Merkel Cell Polyomavirus Large T Antigen Unique Domain Regulates Its Own Protein Stability and Cell Growth
Merkel cell polyomavirus (MCV) is the only known human oncogenic virus in the polyomaviridae family and the etiological agent of most Merkel cell carcinomas (MCC). MCC is an aggressive and highly metastatic skin cancer with a propensity for recurrence and poor prognosis. Large tumor antigen (LT), is...
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MDPI AG
2020-09-01
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| Series: | Viruses |
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| Online Access: | https://www.mdpi.com/1999-4915/12/9/1043 |
| _version_ | 1827705908425129984 |
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| author | Nnenna Nwogu Luz E. Ortiz Hyun Jin Kwun |
| author_facet | Nnenna Nwogu Luz E. Ortiz Hyun Jin Kwun |
| author_sort | Nnenna Nwogu |
| collection | DOAJ |
| description | Merkel cell polyomavirus (MCV) is the only known human oncogenic virus in the polyomaviridae family and the etiological agent of most Merkel cell carcinomas (MCC). MCC is an aggressive and highly metastatic skin cancer with a propensity for recurrence and poor prognosis. Large tumor antigen (LT), is an essential oncoprotein for MCV transcription, viral replication, and cancer cell proliferation. MCV LT is a short-lived protein that encodes a unique domain: MCV LT unique regions (MURs). These domains consist of phosphorylation sites that interact with multiple E3 ligases, thus limiting LT expression and consequently, viral replication. In this study, we show that MURs are necessary for regulating LT stability via multiple E3 ligase interactions, resulting in cell growth arrest. While expression of wild-type MCV LT induced a decrease in cellular proliferation, deletion of the MUR domains resulted in increased LT stability and cell proliferation. Conversely, addition of MURs to SV40 LT propagated E3 ligase interactions, which in turn, reduced SV40 LT stability and decreased cell growth activity. Our results demonstrate that compared to other human polyomaviruses (HPyVs), MCV LT has evolved to acquire the MUR domains that are essential for MCV LT autoregulation, potentially leading to viral latency and MCC. |
| first_indexed | 2024-03-10T16:13:13Z |
| format | Article |
| id | doaj.art-0964c56c8ade47649164a6f33c6ca6ac |
| institution | Directory Open Access Journal |
| issn | 1999-4915 |
| language | English |
| last_indexed | 2024-03-10T16:13:13Z |
| publishDate | 2020-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj.art-0964c56c8ade47649164a6f33c6ca6ac2023-11-20T14:15:59ZengMDPI AGViruses1999-49152020-09-01129104310.3390/v12091043Merkel Cell Polyomavirus Large T Antigen Unique Domain Regulates Its Own Protein Stability and Cell GrowthNnenna Nwogu0Luz E. Ortiz1Hyun Jin Kwun2Department of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USADepartment of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USADepartment of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USAMerkel cell polyomavirus (MCV) is the only known human oncogenic virus in the polyomaviridae family and the etiological agent of most Merkel cell carcinomas (MCC). MCC is an aggressive and highly metastatic skin cancer with a propensity for recurrence and poor prognosis. Large tumor antigen (LT), is an essential oncoprotein for MCV transcription, viral replication, and cancer cell proliferation. MCV LT is a short-lived protein that encodes a unique domain: MCV LT unique regions (MURs). These domains consist of phosphorylation sites that interact with multiple E3 ligases, thus limiting LT expression and consequently, viral replication. In this study, we show that MURs are necessary for regulating LT stability via multiple E3 ligase interactions, resulting in cell growth arrest. While expression of wild-type MCV LT induced a decrease in cellular proliferation, deletion of the MUR domains resulted in increased LT stability and cell proliferation. Conversely, addition of MURs to SV40 LT propagated E3 ligase interactions, which in turn, reduced SV40 LT stability and decreased cell growth activity. Our results demonstrate that compared to other human polyomaviruses (HPyVs), MCV LT has evolved to acquire the MUR domains that are essential for MCV LT autoregulation, potentially leading to viral latency and MCC.https://www.mdpi.com/1999-4915/12/9/1043Merkel cell carcinomaskin cancerMerkel cell polyomavirusLarge T antigencell proliferationE3 ligases |
| spellingShingle | Nnenna Nwogu Luz E. Ortiz Hyun Jin Kwun Merkel Cell Polyomavirus Large T Antigen Unique Domain Regulates Its Own Protein Stability and Cell Growth Viruses Merkel cell carcinoma skin cancer Merkel cell polyomavirus Large T antigen cell proliferation E3 ligases |
| title | Merkel Cell Polyomavirus Large T Antigen Unique Domain Regulates Its Own Protein Stability and Cell Growth |
| title_full | Merkel Cell Polyomavirus Large T Antigen Unique Domain Regulates Its Own Protein Stability and Cell Growth |
| title_fullStr | Merkel Cell Polyomavirus Large T Antigen Unique Domain Regulates Its Own Protein Stability and Cell Growth |
| title_full_unstemmed | Merkel Cell Polyomavirus Large T Antigen Unique Domain Regulates Its Own Protein Stability and Cell Growth |
| title_short | Merkel Cell Polyomavirus Large T Antigen Unique Domain Regulates Its Own Protein Stability and Cell Growth |
| title_sort | merkel cell polyomavirus large t antigen unique domain regulates its own protein stability and cell growth |
| topic | Merkel cell carcinoma skin cancer Merkel cell polyomavirus Large T antigen cell proliferation E3 ligases |
| url | https://www.mdpi.com/1999-4915/12/9/1043 |
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