title: Phosphorylation of herpes simplex virus 1 dUTPase regulates viral virulence and genome integrity by compensating for low cellular dUTPase activity in the central nervous system.
abstract: A mutation in herpes simplex virus 1 dUTPase (vdUTPase), which precluded its phosphorylation at Ser-187, decreased viral neurovirulence and increased mutation frequency in progeny virus genomes in the brains of mice where endogenous cellular dUTPase activity was relatively low, and overexpression of cellular dUTPase restored viral neurovirulence and mutation frequency altered by the mutation. Thus, phosphorylation of vdUTPase appeared to regulate viral virulence and genome integrity by compensating for low cellular dUTPase activity in vivo.
  
  
  OBJECTIVE
  Many DNA viruses encode a homolog of host cell dUTPases, which are known to function in accurate replication of cellular DNA genomes. The viral dUTPase activity has long been assumed to play a role in viral replication by preventing mutations in progeny virus genomes if cellular dUTPase activity was not sufficient. Here, we showed that a mutation in herpes simplex virus 1 dUTPase, which precluded its phosphorylation at Ser-187 and reduced its activity, decreased viral neurovirulence and increased mutation frequency in progeny virus genomes in the brains of mice where endogenous cellular dUTPase activity was relatively low. In contrast, overexpression of cellular dUTPase restored viral neurovirulence and mutation frequency altered by the mutation in the brains of mice. This is the first report, to our knowledge, directly showing that viral dUTPase activity regulates viral genome integrity and pathogenicity by compensating for insufficient cellular dUTPase activity in vivo.
authors.affiliation: Division of Molecular Virology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan Department of Infectious Disease Control, International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Akihisa
authors.initials: A
authors.lastname: Kato
authors.affiliation: Division of Molecular Virology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan Department of Infectious Disease Control, International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Arii
authors.affiliation: Laboratory of Viral Pathogenesis, Institute for Virus Research, Kyoto University, Kyoto, Japan.
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Koyanagi
authors.affiliation: Division of Molecular Virology, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan Department of Infectious Disease Control, International Research Center for Infectious Diseases, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan ykawagu@ims.u-tokyo.ac.jp.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kawaguchi
mesh_terms: D000818:Animals; D001921:Brain / Q000821:virology; D002460:Cell Line; D002490:Central Nervous System / Q000821:virology*; D005260:Female; D042822:Genomic Instability; D018259:Herpesvirus 1, Human / Q000201:enzymology* / Q000235:genetics* / Q000472:pathogenicity; D006801:Humans; D008813:Mice, Inbred ICR; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011755:Pyrophosphatases / Q000235:genetics / Q000378:metabolism*; D016019:Survival Analysis; D019562:Viral Load; D014774:Virulence; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D050505:Mutant Proteins; D037521:Virulence Factors; D011755:Pyrophosphatases; C020020:dUTP pyrophosphatase