Abstract
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.
Highlights
Infection by human papillomaviruses (HPVs), small, double-stranded DNA viruses that infect keratinocytes of stratified squamous epithelia, can lead to the development of benign lesions and anogenital and oropharyngeal cancers [1,2]
Our findings suggest a novel mechanism by which E7 transcriptionally suppresses a subset
Our findings suggest a novel mechanism by which E7 transcriptionally suppresses a subset of
Summary
Infection by human papillomaviruses (HPVs), small, double-stranded DNA viruses that infect keratinocytes of stratified squamous epithelia, can lead to the development of benign lesions and anogenital and oropharyngeal cancers [1,2]. As the host cell detaches from the basal layer and undergoes terminal differentiation, the viral late promoter is activated to drive the productive phase of infection in which genomes are replicated to high copy numbers, capsid proteins. Viruses 2020, 12, 311 are synthesized, and progeny virions are assembled and released [4,5,6] This life cycle organization is one mechanism by which the virus persists as it restricts the production of antigenic viral proteins to the upper, differentiated layers of the skin that have reduced immune-surveillance [7,8,9,10]. Persistent infection by high risk HPV types is the major risk factor for the development of cancer as this allows for genetic mutations to accumulate in proliferating, infected cells [1]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
