Hyperphosphorylation of histone deacetylase 2 by alphaherpesvirus US3 kinases.
A serine/threonine (S/T) kinase encoded by the US3 gene of herpes simplex virus type 1 (HSV-1) is conserved in varicella-zoster virus (VZV) and pseudorabies virus (PRV). Expression of US3 kinase in cells transformed with US3 expression plasmids or infected with each virus results in hyperphosphorylation of histone deacetylase 2 (HDAC2). Mapping studies revealed that each US3 kinase phosphorylates HDAC2 at the same unique conserved Ser residue in its C terminus. HDAC2 was also hyperphosphorylated in cells infected with PRV lacking US3 kinase, indicating that hyperphosphorylation of HDAC2 by PRV occurs in a US3-independent manner. Specific chemical inhibition of class I HDAC activity increases the plaquing efficiency of VZV and PRV lacking US3 or its enzymatic activity, whereas only minimal effects are observed with wild-type viruses, suggesting that VZV and PRV US3 kinase activities target HDACs to reduce viral genome silencing and allow efficient viral replication. However, no effect was observed for wild-type or US3 null HSV-1. Thus, we have demonstrated that while HDAC2 is a conserved target of alphaherpesvirus US3 kinases, the functional significance of these events is virus specific.
Walters
Matthew S
MS
Department of Microbiology and Immunology, College of Physicians and Surgeons, Columbia University, 701 W. 168th St., New York, NY 10032, USA.
Kinchington
Paul R
PR
Banfield
Bruce W
BW
Silverstein
Saul
S
D018138:Alphaherpesvirinae / Q000201:enzymology* / Q000235:genetics / Q000472:pathogenicity; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D002522:Chlorocebus aethiops; D017931:DNA Primers / Q000235:genetics; D005814:Genes, Viral; D018259:Herpesvirus 1, Human / Q000201:enzymology / Q000235:genetics; D011558:Herpesvirus 1, Suid / Q000201:enzymology / Q000235:genetics; D014645:Herpesvirus 3, Human / Q000201:enzymology / Q000235:genetics; D056464:Histone Deacetylase 2 / Q000378:metabolism*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D014709:Vero Cells; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*
D017931:DNA Primers; D014764:Viral Proteins; D017346:Protein Serine-Threonine Kinases; C095207:US3 protein, Human herpesvirus 1; D056464:Histone Deacetylase 2