title: Type I interferon inhibits varicella-zoster virus replication by interfering with the dynamic interaction between mediator and IE62 within replication compartments.
abstract: BACKGROUND
  Varicella-zoster virus (VZV) is the causative agent of varicella and zoster. The immediate-early protein, IE62 is the predominant VZ virion tegument protein, transactivating the expression of all kinetic classes of VZV genes. IE62 is localized to punctae that form DNA replication compartments in the nuclei of VZV infected cells. The morphological changes and the increase in the size of replication compartments that express IE62 are correlated with production of VZ virions. Mammalian Mediator serves as a coactivator of IE62 and functions by bridging DNA-binding transcription factors¸ RNA polymerase II (RNAP II) and their target DNAs for VZV replication. While VZV is highly sensitive to type I interferons (IFNs), how IFN-α inhibits early events during VZV replication is poorly understood.
  
  
  RESULTS
  In this study, we performed in situ analysis to investigate the effects of IFN-α on the dynamic interactions of IE62 with the Mediator MED25 subunit and the RNAP II negative regulator cycle-dependent kinase 8 (CDK8) in VZV infected cells by confocal immunofluorescence. We found that in addition to dose-dependent inhibition of the yields of infectious virus by IFN treatment, IFN-α prominently impeded the development of large IE62(+) nuclear compartments and significantly decreased transcription of VZV genes. Both the expression level and stable recruitment of MED25 to IE62(+) replication compartments were inhibited by IFN-α. While IFN-α treatment upregulated CDK8 expression, redistribution and recruitment of CDK8 to IE62(+) replication compartments in infected cells was not affected by VZV.
  
  
  CONCLUSIONS
  IFN-α exerts multiple inhibitory activities against virus infections. In this study, we provide visionary demonstration that continuous translocation of MED25 into VZV replication compartments ensures production of virions. IFN-α greatly impedes the formation of a stable complex between IE62 and the Mediator complex thereby suppresses VZV gene transcription. Our demonstration that IFN-α-induced antiviral effect against VZV infection is through inhibiting the reorganization of nuclear components uncovers a novel function of IFN-α. Targeting the interaction between IE62 and MED25 may offer a novel approach to the development of antiviral agents against VZV infection.
authors.affiliation: Institute of Immunology, College of Medicine, National Taiwan University, No.1 Section 1 Jen-Ai Road, Taipei, Taiwan.
authors.forename: Chia-Chi
authors.identifier: 0000-0002-5740-1505
authors.initials: CC
authors.lastname: Ku
authors.affiliation: Institute of Immunology, College of Medicine, National Taiwan University, No.1 Section 1 Jen-Ai Road, Taipei, Taiwan.
authors.forename: Yi-Hsuan
authors.initials: YH
authors.lastname: Chang
authors.affiliation: Institute of Immunology, College of Medicine, National Taiwan University, No.1 Section 1 Jen-Ai Road, Taipei, Taiwan.
authors.forename: Yun
authors.initials: Y
authors.lastname: Chien
authors.affiliation: Institute of Immunology, College of Medicine, National Taiwan University, No.1 Section 1 Jen-Ai Road, Taipei, Taiwan.
authors.forename: Tsung-Lin
authors.initials: TL
authors.lastname: Lee
keywords: IE62; Mediator complex; Replication compartment; Type I interferons; Varicella-zoster virus