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

Proc Natl Acad Sci U S A. 2013 Oct 22;110(43):17510-5. doi: 10.1073/pnas.1312235110. Epub 2013 Oct 7.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs / genetics
  • Amino Acid Sequence
  • Cell Cycle*
  • Cell Differentiation*
  • Cell Line
  • Cell Line, Tumor
  • Cyclin A2 / genetics
  • Cyclin A2 / metabolism*
  • Cyclin-Dependent Kinases / genetics
  • Cyclin-Dependent Kinases / metabolism*
  • Cytomegalovirus / genetics
  • Cytomegalovirus / metabolism*
  • Cytomegalovirus / physiology
  • Flow Cytometry
  • Gene Expression Regulation, Viral
  • Genes, Immediate-Early / genetics
  • HEK293 Cells
  • Host-Pathogen Interactions
  • Humans
  • Immunoblotting
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Microscopy, Fluorescence
  • Mutation
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Phosphorylation
  • Protein Binding
  • Viral Matrix Proteins / genetics
  • Viral Matrix Proteins / metabolism*

Substances

  • Cyclin A2
  • Luminescent Proteins
  • Phosphoproteins
  • Viral Matrix Proteins
  • pp150 protein, Cytomegalovirus
  • Cyclin-Dependent Kinases