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Mol Med. 2018 Dec 22;24(1):65. doi: 10.1186/s10020-018-0066-x.

Heat-shock protein 90α is involved in maintaining the stability of VP16 and VP16-mediated transactivation of α genes from herpes simplex virus-1.

Wang Y1,2,3, Wang R1,2,3,4, Li F1,2,3, Wang Y5, Zhang Z1,2,3, Wang Q1,2,3, Ren Z1,2,3, Jin F6,7,8,9, Kitazato K10, Wang Y11,12,13.

Author information

1
Guangzhou Jinan Biomedicine Research and Development Center, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, China.
2
Key Laboratory of Virology of Guangzhou, Jinan University, Guangzhou, China.
3
Key Laboratory of Bioengineering Medicine of Guangdong Province, Jinan University, Guangzhou, China.
4
College of Pharmacy, Jinan University, Guangzhou, China.
5
Key Laboratory for Major Obstetric Diseases of Guangdong Province, Department of Obstetrics and Gynecology, Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
6
Guangzhou Jinan Biomedicine Research and Development Center, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, China. fujun_jin@163.com.
7
Key Laboratory of Virology of Guangzhou, Jinan University, Guangzhou, China. fujun_jin@163.com.
8
Key Laboratory of Bioengineering Medicine of Guangdong Province, Jinan University, Guangzhou, China. fujun_jin@163.com.
9
Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, Guangzhou, China. fujun_jin@163.com.
10
Division of Molecular Pharmacology of Infectious Agents, Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki, 852-8521, Japan. kkholi@nagasaki-u.ac.jp.
11
Guangzhou Jinan Biomedicine Research and Development Center, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, China. twang-yf@163.com.
12
Key Laboratory of Virology of Guangzhou, Jinan University, Guangzhou, China. twang-yf@163.com.
13
Key Laboratory of Bioengineering Medicine of Guangdong Province, Jinan University, Guangzhou, China. twang-yf@163.com.

Abstract

BACKGROUND:

Numerous host cellular factors are exploited by viruses to facilitate infection. Our previous studies and those of others have shown heat-shock protein 90 (Hsp90), a cellular molecular chaperone, is involved in herpes simplex virus (HSV)-1 infection. However, the function of the dominant Hsp90 isoform and the relationship between Hsp90 and HSV-1 α genes remain unclear.

METHODS AND RESULTS:

Hsp90α knockdown or inhibition significantly inhibited the promoter activity of HSV-1 α genes and downregulated virion protein 16(VP16) expression from virus and plasmids. The Hsp90α knockdown-induced suppression of α genes promoter activity and downregulation of α genes was reversed by VP16 overexpression, indicating that Hsp90α is involved in VP16-mediated transcription of HSV-1 α genes. Co-immunoprecipitation experiments indicated that VP16 interacted with Hsp90α through the conserved core domain within VP16. Based on using autophagy inhibitors and the presence of Hsp90 inhibitors in ATG7-/- (autophagy-deficient) cells, Hsp90 inhibition-induced degradation of VP16 is dependent on macroautophagy-mediated degradation but not chaperone-mediated autophagy (CMA) pathway. In vivo studies demonstrated that treatment with gels containing Hsp90 inhibitor effectively reduced the level of VP16 and α genes, which may contribute to the amelioration of the skin lesions in an HSV-1 infection mediated zosteriform model.

CONCLUSION:

Our study provides new insights into the mechanisms by which Hsp90α facilitates the transactivation of HSV-1 α genes and viral infection, and highlights the importance of developing selective inhibitors targeting the interaction between Hsp90α and VP16 to reduce toxicity, a major challenge in the clinical use of Hsp90 inhibitors.

KEYWORDS:

Autophagy; Heat-shock protein 90α; Herpes simplex virus-1; VP16; α genes

PMID:
30577726
PMCID:
PMC6303900
DOI:
10.1186/s10020-018-0066-x
[Indexed for MEDLINE]
Free PMC Article

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