PLK1-dependent phosphorylation restrains EBNA2 activity and lymphomagenesis in EBV-infected mice

Xiang Zhang; Patrick Schuhmachers; André Mourão; Piero Giansanti; Anita Murer; Sybille Thumann; Cornelia Kuklik-Roos; Sophie Beer; Stefanie M. Hauck; Wolfgang Hammerschmidt; Ralf Küppers; Bernhard Kuster; Monika Raab; Klaus Strebhardt; Michael Sattler; Christian Münz; Bettina Kempkes

doi:10.15252/embr.202153007

PLK1-dependent phosphorylation restrains EBNA2 activity and lymphomagenesis in EBV-infected mice

Xiang Zhang, Patrick Schuhmachers, André Mourão, Piero Giansanti, Anita Murer, Sybille Thumann, Cornelia Kuklik-Roos, Sophie Beer, Stefanie M. Hauck, Wolfgang Hammerschmidt, Ralf Küppers, Bernhard Kuster, Monika Raab, Klaus Strebhardt, Michael Sattler, Christian Münz, Bettina Kempkes

Research output: Contribution to journal › Article › peer-review

4 Scopus citations

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.

Original language	English
Article number	e53007
Journal	EMBO Reports
Volume	22
Issue number	12
DOIs	https://doi.org/10.15252/embr.202153007
State	Published - 6 Dec 2021
Externally published	Yes

Keywords

B-lymphomagenesis
EBNA2
EBV
PLK1
humanized mice

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Zhang, X., Schuhmachers, P., Mourão, A., Giansanti, P., Murer, A., Thumann, S., Kuklik-Roos, C., Beer, S., Hauck, S. M., Hammerschmidt, W., Küppers, R., Kuster, B., Raab, M., Strebhardt, K., Sattler, M., Münz, C., & Kempkes, B. (2021). PLK1-dependent phosphorylation restrains EBNA2 activity and lymphomagenesis in EBV-infected mice. EMBO Reports, 22(12), Article e53007. https://doi.org/10.15252/embr.202153007

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title = "PLK1-dependent phosphorylation restrains EBNA2 activity and lymphomagenesis in EBV-infected mice",

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.",

keywords = "B-lymphomagenesis, EBNA2, EBV, PLK1, humanized mice",

author = "Xiang Zhang and Patrick Schuhmachers and Andr{\'e} Mour{\~a}o and Piero Giansanti and Anita Murer and Sybille Thumann and Cornelia Kuklik-Roos and Sophie Beer and Hauck, {Stefanie M.} and Wolfgang Hammerschmidt and Ralf K{\"u}ppers and Bernhard Kuster and Monika Raab and Klaus Strebhardt and Michael Sattler and Christian M{\"u}nz and Bettina Kempkes",

note = "Publisher Copyright: {\textcopyright} 2021 The Authors. Published under the terms of the CC BY 4.0 license",

year = "2021",

month = dec,

day = "6",

doi = "10.15252/embr.202153007",

language = "English",

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Zhang, X, Schuhmachers, P, Mourão, A, Giansanti, P, Murer, A, Thumann, S, Kuklik-Roos, C, Beer, S, Hauck, SM, Hammerschmidt, W, Küppers, R, Kuster, B, Raab, M, Strebhardt, K, Sattler, M, Münz, C & Kempkes, B 2021, 'PLK1-dependent phosphorylation restrains EBNA2 activity and lymphomagenesis in EBV-infected mice', EMBO Reports, vol. 22, no. 12, e53007. https://doi.org/10.15252/embr.202153007

TY - JOUR

T1 - PLK1-dependent phosphorylation restrains EBNA2 activity and lymphomagenesis in EBV-infected mice

AU - Zhang, Xiang

AU - Schuhmachers, Patrick

AU - Mourão, André

AU - Giansanti, Piero

AU - Murer, Anita

AU - Thumann, Sybille

AU - Kuklik-Roos, Cornelia

AU - Beer, Sophie

AU - Hauck, Stefanie M.

AU - Hammerschmidt, Wolfgang

AU - Küppers, Ralf

AU - Kuster, Bernhard

AU - Raab, Monika

AU - Strebhardt, Klaus

AU - Sattler, Michael

AU - Münz, Christian

AU - Kempkes, Bettina

PY - 2021/12/6

Y1 - 2021/12/6

N2 - 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.

AB - 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.

KW - B-lymphomagenesis

KW - EBNA2

KW - EBV

KW - PLK1

KW - humanized mice

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U2 - 10.15252/embr.202153007

DO - 10.15252/embr.202153007

M3 - Article

C2 - 34605140

AN - SCOPUS:85116141002

SN - 1469-221X

VL - 22

JO - EMBO Reports

JF - EMBO Reports

IS - 12

M1 - e53007

ER -

PLK1-dependent phosphorylation restrains EBNA2 activity and lymphomagenesis in EBV-infected mice

Abstract

Keywords

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