Intrinsic p53 activation restricts gammaherpesvirus driven germinal center B cell expansion during latency establishment
Abstract Gammaherpesviruses are DNA tumor viruses that establish lifelong latent infections in lymphocytes. For viruses such as Epstein-Barr virus and murine gammaherpesvirus 68, this is accomplished through a viral gene-expression program that promotes cellular proliferation and differentiation, es...
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Nature Portfolio
2025-01-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-025-56247-5 |
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| author | Shana M. Owens Jeffrey M. Sifford Gang Li Steven J. Murdock Eduardo Salinas Darby Oldenburg Debopam Ghosh Jason S. Stumhofer Intawat Nookaew Mark Manzano J. Craig Forrest |
| author_facet | Shana M. Owens Jeffrey M. Sifford Gang Li Steven J. Murdock Eduardo Salinas Darby Oldenburg Debopam Ghosh Jason S. Stumhofer Intawat Nookaew Mark Manzano J. Craig Forrest |
| author_sort | Shana M. Owens |
| collection | DOAJ |
| description | Abstract Gammaherpesviruses are DNA tumor viruses that establish lifelong latent infections in lymphocytes. For viruses such as Epstein-Barr virus and murine gammaherpesvirus 68, this is accomplished through a viral gene-expression program that promotes cellular proliferation and differentiation, especially of germinal center B cells. Intrinsic host mechanisms that control virus-driven cellular expansion are incompletely defined. Using a small-animal model of gammaherpesvirus pathogenesis, we demonstrate in vivo that the tumor suppressor p53 is activated specifically in B cells latently infected by murine gammaherpesvirus 68. In the absence of p53, the early expansion of murine gammaherpesvirus 68 latency greatly increases, especially in germinal center B cells, a cell type whose proliferation is conversely restricted by p53. We identify the B cell-specific latency gene M2, a viral promoter of germinal center B cell differentiation, as a viral protein sufficient to elicit a p53-dependent anti-proliferative response caused by Src-family kinase activation. We further demonstrate that Epstein-Barr virus-encoded latent membrane protein 1 similarly triggers a p53 response in primary B cells. Our data highlight a model in which gammaherpesvirus latency gene-expression programs that promote B cell proliferation and differentiation to facilitate viral colonization of the host trigger aberrant cellular proliferation that is controlled by p53. |
| format | Article |
| id | doaj-art-503412ed69b74c36ae89c2b90e11d368 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
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| series | Nature Communications |
| spelling | doaj-art-503412ed69b74c36ae89c2b90e11d3682025-01-26T12:41:36ZengNature PortfolioNature Communications2041-17232025-01-0116111910.1038/s41467-025-56247-5Intrinsic p53 activation restricts gammaherpesvirus driven germinal center B cell expansion during latency establishmentShana M. Owens0Jeffrey M. Sifford1Gang Li2Steven J. Murdock3Eduardo Salinas4Darby Oldenburg5Debopam Ghosh6Jason S. Stumhofer7Intawat Nookaew8Mark Manzano9J. Craig Forrest10Dept. of Microbiology and Immunology and Center for Microbial Pathogenesis and Host Inflammatory Responses, University of Arkansas for Medical SciencesDept. of Microbiology and Immunology and Center for Microbial Pathogenesis and Host Inflammatory Responses, University of Arkansas for Medical SciencesDept. of Microbiology and Immunology and Center for Microbial Pathogenesis and Host Inflammatory Responses, University of Arkansas for Medical SciencesDept. of Microbiology and Immunology and Center for Microbial Pathogenesis and Host Inflammatory Responses, University of Arkansas for Medical SciencesDept. of Microbiology and Immunology and Center for Microbial Pathogenesis and Host Inflammatory Responses, University of Arkansas for Medical SciencesGunderson Research InstituteDept. of Microbiology and Immunology and Center for Microbial Pathogenesis and Host Inflammatory Responses, University of Arkansas for Medical SciencesDept. of Microbiology and Immunology and Center for Microbial Pathogenesis and Host Inflammatory Responses, University of Arkansas for Medical SciencesDept. of Biomedical Informatics, University of Arkansas for Medical SciencesDept. of Microbiology and Immunology, Center for Microbial Pathogenesis and Host Inflammatory Responses, and Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical SciencesDept. of Microbiology and Immunology, Center for Microbial Pathogenesis and Host Inflammatory Responses, and Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical SciencesAbstract Gammaherpesviruses are DNA tumor viruses that establish lifelong latent infections in lymphocytes. For viruses such as Epstein-Barr virus and murine gammaherpesvirus 68, this is accomplished through a viral gene-expression program that promotes cellular proliferation and differentiation, especially of germinal center B cells. Intrinsic host mechanisms that control virus-driven cellular expansion are incompletely defined. Using a small-animal model of gammaherpesvirus pathogenesis, we demonstrate in vivo that the tumor suppressor p53 is activated specifically in B cells latently infected by murine gammaherpesvirus 68. In the absence of p53, the early expansion of murine gammaherpesvirus 68 latency greatly increases, especially in germinal center B cells, a cell type whose proliferation is conversely restricted by p53. We identify the B cell-specific latency gene M2, a viral promoter of germinal center B cell differentiation, as a viral protein sufficient to elicit a p53-dependent anti-proliferative response caused by Src-family kinase activation. We further demonstrate that Epstein-Barr virus-encoded latent membrane protein 1 similarly triggers a p53 response in primary B cells. Our data highlight a model in which gammaherpesvirus latency gene-expression programs that promote B cell proliferation and differentiation to facilitate viral colonization of the host trigger aberrant cellular proliferation that is controlled by p53.https://doi.org/10.1038/s41467-025-56247-5 |
| spellingShingle | Shana M. Owens Jeffrey M. Sifford Gang Li Steven J. Murdock Eduardo Salinas Darby Oldenburg Debopam Ghosh Jason S. Stumhofer Intawat Nookaew Mark Manzano J. Craig Forrest Intrinsic p53 activation restricts gammaherpesvirus driven germinal center B cell expansion during latency establishment Nature Communications |
| title | Intrinsic p53 activation restricts gammaherpesvirus driven germinal center B cell expansion during latency establishment |
| title_full | Intrinsic p53 activation restricts gammaherpesvirus driven germinal center B cell expansion during latency establishment |
| title_fullStr | Intrinsic p53 activation restricts gammaherpesvirus driven germinal center B cell expansion during latency establishment |
| title_full_unstemmed | Intrinsic p53 activation restricts gammaherpesvirus driven germinal center B cell expansion during latency establishment |
| title_short | Intrinsic p53 activation restricts gammaherpesvirus driven germinal center B cell expansion during latency establishment |
| title_sort | intrinsic p53 activation restricts gammaherpesvirus driven germinal center b cell expansion during latency establishment |
| url | https://doi.org/10.1038/s41467-025-56247-5 |
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