Human cytomegalovirus tegument protein pp150 acts as a cyclin A2–CDK-dependent sensor of the host cell cycle and differentiation state

Significance
Depending on the host cell type and differentiation status, herpesviruses establish different modes of infection to either maintain or replicate their genomes. How viruses discriminate between individual host cell environments upon infection is poorly understood. Here we identify a viral sensor mechanism that restricts human cytomegalovirus (HCMV) replication to the G0/G1 phase of the cell division cycle and to differentiated cells. The mechanism is based on the HCMV tegument 150-kDa phosphoprotein which enters the cell as a constituent of the virus particle, interacts with cyclin A2, and blocks the onset of viral lytic gene expression when cyclin A2-dependent kinase activity is high. This suggests a scenario where specific tegument–host interactions enable herpesviruses to select sites of silent or productive infection.

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.