The human papillomavirus type 16 E7 oncoprotein induces a transcriptional repressor complex on the Toll-like receptor 9 promoter.
The human papillomavirus type 16 E7 oncoprotein induces a transcriptional repressor complex on the Toll-like receptor 9 promoter.
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人类乳头瘤病毒16 E7癌蛋白诱导Toll样受体9启动子上的转录阻遏物复合物。
DOI：
10.1084/jem.20122394
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发表时间：
2013-07-01
期刊：
影响因子：
--
通讯作者：
Tommasino M
中科院分区：
文献类型：
--
作者：
Hasan UA;Zannetti C;Parroche P;Goutagny N;Malfroy M;Roblot G;Carreira C;Hussain I;Müller M;Taylor-Papadimitriou J;Picard D;Sylla BS;Trinchieri G;Medzhitov R;Tommasino M
HPV 16阳性宫颈癌病变含有NFκB-ERα核复合物，以抑制TLR 9启动子。据报道，人乳头瘤病毒16型（HPV 16）和其他致癌病毒通过抑制双链DNA先天传感器TLR 9的功能来解除免疫调节。然而，导致这些事件的机制仍有待阐明。我们发现HPV 16感染人上皮细胞可促进E7癌蛋白诱导的含有NF-κ Bp 50-p65和ERα的抑制性转录复合物的形成。E7介导的转录复合物还募集组蛋白去甲基化酶JARID 1B和组蛋白去乙酰化酶HDAC 1。整个复合物结合到TLR 9启动子上的特定区域，这导致TLR 9转录起始位点上游组蛋白的甲基化和乙酰化降低。NF-κB和ERα参与了HPV 16 E7下调TLR 9的过程，这在人类患者的宫颈组织中得到了充分证实。重要的是，我们提出的证据表明，HPV 16诱导的TLR 9下调影响干扰素反应，负调节病毒感染。我们的研究强调了一种新的HPV 16介导的机制，该机制结合了表观遗传和转录事件来抑制关键的先天免疫传感器。
HPV16-positive cervical cancer lesions contain NFκB–ERα nuclear complexes to repress the TLR9 promoter. Human papillomavirus type 16 (HPV16) and other oncogenic viruses have been reported to deregulate immunity by suppressing the function of the double-stranded DNA innate sensor TLR9. However, the mechanisms leading to these events remain to be elucidated. We show that infection of human epithelial cells with HPV16 promotes the formation of an inhibitory transcriptional complex containing NF-κBp50–p65 and ERα induced by the E7 oncoprotein. The E7-mediated transcriptional complex also recruited the histone demethylase JARID1B and histone deacetylase HDAC1. The entire complex bound to a specific region on the TLR9 promoter, which resulted in decreased methylation and acetylation of histones upstream of the TLR9 transcriptional start site. The involvement of NF-κB and ERα in the TLR9 down-regulation by HPV16 E7 was fully confirmed in cervical tissues from human patients. Importantly, we present evidence that the HPV16-induced TLR9 down-regulation affects the interferon response which negatively regulates viral infection. Our studies highlight a novel HPV16-mediated mechanism that combines epigenetic and transcriptional events to suppress a key innate immune sensor.
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DOI：
10.1084/jem.20041836
发表时间：
2005-01-03
期刊：
The Journal of experimental medicine
影响因子：
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作者：
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Taylor-Papadimitriou, Joyce