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

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Item Type:

Article

Title:

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

Creators Name:

Bogdanow, B. and Schmidt, M. and Weisbach, H. and Gruska, I. and Vetter, B. and Imami, K. and Ostermann, E. and Brune, W. and Selbach, M. and Hagemeier, C. and Wiebusch, L.

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.

Keywords:

Cyclin A, Cytomegalovirus, DNA, DNA Replication, HEK293 Cells, Herpesviridae, Herpesviridae Infections, NIH 3T3 Cells, Nuclear Localization Signals, Phosphorylation, Protein Interaction Maps, Protein Kinases, Viral Proteins, Animals, Mice

Source:

Nature Communications

ISSN:

2041-1723

Publisher:

Nature Publishing Group

Volume:

Number:

Page Range:

4845

Date:

24 September 2020