Human cytomegalovirus tegument protein pp150 acts as a cyclin A2–CDK-dependent sensor of the host cell cycle and differentiation state
| Autor: | Jens von Einem, Boris Bogdanow, Henry Weisbach, Michael Winkler, Lueder Wiebusch, Sebastian Voigt, Christian Hagemeier, Sarah Straschewski |
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| Rok vydání: | 2013 |
| Předmět: |
Gene Expression Regulation
Viral Human cytomegalovirus viruses Cellular differentiation Amino Acid Motifs Immunoblotting Cyclin A Cytomegalovirus Cell Line Viral Matrix Proteins Cyclin-dependent kinase Cell Line Tumor medicine Humans Amino Acid Sequence Phosphorylation Genes Immediate-Early Cyclin Multidisciplinary biology Cell Cycle virus diseases Cell Differentiation Biological Sciences Cell cycle Flow Cytometry Phosphoproteins medicine.disease Molecular biology Cyclin-Dependent Kinases Cell biology Luminescent Proteins HEK293 Cells Microscopy Fluorescence Lytic cycle Host-Pathogen Interactions Mutation biology.protein Cyclin A2 Protein Binding |
| Zdroj: | Proceedings of the National Academy of Sciences. 110:17510-17515 |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | Upon cell entry, herpesviruses deliver a multitude of premade virion proteins to their hosts. The interplay between these incoming proteins and cell-specific regulatory factors dictates the outcome of infections at the cellular level. Here, we report a unique type of virion-host cell interaction that is essential for the cell cycle and differentiation state-dependent onset of human cytomegalovirus (HCMV) lytic gene expression. The major tegument 150-kDa phosphoprotein (pp150) of HCMV binds to cyclin A2 via a functional RXL/Cy motif resulting in its cyclin A2-dependent phosphorylation. Alanine substitution of the RXL/Cy motif prevents this interaction and allows the virus to fully escape the cyclin-dependent kinase (CDK)-mediated block of immediate early (IE) gene expression in S/G2 phase that normally restricts the onset of the HCMV replication cycle to G0/G1. Furthermore, the cyclin A2-CDK-pp150 axis is also involved in the establishment of HCMV quiescence in NTera2 cells, showing the importance of this molecular switch for differentiation state-dependent regulation of IE gene expression. Consistent with the known nucleocapsid-binding function of pp150, its RXL/Cy-dependent phosphorylation affects gene expression of the parental virion only, suggesting a cis-acting, virus particle-associated mechanism of control. The pp150 homologs of other primate and mammalian CMVs lack an RXL/Cy motif and accordingly even the nearest relative of HCMV, chimpanzee CMV, starts its lytic cycle in a cell cycle-independent manner. Thus, HCMV has evolved a molecular sensor for cyclin A2-CDK activity to restrict its IE gene expression program as a unique level of self-limitation and adaptation to its human host. |
| Databáze: | OpenAIRE |
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