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

Boris Bogdanow, Max Schmidt, Henry Weisbach, Iris Gruska, Barbara Vetter, Koshi Imami, Eleonore Ostermann, Wolfram Brune, Matthias Selbach, Christian Hagemeier and Lüder Wiebusch ()
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Boris Bogdanow: Research group “Proteome Dynamics”, Max Delbrück Center for Molecular Medicine
Max Schmidt: Labor für Pädiatrische Molekularbiologie, Charité Universitätsmedizin Berlin
Henry Weisbach: Labor für Pädiatrische Molekularbiologie, Charité Universitätsmedizin Berlin
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
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
Christian Hagemeier: Labor für Pädiatrische Molekularbiologie, Charité Universitätsmedizin Berlin
Lüder Wiebusch: Labor für Pädiatrische Molekularbiologie, Charité Universitätsmedizin Berlin

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-18542-1

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