The Ubiquitin-Specific Protease 18 Promotes Hepatitis C Virus Production by Increasing Viral Infectivity

Mediators Inflamm. 2019 Nov 18:2019:3124745. doi: 10.1155/2019/3124745. eCollection 2019.

Abstract

Background and aims: Ubiquitin-specific protease 18 (USP18) is involved in immunoregulation and response to interferon- (IFN-) based treatment in patients chronically infected with hepatitis C virus (HCV). We investigated whether and how its upregulation alters HCV infection.

Methods: Overexpression of wild-type (USP18 WT) or catalytically inactive mutant (USP18 C64S) USP18 was examined for effects on HCV replication in the absence and presence of IFNα or IFNλ using both the HCV-infective model and replicon cells. The IFN signaling pathway was assessed via STAT1 phosphorylation (western blot) and downstream ISG expression (real-time PCR). Mechanistic roles were sought by quantifying microRNA-122 levels and J6/JFH1 infectivity of Huh7.5 cells.

Results: We found that overexpression of either USP18 WT or USP18 C64S stimulated HCV production and blunted the anti-HCV effect of IFNα and IFNλ in the infective model but not in the replicon system. Overexpressed USP18 showed no effect on Jak/STAT signaling nor on microRNA-122 expression. However, USP18 upregulation markedly increased J6/JFH1 infectivity and promoted the expression of the key HCV entry factor CD81 on Huh7.5 cells.

Conclusions: USP18 stimulates HCV production and blunts the effect of both type I and III IFNs by fostering a cellular environment characterized by upregulation of CD81, promoting virus entry and infectivity.

MeSH terms

  • Cell Line
  • Hepacivirus / pathogenicity*
  • Hepacivirus / physiology*
  • Humans
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • Plasmids / genetics
  • Tetraspanin 28 / genetics
  • Tetraspanin 28 / metabolism
  • Ubiquitin Thiolesterase / genetics
  • Ubiquitin Thiolesterase / metabolism*
  • Ubiquitin-Specific Proteases / genetics
  • Ubiquitin-Specific Proteases / metabolism*

Substances

  • MIRN122 microRNA, human
  • MicroRNAs
  • Tetraspanin 28
  • USP18 protein, human
  • Ubiquitin Thiolesterase
  • Ubiquitin-Specific Proteases