Suppression of a Subset of Interferon-Induced Genes by Human Papillomavirus Type 16 E7 via a Cyclin Dependent Kinase 8-Dependent Mechanism
Sadie Rice,
Seong-man Kim,
Cynthia Rodriguez,
William Songock,
Gaurav Raikhy,
Rebecca Lopez,
Lauren Henderson,
Arjun Yusufji,
Jason Bodily
Affiliations
Sadie Rice
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
Seong-man Kim
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
Cynthia Rodriguez
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
William Songock
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
Gaurav Raikhy
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
Rebecca Lopez
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
Lauren Henderson
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
Arjun Yusufji
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
Jason Bodily
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
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.
