1. PLK1-dependent phosphorylation restrains EBNA2 activity and lymphomagenesis in EBV-infected mice
- Author
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Xiang Zhang, André Mourão, Sophie Beer, Anita Murer, Christian Münz, Ralf Küppers, Sybille Thumann, Stefanie M. Hauck, Monika Raab, Klaus Strebhardt, Patrick Schuhmachers, Piero Giansanti, Cornelia Kuklik-Roos, Bernhard Kuster, Wolfgang Hammerschmidt, Michael Sattler, and Bettina Kempkes
- Subjects
Epstein-Barr Virus Infections ,Herpesvirus 4, Human ,Medizin ,Cell Cycle Proteins ,Biology ,Protein Serine-Threonine Kinases ,Biochemistry ,PLK1 ,Virus ,Article ,03 medical and health sciences ,Transactivation ,Mice ,0302 clinical medicine ,Antigen ,EBV ,hemic and lymphatic diseases ,Proto-Oncogene Proteins ,Genetics ,Animals ,Phosphorylation ,Molecular Biology ,Transcription factor ,030304 developmental biology ,Cancer ,EBNA2 ,0303 health sciences ,B-lymphomagenesis ,Ebna2 ,Ebv ,Plk1 ,Humanized Mice ,Kinase ,Articles ,B‐lymphomagenesis ,Microbiology, Virology & Host Pathogen Interaction ,3. Good health ,Virus Latency ,humanized mice ,Epstein-Barr Virus Nuclear Antigens ,030220 oncology & carcinogenesis ,Monoclonal ,Cancer research ,Signal Transduction - Abstract
While Epstein–Barr virus (EBV) establishes a life‐long latent infection in apparently healthy human immunocompetent hosts, immunodeficient individuals are at particular risk to develop lymphoproliferative B‐cell malignancies caused by EBV. A key EBV protein is the transcription factor EBV nuclear antigen 2 (EBNA2), which initiates B‐cell proliferation. Here, we combine biochemical, cellular, and in vivo experiments demonstrating that the mitotic polo‐like kinase 1 (PLK1) binds to EBNA2, phosphorylates its transactivation domain, and thereby inhibits its biological activity. EBNA2 mutants that impair PLK1 binding or prevent EBNA2 phosphorylation are gain‐of‐function mutants. They exhibit enhanced transactivation capacities, accelerate the proliferation of infected B cells, and promote the development of monoclonal B‐cell lymphomas in infected mice. Thus, PLK1 coordinates the activity of EBNA2 to attenuate the risk of tumor incidences in favor of the establishment of latency in the infected but healthy host., EBNA2 is a key transactivator that initiates B cell immortalization. PLK1 phosphorylates the C‐ terminal transactivation domain of EBNA2 to attenuate its oncogenic activities and promote the establishment of long term latency in the infected host.
- Published
- 2021