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

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

Yiliang Wang ¹ ² ³, Rongze Wang ¹ ² ³ ⁴, Feng Li ¹ ² ³, Yun Wang ⁵, Zhen Zhang ¹ ² ³, Qiaoli Wang ¹ ² ³, Zhe Ren ¹ ² ³, Fujun Jin ⁶ ⁷ ⁸ ⁹, Kaio Kitazato ¹⁰, Yifei Wang ¹¹ ¹² ¹³

Affiliations

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. [email protected].
7 Key Laboratory of Virology of Guangzhou, Jinan University, Guangzhou, China. [email protected].
8 Key Laboratory of Bioengineering Medicine of Guangdong Province, Jinan University, Guangzhou, China. [email protected].
9 Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, Guangzhou, China. [email protected].
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. [email protected].
11 Guangzhou Jinan Biomedicine Research and Development Center, Institute of Biomedicine, College of Life Science and Technology, Jinan University, Guangzhou, China. [email protected].
12 Key Laboratory of Virology of Guangzhou, Jinan University, Guangzhou, China. [email protected].
13 Key Laboratory of Bioengineering Medicine of Guangdong Province, Jinan University, Guangzhou, China. [email protected].

PMID: 30577726 DOI: 10.1186/s10020-018-0066-x

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.

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