Researchers uncover regulatory mechanisms by which viral proteins mimic host kinases to support their survival and persistence
Herpesviruses, which cause skin and genital infections, neonatal diseases, and meningitis, can successfully persist over a lifetime and transmit from one host to another. One key strategy that enables them to coexist within host cells is mimicry of cyclin-dependent kinases (CDKs)—proteins that regulate crucial cellular processes. A new study by researchers from Japan reveals novel insights into mechanisms underlying CDK mimicry by viral kinases, driven by phosphorylation of conserved amino acid residues.
Viruses are microscopic pathogens composed of genetic material housed within a protective protein shell. While they carry the blueprint required for producing additional viral proteins, they lack the equipment needed for the same. For this, they hijack host cells and rely on their machinery for multiplication.
Viruses have evolved multiple strategies that help them gain control of the host’s cellular processes and make the environment conducive to their survival and replication. One key strategy is mimicking the host’s regulatory factors that govern important cellular pathways. However, viral infection dramatically transforms the host’s cellular environment. Therefore, the regulatory mechanisms of viral factors are likely distinct from those of host factors.
Phosphorylation—the reversible addition of phosphate groups carried out by proteins known as kinases—acts as a switch that turns key cell cycle-related proteins on and off. Interestingly, some viral protein kinases in herpesviruses are structurally conserved and mimic human cyclin-dependent kinases (CDKs). Herpes simplex virus 2 (HSV-2) causes skin and genital infections, meningitis, and neonatal diseases and often establishes a lifelong infection characterized by periods of latency and recurrent outbreaks. Understanding the mechanisms that regulate CDK mimicry by HSV-2 can aid the development of novel antiviral therapies and preventive vaccines.
To this end, Professor Yasushi Kawaguchi and Assistant Professor Naoto Koyanagi from the Division of Molecular Virology, Department of Microbiology and Immunology, Institute of Medical Science, The University of Tokyo, Japan, investigated the mechanisms underlying phosphorylation-mediated CDK mimicry by conserved herpesvirus protein kinases (CHPKs).
Providing further insight into their work, Prof. Kawaguchi explains, “We demonstrated that UL13, which is the CHPK of HSV-2, mimics the functional and regulatory mechanisms of CDKs. This mimicry by UL13 contributes not only to the suppression of lethal viral infection in the brain but also to the efficient recurrence of the virus. Our findings unveil part of the sophisticated strategy employed by the virus to ensure its persistence within the host.” Their findings were published in the Proceedings of the National Academy of Sciences (PNAS) on April 16, 2025.
CDKs contain two structurally and functionally distinct lobes: the N- and C-lobes. The N-lobe contains a highly conserved motif across CDKs and CHPKs, in which phosphorylation of specific serine/threonine and tyrosine residues inhibits its catalytic activity. The researchers examined whether UL13 was phosphorylated at the corresponding tyrosine residue in the conserved motif in cells infected with either wild-type HSV-2, UL13-deficient HSV-2, or HSV-2 UL13-Y162F, in which UL13 Tyr-162 was replaced with phenylalanine. An antibody targeting tyrosine-phosphorylated UL13 reacted strongly with lysates obtained from wild-type-infected cells. Conversely, there was no reaction in lysates from mock-infected control cells, cells infected with UL13-deficient HSV-2 or HSV-2 UL13-Y162F. Notably, phosphorylation was more pronounced at 24 hours post-infection than 12 hours, suggesting that tyrosine phosphorylation by UL13 occurred later during HSV-2 infection.
Further, mutational analyses revealed that phosphomimetic mutation of tyrosine in UL13 reduced the phosphorylation of all UL13 substrates (proteins phosphorylated by UL13), suggesting that phosphorylation downregulates its catalytic activity. Similar effects were noted in other subfamilies of herpesviruses as well. Additionally, phosphomimetic mutation at tyrosine in HSV-2 UL13 downregulated viral replication and pathogenicity in the brain of mice injected with HSV-2, during the active lytic phase (when new viral particles are released). Conversely, in guinea pigs infected with HSV-2, phosphorylation of UL13 tyrosine residue was required to establish recurrent infection following the latent phase. These findings suggest that CDK mimicry by UL13 may regulate both acute lytic and latent HSV-2 infections in vivo.
Overall, the study highlights a novel regulatory mechanism of CDK mimicry that may help herpesviruses coexist and expand within host cells while balancing host survival with viral persistence throughout the host’s lifespan.
