Inhibition of PLK1-dependent EBNA2 phosphorylation promotes lymphomagenesis in EBV-infected mice.

Zhang, X.; Schuhmachers, P.; Mourao, A.; Giansanti, P.; Murer, A.; Thumann, S.; Kuklik-Roos, C.; Beer, S.; Hauck, S. M.; Hammerschmidt, W.; Küppers, R.; Küster, B.; Raab, M.; Strebhardt, K.; Sattler, M.; Münz, C.; Kempkes, B.

doi:10.1101/2021.03.29.437455

bioRxiv · 10.1101/2021.03.29.437455

Inhibition of PLK1-dependent EBNA2 phosphorylation promotes lymphomagenesis in EBV-infected mice.

Zhang, X.·Schuhmachers, P.·Mourao, A.·Giansanti, P.·Murer, A.·Thumann, S.·Kuklik-Roos, C.·Beer, S.·Hauck, S. M.·Hammerschmidt, W.·Küppers, R.·Küster, B.·Raab, M.·Strebhardt, K.·Sattler, M.·Münz, C.·Kempkes, B.

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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 have 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.

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Zhang, X., Schuhmachers, P., Mourao, A., Giansanti, P., Murer, A., Thumann, S., Kuklik-Roos, C., Beer, S., Hauck, S. M., Hammerschmidt, W., Küppers, R., Küster, B., Raab, M., Strebhardt, K., Sattler, M., Münz, C., Kempkes, B.. 2021-03-30. Inhibition of PLK1-dependent EBNA2 phosphorylation promotes lymphomagenesis in EBV-infected mice.. https://doi.org/10.1101/2021.03.29.437455

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