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

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 ? genes remain unclear. METHODS AND RESULTS:Hsp90? knockdown or inhibition significantly inhibited the promoter activity of HSV-1 ? genes and downregulated virion protein 16(VP16) expression from virus and plasmids. The Hsp90? knockdown-induced suppression of ? genes promoter activity and downregulation of ? genes was reversed by VP16 overexpression, indicating that Hsp90? is involved in VP16-mediated transcription of HSV-1 ? genes. Co-immunoprecipitation experiments indicated that VP16 interacted with Hsp90? 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 ? 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 Hsp90? facilitates the transactivation of HSV-1 ? genes and viral infection, and highlights the importance of developing selective inhibitors targeting the interaction between Hsp90? and VP16 to reduce toxicity, a major challenge in the clinical use of Hsp90 inhibitors.

SUBMITTER: Wang Y 

PROVIDER: S-EPMC6303900 | biostudies-other | 2018 Dec

REPOSITORIES: biostudies-other