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.
Laboratory of Viral Pathogenesis, Institute for Virus Research, Kyoto University, Kyoto, Japan.
J Virol. 2015 Jan;89(1):241-8. doi: 10.1128/JVI.02497-14. Epub 2014 Oct 15.
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.
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.
单纯疱疹病毒 1 脱氧尿苷三磷酸酶 (vdUTPase) 的突变使其无法在丝氨酸 187 位磷酸化，降低了病毒的神经毒力，并增加了在内源性细胞 dUTPase 活性相对较低的小鼠脑中病毒子代基因组的突变频率，而细胞 dUTPase 的过度表达恢复了突变改变的病毒神经毒力和突变频率。因此，vdUTPase 的磷酸化似乎通过补偿体内低细胞 dUTPase 活性来调节病毒毒力和基因组完整性。
许多 DNA 病毒编码宿主细胞 dUTPase 的同源物，已知其在细胞 DNA 基因组的准确复制中发挥作用。病毒 dUTPase 活性长期以来一直被认为通过防止细胞 dUTPase 活性不足导致子代病毒基因组发生突变，从而在病毒复制中发挥作用。在这里，我们表明单纯疱疹病毒 1 dUTPase 的突变使其无法在丝氨酸 187 位磷酸化并降低其活性，从而降低了病毒的神经毒力，并增加了在内源性细胞 dUTPase 活性相对较低的小鼠脑中病毒子代基因组的突变频率。相比之下，细胞 dUTPase 的过度表达恢复了在小鼠脑中由突变改变的病毒神经毒力和突变频率。据我们所知，这是第一个直接表明病毒 dUTPase 活性通过补偿体内不足的细胞 dUTPase 活性来调节病毒基因组完整性和致病性的报告。
