IFN-λ4 desensitizes the response to IFN-α treatment in chronic hepatitis C through long-term induction of USP18

Fan, Wendy; Xie, Shiqi; Zhao, Xinhao; Li, Nan; Chang, Chong E.; Li, Li; Yu, Ge; Chi, Xiumei; Pan, Yu; Niu, Junqi; Zhong, Jin; Sun, Bing

doi:10.1099/jgv.0.000522

Cited by 21 publications

(15 citation statements)

References 40 publications

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“…USP18 was proposed as a key inhibitor of anti-HCV activity of IFNα (37, 49, 50), with attenuation of USP18 expression correlating with restoration of intrahepatic IFNα signaling and success of IFN-free HCV therapy (6, 9). Our analysis of ISG expression in liver biopsies pre- and post-treatment with DAA, showed that HCV-associated increase in USP18 expression occurred only in individuals that can produce IFN-λ4.…”

Section: Discussionmentioning

confidence: 99%

“…In PHH treated with IFN-λ4 compared to IFN-λ3, USP18 protein expression was induced faster (already at 8 hrs), but consequences of this faster induction on the IFN response are unclear. Treatment of a hepatic cell line (Huh7) with IFN-λ4 led to a sustained induction of USP18 , making cells refractory to IFNα stimulation, but kinetics of USP18 expression induced by IFN-λ4 vs. other IFNs was not explored (49). …”

Section: Discussionmentioning

confidence: 99%

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IFN-λ4 Attenuates Antiviral Responses by Enhancing Negative Regulation of IFN Signaling

Obajemu

Rao

Dilley

et al. 2017

The Journal of Immunology

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Type-III interferons (IFNs) are important mediators of antiviral immunity. IFN-λ4 is a unique type-III IFN because it is produced only in individuals who carry a dG allele of a genetic variant rs368234815-dG/TT. Counterintuitively, those individuals who can produce IFN-λ4, an antiviral cytokine, are also less likely to clear HCV infection. Here, we searched for unique functional properties of IFN-λ4 that might explain its negative effect on HCV clearance. We used fresh primary human hepatocytes (PHH) treated with recombinant type-III IFNs or infected with Sendai virus (SeV) to model acute viral infection, and subsequently validated our findings in HepG2 cell line models. Endogenous IFN-λ4 protein was detectable only in SeV-infected PHH from individuals with the dG allele, where it was poorly secreted but highly functional even at concentrations below 50 pg/ml. IFN-λ4 acted faster than other type-III IFNs in inducing antiviral genes as well as negative regulators of IFN response, such as USP18 and SOCS1. Transient treatment of PHH with IFN-λ4 but not IFN-λ3 caused a strong and sustained induction of SOCS1, and refractoriness to further stimulation with IFN-λ3. Our results suggest unique functional properties of IFN-λ4 that can be important in viral clearance and other clinical conditions.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

IFN-λ4 Attenuates Antiviral Responses by Enhancing Negative Regulation of IFN Signaling

Obajemu

Rao

Dilley

et al. 2017

The Journal of Immunology

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“…Recently, Fan et al . also demonstrated that IFN-λ4 inhibits the JAK–STAT signalling pathway by inducing USP18 expression 28 . However, our current study showed the expression of IFN-λ4 after HCV infection for the first time.…”

Section: Discussionmentioning

confidence: 98%

IFN-λ4 potently blocks IFN-α signalling by ISG15 and USP18 in hepatitis C virus infection

Sung

Hong

Chung

et al. 2017

Sci Rep

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Genetic polymorphisms in IFNL4 have been shown to predict responses to IFN-α-based therapy in hepatitis C virus (HCV)-infected patients. The IFNL4-ΔG genotype, which encodes functional IFN-λ4 protein, is associated with a poor treatment response. In the present study, we investigated the induction and biological effects of IFN-λ4 in HCV-infected hepatocytes and their association with responsiveness to IFN-α. We also studied the effects of direct-acting antiviral (DAA) treatment on IFN-λ4 expression and IFN-α responsiveness. HCV infection induced IFN-λ4 expression at mRNA and protein levels in primary human hepatocytes (PHHs). In hepatoma cells, IFNL4 gene transfection or recombinant IFN-λ4 protein treatment robustly increased the protein levels of ISG15 and USP18 in an IFNLR1-dependent manner and potently blocked IFN-α signalling. The ISG15/USP18-mediated IFN-α unresponsiveness was demonstrated by transfection of siRNAs targeting ISG15 and/or USP18. This potent IFN-λ4 effect was related to prolonged ISG expression after IFNL4 gene transfection. DAA treatment of HCV-infected PHHs reduced the expression of IFN-λs, including IFN-λ4, and restored IFN-α responsiveness. These results demonstrate that virus-induced IFN-λ4 potently blocks IFN-α signalling by inducing high protein levels of ISG15 and USP18. Moreover, the data clearly demonstrate that DAA therapy restores IFN-α responsiveness in HCV-infected cells.

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“…HCV clearance was also associated with more rapid down-regulation of endogenous hepatic ISGs. Studies from our group and others clearly demonstrated that USP18 play a critical role in host innate immune response against HBV and HCV infections [ 11 , 26 , 27 ].…”

Section: Discussionmentioning

confidence: 99%

Insulin receptor substrate-4 interacts with ubiquitin-specific protease 18 to activate the Jak/STAT signaling pathway

et al. 2017

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Ubiquitin-specific protease 18 (USP18) as a negative regulator of the Jak/STAT signaling pathway plays an important role in the host innate immune response. USP18 has been shown to bind to the type I interferon receptor subunit 2 (IFNAR2) to down-regulate the Jak/STAT signaling. In this study, we showed that insulin receptor substrate (IRS)-4 functioned as a novel USP18-binding protein. Co-precipitation assays revealed that two regions (amino acids 335–400 and 1094-1257) of IRS4 were related to bind to the C- terminal region of USP18. IRS4 binding to USP18 diminished the inhibitory effect of USP18 on Jak/STAT signaling. IRS4 over-expression enhanced while IRS4 knock-down suppressed the Jak/STAT signaling in the presence of IFN-a stimulation. As such, IRS4 increased IFN-a-mediated anti-HCV activity. Mechanistically, IRS4 promoted the IFN-a-induced Jak/STAT signaling by interact with USP18. These results suggested that IRS4 binds to USP18 to diminish the blunting effect of USP18 on IFN-a-induced Jak/STAT signaling. Our findings indicated that IRS4 is a novel USP18-binding protein that can be used to boost the host innate immunity to control HCV, and potentially other viruses that are sensitive to IFN-a.

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IFN-λ4 desensitizes the response to IFN-α treatment in chronic hepatitis C through long-term induction of USP18

Cited by 21 publications

References 40 publications

IFN-λ4 Attenuates Antiviral Responses by Enhancing Negative Regulation of IFN Signaling

IFN-λ4 Attenuates Antiviral Responses by Enhancing Negative Regulation of IFN Signaling

IFN-λ4 potently blocks IFN-α signalling by ISG15 and USP18 in hepatitis C virus infection

Insulin receptor substrate-4 interacts with ubiquitin-specific protease 18 to activate the Jak/STAT signaling pathway

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