Koyanagi Naoto, Hengphasatporn Kowit, Kato Akihisa, Nobe Moeka, Takeshima Kosuke, Maruzuru Yuhei, Maenaka Katsumi, Shigeta Yasuteru, Kawaguchi Yasushi
Division of Molecular Virology, Department of Microbiology and Immunology, the Institute of Medical Science, The University of Tokyo, Minato-ku 108-8639, Tokyo, Japan.
Department of Infectious Disease Control, International Research Center for Infectious Diseases, the Institute of Medical Science, The University of Tokyo, Minato-ku 108-8639, Tokyo, Japan.
Proc Natl Acad Sci U S A. 2025 Apr 22;122(16):e2500264122. doi: 10.1073/pnas.2500264122. Epub 2025 Apr 16.
Herpesviruses encode conserved protein kinases (CHPKs) that target cellular cyclin-dependent kinase (CDK) phosphorylation sites; thus, they are termed viral CDK-like kinases. Tyrosine 15 in the GxGxxG motifs of CDK1 and CDK2, whose phosphorylation down-regulates their catalytic activities, is conserved in the corresponding motifs of CHPKs. We found that CHPK UL13, the corresponding Tyr-162 in herpes simplex virus 2 (HSV-2), was phosphorylated in HSV-2-infected cells. Mutational analyses of HSV-2 UL13 Tyr-162 suggested that phosphorylation of UL13 Tyr-162 reduced the phosphorylation of all UL13 substrates tested in HSV-2-infected cells. These findings suggested that HSV-2 UL13 mimicked the regulatory mechanism of CDKs and that this CHPK has regulatory and functional mimicry with CDKs. Furthermore, phosphorylation of HSV-2 UL13 Tyr-162 was suggested to be required for the downregulation of viral replication and pathogenicity, specifically in the brains of mice, and for efficient viral recurrence in guinea pigs. These findings highlight the dual impact of the regulatory mimicry of CDKs by CHPK on the fine-tuned regulation of lytic and latent HSV-2 infections in vivo.
疱疹病毒编码保守的蛋白激酶（CHPKs），这些激酶靶向细胞周期蛋白依赖性激酶（CDK）的磷酸化位点；因此，它们被称为病毒CDK样激酶。CDK1和CDK2的GxGxxG基序中的酪氨酸15，其磷酸化会下调它们的催化活性，在CHPKs的相应基序中是保守的。我们发现，单纯疱疹病毒2（HSV-2）中的CHPK UL13（对应于酪氨酸162）在HSV-2感染的细胞中被磷酸化。对HSV-2 UL13酪氨酸162的突变分析表明，UL13酪氨酸162的磷酸化降低了HSV-2感染细胞中所有测试的UL13底物的磷酸化。这些发现表明，HSV-2 UL13模仿了CDKs的调节机制，并且这种CHPK与CDKs具有调节和功能上的模拟。此外，HSV-2 UL13酪氨酸162的磷酸化被认为是病毒复制和致病性下调所必需的，特别是在小鼠大脑中，并且对于豚鼠中的有效病毒复发也是必需的。这些发现突出了CHPK对CDKs的调节模拟对体内HSV-2裂解性和潜伏性感染的精细调节的双重影响。
