Inhibition of histone methyltransferase SETD8 represses DNA virus replication
Lin Chen,
Chen Yang,
Shan-Bo Tang,
Qiao-Yun Long,
Ji-Dong Chen,
Min Wu,
Lian-Yun Li
Affiliations
Lin Chen
Frontier Science Center for Immunology and Metabolism, Hubei Key Laboratory of Cell Homeostasis, Hubei Key Laboratory of Developmentally Originated Disease, Hubei Key Laboratory of Enteropathy, Renmin Hospital of Wuhan University, College of Life Sciences, Wuhan University, Wuhan, 430072, China
Chen Yang
Frontier Science Center for Immunology and Metabolism, Hubei Key Laboratory of Cell Homeostasis, Hubei Key Laboratory of Developmentally Originated Disease, Hubei Key Laboratory of Enteropathy, Renmin Hospital of Wuhan University, College of Life Sciences, Wuhan University, Wuhan, 430072, China
Shan-Bo Tang
Frontier Science Center for Immunology and Metabolism, Hubei Key Laboratory of Cell Homeostasis, Hubei Key Laboratory of Developmentally Originated Disease, Hubei Key Laboratory of Enteropathy, Renmin Hospital of Wuhan University, College of Life Sciences, Wuhan University, Wuhan, 430072, China
Qiao-Yun Long
Frontier Science Center for Immunology and Metabolism, Hubei Key Laboratory of Cell Homeostasis, Hubei Key Laboratory of Developmentally Originated Disease, Hubei Key Laboratory of Enteropathy, Renmin Hospital of Wuhan University, College of Life Sciences, Wuhan University, Wuhan, 430072, China
Ji-Dong Chen
Frontier Science Center for Immunology and Metabolism, Hubei Key Laboratory of Cell Homeostasis, Hubei Key Laboratory of Developmentally Originated Disease, Hubei Key Laboratory of Enteropathy, Renmin Hospital of Wuhan University, College of Life Sciences, Wuhan University, Wuhan, 430072, China
Min Wu
Corresponding author.; Frontier Science Center for Immunology and Metabolism, Hubei Key Laboratory of Cell Homeostasis, Hubei Key Laboratory of Developmentally Originated Disease, Hubei Key Laboratory of Enteropathy, Renmin Hospital of Wuhan University, College of Life Sciences, Wuhan University, Wuhan, 430072, China
Lian-Yun Li
Corresponding author.; Frontier Science Center for Immunology and Metabolism, Hubei Key Laboratory of Cell Homeostasis, Hubei Key Laboratory of Developmentally Originated Disease, Hubei Key Laboratory of Enteropathy, Renmin Hospital of Wuhan University, College of Life Sciences, Wuhan University, Wuhan, 430072, China
Multiple diseases, such as cancer and neural degeneration diseases, are related with the latent infection of DNA viruses. However, it is still difficult to clean up the latent DNA viruses and new anti-viral strategies are critical for disease treatment. Here, we screen a pool of small chemical molecules and identify UNC0379, an inhibitor for histone H4K20 methyltransferase SETD8, as an effective inhibitor for multiple DNA viruses. UNC0379 not only enhances the expression of anti-viral genes in THP-1 cells, but also repress DNA virus replication in multiple cell lines with defects in cGAS pathway. We prove that SETD8 promotes DNA virus replication in a manner dependent on its enzyme activity. Our results further indicated that SETD8 is required for PCNA stability, one factor critical for viral DNA replication. Viral infection stimulates the interaction between SETD8 and PCNA and thus enhances PCNA stability and viral DNA replication. Taken together, our study reveals a new mechanism for regulating viral DNA replication and provides a potential strategy for treatment of diseases related with DNA viruses.
