Human Papillomavirus 16 E6 and E7 Oncoproteins Alter the Abundance of Proteins Associated with DNA Damage Response, Immune Signaling and Epidermal Differentiation
The high-risk human papillomaviruses are oncogenic viruses associated with almost all cases of cervical carcinomas, and increasing numbers of anal, and oral cancers. Two oncogenic HPV proteins, E6 and E7, are capable of immortalizing keratinocytes and are required for HPV associated cell transformat...
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| Format: | Article |
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MDPI AG
2022-08-01
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| Series: | Viruses |
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| Online Access: | https://www.mdpi.com/1999-4915/14/8/1764 |
| _version_ | 1797441359140880384 |
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| author | Kerry Dust Michael Carpenter Julie Chih-yu Chen Chris Grant Stuart McCorrister Garret R. Westmacott Alberto Severini |
| author_facet | Kerry Dust Michael Carpenter Julie Chih-yu Chen Chris Grant Stuart McCorrister Garret R. Westmacott Alberto Severini |
| author_sort | Kerry Dust |
| collection | DOAJ |
| description | The high-risk human papillomaviruses are oncogenic viruses associated with almost all cases of cervical carcinomas, and increasing numbers of anal, and oral cancers. Two oncogenic HPV proteins, E6 and E7, are capable of immortalizing keratinocytes and are required for HPV associated cell transformation. Currently, the influence of these oncoproteins on the global regulation of the host proteome is not well defined. Liquid chromatography coupled with quantitative tandem mass spectrometry using isobaric-tagged peptides was used to investigate the effects of the HPV16 oncoproteins E6 and E7 on protein levels in human neonatal keratinocytes (HEKn). Pathway and gene ontology enrichment analyses revealed that the cells expressing the HPV oncoproteins have elevated levels of proteins related to interferon response, inflammation and DNA damage response, while the proteins related to cell organization and epithelial development are downregulated. This study identifies dysregulated pathways and potential biomarkers associated with HPV oncoproteins in primary keratinocytes which may have therapeutic implications. Most notably, DNA damage response pathways, DNA replication, and interferon signaling pathways were affected in cells transduced with HPV16 E6 and E7 lentiviruses. Moreover, proteins associated with cell organization and differentiation were significantly downregulated in keratinocytes expressing HPV16 E6 + E7. High-risk HPV E6 and E7 oncoproteins are necessary for the HPV-associated transformation of keratinocytes. However their influence on the global dysregulation of keratinocyte proteome is not well documented. Here shotgun proteomics using TMT-labeling detected over 2500 significantly dysregulated proteins associated with E6 and E7 expression. Networks of proteins related to interferon response, inflammation and DNA damage repair pathways were altered. |
| first_indexed | 2024-03-09T12:21:53Z |
| format | Article |
| id | doaj.art-7b4d9f3781e04234920d6d8981a9eb99 |
| institution | Directory Open Access Journal |
| issn | 1999-4915 |
| language | English |
| last_indexed | 2024-03-09T12:21:53Z |
| publishDate | 2022-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj.art-7b4d9f3781e04234920d6d8981a9eb992023-11-30T22:39:28ZengMDPI AGViruses1999-49152022-08-01148176410.3390/v14081764Human Papillomavirus 16 E6 and E7 Oncoproteins Alter the Abundance of Proteins Associated with DNA Damage Response, Immune Signaling and Epidermal DifferentiationKerry Dust0Michael Carpenter1Julie Chih-yu Chen2Chris Grant3Stuart McCorrister4Garret R. Westmacott5Alberto Severini6Department of Medical Microbiology, Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0W2, CanadaNational Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB R3E 3M4, CanadaNational Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB R3E 3M4, CanadaNational Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB R3E 3M4, CanadaNational Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB R3E 3M4, CanadaNational Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB R3E 3M4, CanadaDepartment of Medical Microbiology, Faculty of Health Sciences, University of Manitoba, Winnipeg, MB R3E 0W2, CanadaThe high-risk human papillomaviruses are oncogenic viruses associated with almost all cases of cervical carcinomas, and increasing numbers of anal, and oral cancers. Two oncogenic HPV proteins, E6 and E7, are capable of immortalizing keratinocytes and are required for HPV associated cell transformation. Currently, the influence of these oncoproteins on the global regulation of the host proteome is not well defined. Liquid chromatography coupled with quantitative tandem mass spectrometry using isobaric-tagged peptides was used to investigate the effects of the HPV16 oncoproteins E6 and E7 on protein levels in human neonatal keratinocytes (HEKn). Pathway and gene ontology enrichment analyses revealed that the cells expressing the HPV oncoproteins have elevated levels of proteins related to interferon response, inflammation and DNA damage response, while the proteins related to cell organization and epithelial development are downregulated. This study identifies dysregulated pathways and potential biomarkers associated with HPV oncoproteins in primary keratinocytes which may have therapeutic implications. Most notably, DNA damage response pathways, DNA replication, and interferon signaling pathways were affected in cells transduced with HPV16 E6 and E7 lentiviruses. Moreover, proteins associated with cell organization and differentiation were significantly downregulated in keratinocytes expressing HPV16 E6 + E7. High-risk HPV E6 and E7 oncoproteins are necessary for the HPV-associated transformation of keratinocytes. However their influence on the global dysregulation of keratinocyte proteome is not well documented. Here shotgun proteomics using TMT-labeling detected over 2500 significantly dysregulated proteins associated with E6 and E7 expression. Networks of proteins related to interferon response, inflammation and DNA damage repair pathways were altered.https://www.mdpi.com/1999-4915/14/8/1764human papillomavirusE6 proteinE7 proteinproteomicskeratinocytestransformation |
| spellingShingle | Kerry Dust Michael Carpenter Julie Chih-yu Chen Chris Grant Stuart McCorrister Garret R. Westmacott Alberto Severini Human Papillomavirus 16 E6 and E7 Oncoproteins Alter the Abundance of Proteins Associated with DNA Damage Response, Immune Signaling and Epidermal Differentiation Viruses human papillomavirus E6 protein E7 protein proteomics keratinocytes transformation |
| title | Human Papillomavirus 16 E6 and E7 Oncoproteins Alter the Abundance of Proteins Associated with DNA Damage Response, Immune Signaling and Epidermal Differentiation |
| title_full | Human Papillomavirus 16 E6 and E7 Oncoproteins Alter the Abundance of Proteins Associated with DNA Damage Response, Immune Signaling and Epidermal Differentiation |
| title_fullStr | Human Papillomavirus 16 E6 and E7 Oncoproteins Alter the Abundance of Proteins Associated with DNA Damage Response, Immune Signaling and Epidermal Differentiation |
| title_full_unstemmed | Human Papillomavirus 16 E6 and E7 Oncoproteins Alter the Abundance of Proteins Associated with DNA Damage Response, Immune Signaling and Epidermal Differentiation |
| title_short | Human Papillomavirus 16 E6 and E7 Oncoproteins Alter the Abundance of Proteins Associated with DNA Damage Response, Immune Signaling and Epidermal Differentiation |
| title_sort | human papillomavirus 16 e6 and e7 oncoproteins alter the abundance of proteins associated with dna damage response immune signaling and epidermal differentiation |
| topic | human papillomavirus E6 protein E7 protein proteomics keratinocytes transformation |
| url | https://www.mdpi.com/1999-4915/14/8/1764 |
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