ICP0 and the US3 protein kinase of herpes simplex virus 1 independently block histone deacetylation to enable gene expression.
SK-N-SH cells exposed to low ratios of ICP0-null (DeltaICP0) mutants of herpes simplex virus per cell express the viral alpha proteins, but the progression to beta and gamma gene expression does not ensue. In these restrictive cells, post-alpha gene expression can be induced after exposure of the infected cells to sodium butyrate, an indication that VP16 brought into cells by the virus and the alpha gene products made after infection cannot block the silencing of viral post-alpha genes by histone deacetylases (HDACs). This observation is consistent with evidence reported earlier that ICP0 dissociates HDAC1/2 from the CoREST/REST complex. In permissive U2OS cells, replication is independent of the ratio of DeltaICP0 mutant per cell. To determine whether other viral genes are involved in blocking HDACs, we used a surrogate system consisting of baculoviruses carrying viral or cellular genes driven by CMV immediate-early promoter. Expression of these genes requires blocking of histone deacetylation. We report that (i) cotransduced U(S)3 or U(S)3.5 protein kinase substitutes for sodium butyrate in enabling the expression of a reporter gene in restrictive cells and enhancing it in permissive cells; (ii) HDAC1 is phosphorylated concomitant with the expression of reporter genes; and (iii) the amounts and appearance of HDAC1 are altered in transduced cells expressing U(S)3 protein kinase in the absence of other viral proteins. We conclude that the U(S)3 protein kinase blocks histone deacetylation by a mechanism distinct from that of ICP0 and that debilitated histone deacetylation contributes to the permissiveness of U2OS cells for DeltaICP0 mutants.
Poon
Alice P W
AP
The Marjorie B. Kovler Viral Oncology Laboratories, University of Chicago, 910 East 58th Street, Chicago, IL 60637, USA.
Gu
Haidong
H
Roizman
Bernard
B
D000107:Acetylation; D000818:Animals; D020148:Butyric Acid / Q000494:pharmacology; D002478:Cells, Cultured; D015967:Gene Expression Regulation, Viral; D017930:Genes, Reporter / Q000187:drug effects; D018259:Herpesvirus 1, Human / Q000201:enzymology / Q000235:genetics*; D056284:Histone Deacetylase 1; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D014161:Transduction, Genetic; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*
D056572:Histone Deacetylase Inhibitors; D006657:Histones; D017874:Immediate-Early Proteins; D014764:Viral Proteins; D020148:Butyric Acid; D044767:Ubiquitin-Protein Ligases; C051804:Vmw110 protein, Human herpesvirus 1; D017346:Protein Serine-Threonine Kinases; C095207:US3 protein, Human herpesvirus 1; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1