近日,，國(guó)際學(xué)術(shù)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(gè)抑制炎癥因子IFNg轉(zhuǎn)錄表達(dá)的TIP60-ThPOK-Eomes信號(hào)通路,。在炎癥情況下該通路反向調(diào)控CD4+ T細(xì)胞表達(dá)I型促炎癥因子IFNg的功能。本發(fā)現(xiàn)對(duì)進(jìn)一步深入理解炎癥微環(huán)境中人源CD4+ T細(xì)胞功能動(dòng)態(tài)調(diào)節(jié)具有重要指導(dǎo)性意義,。
本課題組研究人員前期研究發(fā)現(xiàn),，決定調(diào)節(jié)性T細(xì)胞(Treg)中FOXP3轉(zhuǎn)錄活性的關(guān)鍵性調(diào)控蛋白TIP60， 主要在CD4+ T細(xì)胞中表達(dá),。作為蛋白乙酰轉(zhuǎn)移酶,，TIP60還與CD4+ T細(xì)胞中許多其他關(guān)鍵性轉(zhuǎn)錄調(diào)控蛋白形成不同的轉(zhuǎn)錄復(fù)合體，并通過促進(jìn)轉(zhuǎn)錄因子蛋白或組蛋白的乙?；?，從而激活或抑制基因轉(zhuǎn)錄。理解炎癥條件下CD4+T細(xì)胞內(nèi)關(guān)鍵性轉(zhuǎn)錄因子的調(diào)節(jié)機(jī)制,，將為病毒感染及腫瘤相關(guān)疾病治療提供新的藥物靶點(diǎn)及臨床干預(yù)手段,。
ThPOK作為CD4+ 輔助性T細(xì)胞高表達(dá)的關(guān)鍵性轉(zhuǎn)錄因子，其轉(zhuǎn)錄活性對(duì)CD4+ T細(xì)胞分化及功能至關(guān)重要,。例如,，ThPOK通過下調(diào)轉(zhuǎn)錄因子Eomesodermin (Eomes) 的表達(dá)從而抑制Th1型促炎癥因子 IFNγ的表達(dá)，但其分子機(jī)制尚不清楚,。在本研究中,，博士研究生李揚(yáng)揚(yáng)等在李斌研究員的指導(dǎo)下發(fā)現(xiàn)在TCR信號(hào)刺激條件下，內(nèi)源性TIP60可以和ThPOK結(jié)合形成蛋白復(fù)合體,。TIP60乙?；揎桾hPOK蛋白的第360位賴氨酸位點(diǎn)，進(jìn)而增強(qiáng)了ThPOK蛋白的穩(wěn)定性,。在CD4+ T細(xì)胞中沉默TIP60基因表達(dá),，會(huì)導(dǎo)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(diào)控因子。其外,，轉(zhuǎn)錄因子ThPOK直接結(jié)合于Eomesdermin基因啟動(dòng)子區(qū),，調(diào)控其基因轉(zhuǎn)錄。過表達(dá)ThPOK能夠抑制Eomes在Jurkat細(xì)胞中的轉(zhuǎn)錄,；其外熒光素酶報(bào)告基因?qū)嶒?yàn)也證實(shí)ThPOK可以抑制Eomes 啟動(dòng)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(hào)通路，從而限制Th1型炎癥反應(yīng),。
該研究獲得了中國(guó)科學(xué)院上海生命科學(xué)研究院優(yōu)秀青年人才領(lǐng)域前沿項(xiàng)目,、國(guó)家自然科學(xué)基金、上海市科委青年科技啟明星計(jì)劃等項(xiàng)目經(jīng)費(fèi)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.
