Department of Microbiology and Immunology, Center for Molecular and Tumor Virology, and Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA 71103, USA.
C.E. Byrd High School, Shreveport, Louisiana 71104, USA.
Viruses. 2020 Mar 13;12(3):311. doi: 10.3390/v12030311.
Persistent infection by human papillomaviruses (HPVs), small, double-stranded DNA viruses that infect keratinocytes of the squamous epithelia, can lead to the development of cervical and other cancers. The viral oncoprotein E7 contributes to viral persistence in part by regulating host gene expression through binding host transcriptional regulators, although mechanisms responsible for E7-mediated transcriptional regulation are incompletely understood. Type I IFN signaling promotes the expression of anti-viral genes, called interferon-stimulated genes (ISGs), through the phosphorylation and activation of STAT1. In this study, we have observed that the CR3 domain of E7 contributes to the episomal maintenance of viral genomes. Transcriptome analysis revealed that E7 transcriptionally suppresses a subset of ISGs but not through regulation of STAT1 activation. Instead, we discovered that E7 associates with Mediator kinase CDK8 and this is correlated with the recruitment of CDK8 to ISG promoters and reduced ISG expression. E7 fails to suppress ISGs in the absence of CDK8, indicating that CDK8 function contributes to the suppression of ISGs by E7. Altogether, E7/CDK8 association may be a novel mechanism by which E7 inhibits innate immune signaling.
人乳头瘤病毒（HPV）是一种小的双链 DNA 病毒，可感染鳞状上皮的角质细胞，持续感染可导致宫颈癌和其他癌症的发生。病毒癌蛋白 E7 通过与宿主转录调节剂结合来调节宿主基因表达，从而有助于病毒的持续存在，尽管 E7 介导的转录调节的机制尚不完全清楚。I 型干扰素信号通过磷酸化和激活 STAT1 来促进抗病毒基因（称为干扰素刺激基因 [ISG]）的表达。在这项研究中，我们观察到 E7 的 CR3 结构域有助于病毒基因组的游离体维持。转录组分析显示，E7 在转录水平上抑制了一组 ISG，但不是通过调节 STAT1 的激活。相反，我们发现 E7 与 Mediator 激酶 CDK8 相关，这与 CDK8 招募到 ISG 启动子并减少 ISG 表达有关。如果没有 CDK8，E7 就无法抑制 ISG，这表明 CDK8 功能有助于 E7 对 ISG 的抑制。总之，E7/CDK8 复合物的形成可能是 E7 抑制先天免疫信号的一种新机制。
