Merkel Cell Polyomavirus Large T Antigen Induces Cellular Senescence for Host Growth Arrest and Viral Genome Persistence through Its Unique Domain
Senescent cells accumulate in the host during the aging process and are associated with age-related pathogeneses, including cancer. Although persistent senescence seems to contribute to many aspects of cellular pathways and homeostasis, the role of senescence in virus-induced human cancer is not wel...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-01-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/12/3/380 |
| _version_ | 1827760241165467648 |
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| author | Alexander M. Pham Luz E. Ortiz Aron E. Lukacher Hyun Jin Kwun |
| author_facet | Alexander M. Pham Luz E. Ortiz Aron E. Lukacher Hyun Jin Kwun |
| author_sort | Alexander M. Pham |
| collection | DOAJ |
| description | Senescent cells accumulate in the host during the aging process and are associated with age-related pathogeneses, including cancer. Although persistent senescence seems to contribute to many aspects of cellular pathways and homeostasis, the role of senescence in virus-induced human cancer is not well understood. Merkel cell carcinoma (MCC) is an aggressive skin cancer induced by a life-long human infection of Merkel cell polyomavirus (MCPyV). Here, we show that MCPyV large T (LT) antigen expression in human skin fibroblasts causes a novel nucleolar stress response, followed by p21-dependent senescence and senescence-associated secretory phenotypes (SASPs), which are required for MCPyV genome maintenance. Senolytic and navitoclax treatments result in decreased senescence and MCPyV genome levels, suggesting a potential therapeutic for MCC prevention. Our results uncover the mechanism of a host stress response regulating human polyomavirus genome maintenance in viral persistency, which may lead to targeted intervention for MCC. |
| first_indexed | 2024-03-11T09:48:46Z |
| format | Article |
| id | doaj.art-1995496fe92e448bb134bdbf40421540 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-11T09:48:46Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-1995496fe92e448bb134bdbf404215402023-11-16T16:20:51ZengMDPI AGCells2073-44092023-01-0112338010.3390/cells12030380Merkel Cell Polyomavirus Large T Antigen Induces Cellular Senescence for Host Growth Arrest and Viral Genome Persistence through Its Unique DomainAlexander M. Pham0Luz E. Ortiz1Aron E. Lukacher2Hyun Jin Kwun3Department 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, USADepartment of Microbiology and Immunology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USASenescent cells accumulate in the host during the aging process and are associated with age-related pathogeneses, including cancer. Although persistent senescence seems to contribute to many aspects of cellular pathways and homeostasis, the role of senescence in virus-induced human cancer is not well understood. Merkel cell carcinoma (MCC) is an aggressive skin cancer induced by a life-long human infection of Merkel cell polyomavirus (MCPyV). Here, we show that MCPyV large T (LT) antigen expression in human skin fibroblasts causes a novel nucleolar stress response, followed by p21-dependent senescence and senescence-associated secretory phenotypes (SASPs), which are required for MCPyV genome maintenance. Senolytic and navitoclax treatments result in decreased senescence and MCPyV genome levels, suggesting a potential therapeutic for MCC prevention. Our results uncover the mechanism of a host stress response regulating human polyomavirus genome maintenance in viral persistency, which may lead to targeted intervention for MCC.https://www.mdpi.com/2073-4409/12/3/380senescencenucleolar stress responseMerkel cell polyomaviruslarge Tp53p21WAF1 |
| spellingShingle | Alexander M. Pham Luz E. Ortiz Aron E. Lukacher Hyun Jin Kwun Merkel Cell Polyomavirus Large T Antigen Induces Cellular Senescence for Host Growth Arrest and Viral Genome Persistence through Its Unique Domain Cells senescence nucleolar stress response Merkel cell polyomavirus large T p53 p21WAF1 |
| title | Merkel Cell Polyomavirus Large T Antigen Induces Cellular Senescence for Host Growth Arrest and Viral Genome Persistence through Its Unique Domain |
| title_full | Merkel Cell Polyomavirus Large T Antigen Induces Cellular Senescence for Host Growth Arrest and Viral Genome Persistence through Its Unique Domain |
| title_fullStr | Merkel Cell Polyomavirus Large T Antigen Induces Cellular Senescence for Host Growth Arrest and Viral Genome Persistence through Its Unique Domain |
| title_full_unstemmed | Merkel Cell Polyomavirus Large T Antigen Induces Cellular Senescence for Host Growth Arrest and Viral Genome Persistence through Its Unique Domain |
| title_short | Merkel Cell Polyomavirus Large T Antigen Induces Cellular Senescence for Host Growth Arrest and Viral Genome Persistence through Its Unique Domain |
| title_sort | merkel cell polyomavirus large t antigen induces cellular senescence for host growth arrest and viral genome persistence through its unique domain |
| topic | senescence nucleolar stress response Merkel cell polyomavirus large T p53 p21WAF1 |
| url | https://www.mdpi.com/2073-4409/12/3/380 |
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