Suppression of a Subset of Interferon-Induced Genes by Human Papillomavirus Type 16 E7 via a Cyclin Dependent Kinase 8-Dependent Mechanism
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 expressi...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-03-01
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| Series: | Viruses |
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| Online Access: | https://www.mdpi.com/1999-4915/12/3/311 |
| _version_ | 1819170210878324736 |
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| author | Sadie Rice Seong-man Kim Cynthia Rodriguez William Songock Gaurav Raikhy Rebecca Lopez Lauren Henderson Arjun Yusufji Jason Bodily |
| author_facet | Sadie Rice Seong-man Kim Cynthia Rodriguez William Songock Gaurav Raikhy Rebecca Lopez Lauren Henderson Arjun Yusufji Jason Bodily |
| author_sort | Sadie Rice |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-22T19:31:47Z |
| format | Article |
| id | doaj.art-baa79fa105344bad9ce44d3967ba186c |
| institution | Directory Open Access Journal |
| issn | 1999-4915 |
| language | English |
| last_indexed | 2024-12-22T19:31:47Z |
| publishDate | 2020-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj.art-baa79fa105344bad9ce44d3967ba186c2022-12-21T18:15:05ZengMDPI AGViruses1999-49152020-03-0112331110.3390/v12030311v12030311Suppression of a Subset of Interferon-Induced Genes by Human Papillomavirus Type 16 E7 via a Cyclin Dependent Kinase 8-Dependent MechanismSadie Rice0Seong-man Kim1Cynthia Rodriguez2William Songock3Gaurav Raikhy4Rebecca Lopez5Lauren Henderson6Arjun Yusufji7Jason Bodily8Department of Microbiology and Immunology, Center for Molecular and Tumor Virology, and Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA 71103, USADepartment of Microbiology and Immunology, Center for Molecular and Tumor Virology, and Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA 71103, USADepartment of Microbiology and Immunology, Center for Molecular and Tumor Virology, and Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA 71103, USADepartment of Microbiology and Immunology, Center for Molecular and Tumor Virology, and Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA 71103, USADepartment of Microbiology and Immunology, Center for Molecular and Tumor Virology, and Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA 71103, USADepartment of Microbiology and Immunology, Center for Molecular and Tumor Virology, and Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA 71103, USADepartment of Microbiology and Immunology, Center for Molecular and Tumor Virology, and Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA 71103, USADepartment of Microbiology and Immunology, Center for Molecular and Tumor Virology, and Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA 71103, USADepartment of Microbiology and Immunology, Center for Molecular and Tumor Virology, and Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA 71103, USAPersistent 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.https://www.mdpi.com/1999-4915/12/3/311stat1ifn signalinginterferon-stimulated genestranscriptionmediator kinase cdk8papillomavirusesoncoprotein e7 |
| spellingShingle | Sadie Rice Seong-man Kim Cynthia Rodriguez William Songock Gaurav Raikhy Rebecca Lopez Lauren Henderson Arjun Yusufji Jason Bodily Suppression of a Subset of Interferon-Induced Genes by Human Papillomavirus Type 16 E7 via a Cyclin Dependent Kinase 8-Dependent Mechanism Viruses stat1 ifn signaling interferon-stimulated genes transcription mediator kinase cdk8 papillomaviruses oncoprotein e7 |
| title | Suppression of a Subset of Interferon-Induced Genes by Human Papillomavirus Type 16 E7 via a Cyclin Dependent Kinase 8-Dependent Mechanism |
| title_full | Suppression of a Subset of Interferon-Induced Genes by Human Papillomavirus Type 16 E7 via a Cyclin Dependent Kinase 8-Dependent Mechanism |
| title_fullStr | Suppression of a Subset of Interferon-Induced Genes by Human Papillomavirus Type 16 E7 via a Cyclin Dependent Kinase 8-Dependent Mechanism |
| title_full_unstemmed | Suppression of a Subset of Interferon-Induced Genes by Human Papillomavirus Type 16 E7 via a Cyclin Dependent Kinase 8-Dependent Mechanism |
| title_short | Suppression of a Subset of Interferon-Induced Genes by Human Papillomavirus Type 16 E7 via a Cyclin Dependent Kinase 8-Dependent Mechanism |
| title_sort | suppression of a subset of interferon induced genes by human papillomavirus type 16 e7 via a cyclin dependent kinase 8 dependent mechanism |
| topic | stat1 ifn signaling interferon-stimulated genes transcription mediator kinase cdk8 papillomaviruses oncoprotein e7 |
| url | https://www.mdpi.com/1999-4915/12/3/311 |
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