Prof. Kawaguchi concludes, “Insights into the regulatory mechanisms of CHPK kinase activity may lead to a better understanding of how pathogenicity is controlled across different herpesviruses. Furthermore, the corresponding tyrosine residue in the conserved motif of CDKs and CHPKs is also conserved in viral kinases encoded by poxviruses, suggesting poxviruses might have also evolved CDK regulatory mimicry.”
Viruses have evolved various strategies to coexist and replicate within host cells. Mimicry of host proteins represents a key mechanism that ensures the prolonged persistence of herpesviruses in host cells. A new study by researchers from Japan sheds light on novel regulatory mechanisms of host cyclin-dependent kinase mimicry by a conserved herpesvirus kinase. Their findings demonstrate that phosphorylation of conserved residues in the viral kinase regulates viral replication, active lytic infection, and recurrence following latency.
Reference
Journal：Proceedings of the National Academy of Sciences
Title of original paper：
Regulatory Mimicry of Cyclin-Dependent Kinases by a Conserved Herpesvirus Protein Kinase
DOI：
10.1073/pnas.2500264122
Authors：
Naoto Koyanagi1,2,3, Kowit Hengphasatporn4, Akihisa Kato1,2,3, Moeka Nobe1, Kosuke Takeshima1,2, Yuhei Maruzuru1,2,3, Katsumi Maenaka5,6, Yasuteru Shigeta4 , and Yasushi Kawaguchi1,2,3,7
Affiliations：
1Division of Molecular Virology, Department of Microbiology and Immunology, the Institute of Medical Science, The University of Tokyo, Japan
2Department of Infectious Disease Control, International Research Center for Infectious Diseases, the Institute of Medical Science, The University of Tokyo, Japan
3Research Center for Asian Infectious Diseases, the Institute of Medical Science, The University of Tokyo, Japan
4Center for Computational Sciences, University of Tsukuba, Japan
5Center for Research and Education on Drug Discovery, Faculty of Pharmaceutical Sciences, Hokkaido University, Japan
6Laboratory of Biomolecular Science, Faculty of Pharmaceutical Sciences, Hokkaido University, Japan
7The University of Tokyo, Pandemic Preparedness, Infection and Advanced Research Center, Japan
About The Institute of Medical Science, The University of Tokyo
The Institute of Medical Science, The University of Tokyo (IMSUT), established in 1892 as the Institute of Infectious Diseases and renamed IMSUT in 1967, is a leading research institution with a rich history spanning over 127 years. It focuses on exploring biological phenomena and disease principles to develop innovative strategies for disease prevention and treatment. IMSUT fosters a collaborative, interdisciplinary research environment and is known for its work in genomic medicine, regenerative medicine, and advanced medical approaches like gene therapy and AI in healthcare. It operates core research departments and numerous specialized centers, including the Human Genome Center and the Advanced Clinical Research Center, and is recognized as Japan’s only International Joint Usage/Research Center in life sciences.About Professor Yasushi Kawaguchi from the Institute of Medical Science, The University of Tokyo
Professor Yasushi Kawaguchi is a faculty member at the Division of Molecular Virology, Department of Microbiology and Immunology, Institute of Medical Science, The University of Tokyo, Japan. Research in his lab focuses on promoting strategic basic research with the aim of elucidating the mechanisms of viral proliferation and pathological expression at the molecular to individual level and using this as a basis to develop new methods for controlling viral infections. Furthermore, by using viruses as biological probes, Prof. Kawaguchi and his team are not only unraveling cellular and physiological control mechanisms that cannot be elucidated through human research alone, but also exploring next-generation virology by redefining viruses as homeostatic factors and elucidating their significance. He is affiliated with various graduate schools and has authored numerous publications in the field of virology.
Funding information
This study was supported by Grants for Scientific Research and Grant-in-Aid for Scientific Research (S) (20H05692) from the Japan Society for the Promotion of Science (JSPS), grants for Scientific Research on Innovative Areas (21H00338, 21H00417, 22H04803) and a grant for Transformative Research Areas (22H05584) from the Ministry of Education, Culture, Science, Sports and Technology of Japan, a PRESTO grant (JPMJPR22R5) from Japan Science and Technology Agency (JST), grants (JP20wm0125002, JP22fk0108640, JP22gm1610008, JP223fa627001, JP23wm0225031, JP23wm0225035) from the Japan Agency for Medical Research and Development (AMED), grants from the International Joint Research Project of the Institute of Medical Science, the University of Tokyo, grants from the Takeda Science Foundation, the Mitsubishi Foundation, the Uehara Memorial Foundation, and the Waksman Foundation of Japan, and the GSK Japan Research Grant 2019.Media contact
Affiliation: Project Coordination Office, The Institute of Medical Science, The University of Tokyohttps://www.ims.u-tokyo.ac.jp/