近日,国际学术期刊Journal of Biological Chemistry在线发表了中科院上海巴斯德研究所李斌课题组的研究论文,题为TIP60 Positively Regulates ThPOK-Mediated Repression of Eomesodermin in Human CD4+ T Cells。本研究揭示了一个抑制炎症因子IFNg转录表达的TIP60-ThPOK-Eomes信号通路。在炎症情况下该通路反向调控CD4+ T细胞表达I型促炎症因子IFNg的功能。本发现对进一步深入理解炎症微环境中人源CD4+ T细胞功能动态调节具有重要指导性意义。
本课题组研究人员前期研究发现,决定调节性T细胞(Treg)中FOXP3转录活性的关键性调控蛋白TIP60, 主要在CD4+ T细胞中表达。作为蛋白乙酰转移酶,TIP60还与CD4+ T细胞中许多其他关键性转录调控蛋白形成不同的转录复合体,并通过促进转录因子蛋白或组蛋白的乙酰化,从而激活或抑制基因转录。理解炎症条件下CD4+T细胞内关键性转录因子的调节机制,将为病毒感染及肿瘤相关疾病治疗提供新的药物靶点及临床干预手段。
ThPOK作为CD4+ 辅助性T细胞高表达的关键性转录因子,其转录活性对CD4+ T细胞分化及功能至关重要。例如,ThPOK通过下调转录因子Eomesodermin (Eomes) 的表达从而抑制Th1型促炎症因子 IFNγ的表达,但其分子机制尚不清楚。在本研究中,博士研究生李扬扬等在李斌研究员的指导下发现在TCR信号刺激条件下,内源性TIP60可以和ThPOK结合形成蛋白复合体。TIP60乙酰化修饰ThPOK蛋白的第360位赖氨酸位点,进而增强了ThPOK蛋白的稳定性。在CD4+ T细胞中沉默TIP60基因表达,会导致ThPOK蛋白的快速降解,这表明TIP60蛋白是稳定ThPOK所必需的调控因子。其外,转录因子ThPOK直接结合于Eomesdermin基因启动子区,调控其基因转录。过表达ThPOK能够抑制Eomes在Jurkat细胞中的转录;其外荧光素酶报告基因实验也证实ThPOK可以抑制Eomes 启动子的活性。本研究首次揭示TIP60和ThPOK协同作用抑制了Eomes-IFNγ信号通路,从而限制Th1型炎症反应。
该研究获得了中国科学院上海生命科学研究院优秀青年人才领域前沿项目、国家自然科学基金、上海市科委青年科技启明星计划等项目经费支持。(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.