title: Heat-shock protein 90 promotes nuclear transport of herpes simplex virus 1 capsid protein by interacting with acetylated tubulin.
abstract: Although it is known that inhibitors of heat shock protein 90 (Hsp90) can inhibit herpes simplex virus type 1 (HSV-1) infection, the role of Hsp90 in HSV-1 entry and the antiviral mechanisms of Hsp90 inhibitors remain unclear. In this study, we found that Hsp90 inhibitors have potent antiviral activity against standard or drug-resistant HSV-1 strains and viral gene and protein synthesis are inhibited in an early phase. More detailed studies demonstrated that Hsp90 is upregulated by virus entry and it interacts with virus. Hsp90 knockdown by siRNA or treatment with Hsp90 inhibitors significantly inhibited the nuclear transport of viral capsid protein (ICP5) at the early stage of HSV-1 infection. In contrast, overexpression of Hsp90 restored the nuclear transport that was prevented by the Hsp90 inhibitors, suggesting that Hsp90 is required for nuclear transport of viral capsid protein. Furthermore, HSV-1 infection enhanced acetylation of α-tubulin and Hsp90 interacted with the acetylated α-tubulin, which is suppressed by Hsp90 inhibition. These results demonstrate that Hsp90, by interacting with acetylated α-tubulin, plays a crucial role in viral capsid protein nuclear transport and may provide novel insight into the role of Hsp90 in HSV-1 infection and offer a promising strategy to overcome drug-resistance.
authors.affiliation: Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, PR China; College of Pharmacy, Jinan University, Guangzhou, PR China.
authors.forename: Meigong
authors.initials: M
authors.lastname: Zhong
authors.affiliation: Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, PR China.
authors.forename: Kai
authors.initials: K
authors.lastname: Zheng
authors.affiliation: Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, PR China; College of Pharmacy, Jinan University, Guangzhou, PR China.
authors.forename: Maoyun
authors.initials: M
authors.lastname: Chen
authors.affiliation: Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, PR China.
authors.forename: Yangfei
authors.initials: Y
authors.lastname: Xiang
authors.affiliation: Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, PR China; College of Pharmacy, Jinan University, Guangzhou, PR China.
authors.forename: Fujun
authors.initials: F
authors.lastname: Jin
authors.affiliation: Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, PR China.
authors.forename: Kaiqi
authors.initials: K
authors.lastname: Ma
authors.affiliation: Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, PR China; College of Pharmacy, Jinan University, Guangzhou, PR China.
authors.forename: Xianxiu
authors.initials: X
authors.lastname: Qiu
authors.affiliation: Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, PR China.
authors.forename: Qiaoli
authors.initials: Q
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, PR China.
authors.forename: Tao
authors.initials: T
authors.lastname: Peng
authors.affiliation: Division of Molecular Pharmacology of Infectious Agents, Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
authors.forename: Kaio
authors.initials: K
authors.lastname: Kitazato
authors.affiliation: Guangzhou Jinan Biomedicine Research and Development Center, National Engineering Research Center of Genetic Medicine, Jinan University, Guangzhou, PR China.
authors.forename: Yifei
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000107:Acetylation; D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology; D036022:Capsid Proteins / Q000378:metabolism*; D002460:Cell Line; D002522:Chlorocebus aethiops; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D011485:Protein Binding; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D012367:RNA, Viral / Q000378:metabolism; D014162:Transfection; D014404:Tubulin / Q000378:metabolism*; D015854:Up-Regulation; D014709:Vero Cells; D053586:Virus Internalization / Q000187:drug effects
chemical_list: D016227:Benzoquinones; D036022:Capsid Proteins; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D034741:RNA, Small Interfering; D012367:RNA, Viral; D014404:Tubulin; C112765:tanespimycin