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Cross-regulation of viral kinases with cyclin A secures shutoff of host DNA synthesis

Author

Listed:
  • Boris Bogdanow

    (Research group “Proteome Dynamics”, Max Delbrück Center for Molecular Medicine
    Research group “Structural Interactomics”, Leibniz Forschungsinstitut für Molekulare Pharmakologie)

  • Max Schmidt

    (Labor für Pädiatrische Molekularbiologie, Charité Universitätsmedizin Berlin
    Medizinische Klinik m.S. Hämatologie, Onkologie und Tumorimmunologie, Charité Universitätsmedizin Berlin)

  • Henry Weisbach

    (Labor für Pädiatrische Molekularbiologie, Charité Universitätsmedizin Berlin
    PenCef Pharma GmbH)

  • Iris Gruska

    (Labor für Pädiatrische Molekularbiologie, Charité Universitätsmedizin Berlin)

  • Barbara Vetter

    (Labor für Pädiatrische Molekularbiologie, Charité Universitätsmedizin Berlin)

  • Koshi Imami

    (Research group “Proteome Dynamics”, Max Delbrück Center for Molecular Medicine
    Laboratory of Molecular & Cellular BioAnalysis, Kyoto University)

  • Eleonore Ostermann

    (Heinrich Pette Institute, Leibniz Institute for Experimental Virology)

  • Wolfram Brune

    (Heinrich Pette Institute, Leibniz Institute for Experimental Virology)

  • Matthias Selbach

    (Research group “Proteome Dynamics”, Max Delbrück Center for Molecular Medicine
    Charité-Universitätsmedizin Berlin)

  • Christian Hagemeier

    (Labor für Pädiatrische Molekularbiologie, Charité Universitätsmedizin Berlin)

  • Lüder Wiebusch

    (Labor für Pädiatrische Molekularbiologie, Charité Universitätsmedizin Berlin)

Abstract

Herpesviruses encode conserved protein kinases (CHPKs) to stimulate phosphorylation-sensitive processes during infection. How CHPKs bind to cellular factors and how this impacts their regulatory functions is poorly understood. Here, we use quantitative proteomics to determine cellular interaction partners of human herpesvirus (HHV) CHPKs. We find that CHPKs can target key regulators of transcription and replication. The interaction with Cyclin A and associated factors is identified as a signature of β-herpesvirus kinases. Cyclin A is recruited via RXL motifs that overlap with nuclear localization signals (NLS) in the non-catalytic N termini. This architecture is conserved in HHV6, HHV7 and rodent cytomegaloviruses. Cyclin A binding competes with NLS function, enabling dynamic changes in CHPK localization and substrate phosphorylation. The cytomegalovirus kinase M97 sequesters Cyclin A in the cytosol, which is essential for viral inhibition of cellular replication. Our data highlight a fine-tuned and physiologically important interplay between a cellular cyclin and viral kinases.

Suggested Citation

  • Boris Bogdanow & Max Schmidt & Henry Weisbach & Iris Gruska & Barbara Vetter & Koshi Imami & Eleonore Ostermann & Wolfram Brune & Matthias Selbach & Christian Hagemeier & Lüder Wiebusch, 2020. "Cross-regulation of viral kinases with cyclin A secures shutoff of host DNA synthesis," Nature Communications, Nature, vol. 11(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-18542-1
    DOI: 10.1038/s41467-020-18542-1
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