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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.
Highlights
As one of the key effectors in the innate immune system, type I interferon (IFN) plays diverse roles in host defense against virus infection and has been recommended or studied as important/potential therapy in patients with virus infections such as hepatitis B virus (HBV) [1], hepatitis C virus (HCV) [2], hepatitis D virus (HDV) [3], and enterovirus 71 [4]
Our findings demonstrated that Ubiquitin-specific protease 18 (USP18) could create a cellular milieu that favored HCV and stimulated HCV production in a manner that was independent of interferon-stimulated gene 15 (ISG15)
Wild-type USP18-GFP fusion protein was expressed in Huh7.5 cells with an appropriate dose-response pattern (Figure 1(a)), and the transfection efficiency was shown by the GFP expression in the cells (Supplement Figure 1)
Summary
As one of the key effectors in the innate immune system, type I interferon (IFN) plays diverse roles in host defense against virus infection and has been recommended or studied as important/potential therapy in patients with virus infections such as hepatitis B virus (HBV) [1], hepatitis C virus (HCV) [2], hepatitis D virus (HDV) [3], and enterovirus 71 [4]. Type I IFN signaling is a “double-edged sword” [5], because it confers complicated action by regulating the expression of various interferon-stimulated genes (ISGs), which on the one hand control virus replication but on the other hand are involved in persistent viral infection. It is such an important target for which viruses, such as HCV, developed special survival strategies to evade host immune attack and benefit their replication. 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
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