胞中許多其他關鍵性轉錄調控蛋白形成不同的轉錄復合體，并通過促進轉錄因子蛋白或組蛋白的乙?；?，從而激活或抑制基因轉錄。理解炎癥條件下CD4+T細胞內關鍵性轉錄因子的調節(jié)機制,，將為病毒感染及腫瘤相關疾病治療提供新的藥物靶點及臨床干預手段,。
ThPOK作為CD4+ 輔助性T細胞高表達的關鍵性轉錄因子,，其轉錄活性對CD4+ T細胞分化及功能至關重要,。例如，ThPOK通過下調轉錄因子Eomesodermin (Eomes) 的表達從而抑制Th1型促炎癥因子 IFNγ的表達,，但其分子機制尚不清楚,。在本研究中，博士研究生李揚揚等在李斌研究員的指導下發(fā)現(xiàn)在TCR信號刺激條件下,，內源性TIP60可以和ThPOK結合形成蛋白復合體,。TIP60乙酰化修飾ThPOK蛋白的第360位賴氨酸位點,，進而增強了ThPOK蛋白的穩(wěn)定性,。在CD4+ T細胞中沉默TIP60基因表達，會導致ThPOK蛋白的快速降解,，這表明TIP60蛋白是穩(wěn)定ThPOK所必需的調控因子,。其外，轉錄因子ThPOK直接結合于Eomesdermin基因啟動子區(qū),，調控其基因轉錄,。過表達ThPOK能夠抑制Eomes在Jurkat細胞中的轉錄；其外熒光素酶報告基因實驗也證實ThPOK可以抑制Eomes 啟動子的活性。本研究首次揭示TIP60和ThPOK協(xié)同作用抑制了Eomes-IFNγ信號通路,，從而限制Th1型炎癥反應,。
該研究獲得了中國科學院上海生命科學研究院優(yōu)秀青年人才領域前沿項目、國家自然科學基金,、上海市科委青年科技啟明星計劃等項目經(jīng)費支持,。（生物谷Bioon.com）
doi:10.1074/jbc.M112.430207
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TIP60 Positively Regulates ThPOK-Mediated Repression of Eomesodermin in Human CD4+ T Cells
Yangyang Li1, Andy Tsun1, Zhimei Gao1, Zhijun Han2, Yayi Gao1, Zhiyuan Li1, Fang Lin1, Yan Wang2, Gang Wei2, Zhengju Yao1 and Bin Li1*
The abundant expression of IFNγ in ThPOK-deficient CD4+ T cells requires the activation of Eomesodermin (Eomes); however, the underlying mechanism of this phenomenon remains unclear. Here we report that ThPOK directly binds to the promoter region of the Eomes gene to repress its expression in CD4+ T cells. We identified the histone acetyltransferase TIP60 as a corepressor of ThPOK-target genes, where ectopically expressed TIP60 increased ThPOK protein stability by promoting its acetylation at its K360 residue to then augment the transcriptional repression of Eomes. Moreover, knockdown of endogenous TIP60 abolished the stabilization of ThPOK in CD4+ T cells, which led to the transcriptional activation of Eomes and increased production of IFNγ. Our results reveal a novel pathway by which TIP60 and ThPOK synergistically suppresses Eomes function and IFNγ production, which could contribute to the regulation of inflammation.
