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

Abstract 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 in...

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Autores principales:	Pil Soo Sung, Seon-Hui Hong, Jae-Hee Chung, Sojeong Kim, Su-Hyung Park, Ho Min Kim, Seung Kew Yoon, Eui-Cheol Shin
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/00500f4a1f294b1196287c799b731f7a
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spelling	oai:doaj.org-article:00500f4a1f294b1196287c799b731f7a2021-12-02T11:40:50ZIFN-λ4 potently blocks IFN-α signalling by ISG15 and USP18 in hepatitis C virus infection10.1038/s41598-017-04186-72045-2322https://doaj.org/article/00500f4a1f294b1196287c799b731f7a2017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-04186-7https://doaj.org/toc/2045-2322Abstract 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.Pil Soo SungSeon-Hui HongJae-Hee ChungSojeong KimSu-Hyung ParkHo Min KimSeung Kew YoonEui-Cheol ShinNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-9 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Pil Soo Sung Seon-Hui Hong Jae-Hee Chung Sojeong Kim Su-Hyung Park Ho Min Kim Seung Kew Yoon Eui-Cheol Shin IFN-λ4 potently blocks IFN-α signalling by ISG15 and USP18 in hepatitis C virus infection
description	Abstract 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.
format	article
author	Pil Soo Sung Seon-Hui Hong Jae-Hee Chung Sojeong Kim Su-Hyung Park Ho Min Kim Seung Kew Yoon Eui-Cheol Shin
author_facet	Pil Soo Sung Seon-Hui Hong Jae-Hee Chung Sojeong Kim Su-Hyung Park Ho Min Kim Seung Kew Yoon Eui-Cheol Shin
author_sort	Pil Soo Sung
title	IFN-λ4 potently blocks IFN-α signalling by ISG15 and USP18 in hepatitis C virus infection
title_short	IFN-λ4 potently blocks IFN-α signalling by ISG15 and USP18 in hepatitis C virus infection
title_full	IFN-λ4 potently blocks IFN-α signalling by ISG15 and USP18 in hepatitis C virus infection
title_fullStr	IFN-λ4 potently blocks IFN-α signalling by ISG15 and USP18 in hepatitis C virus infection
title_full_unstemmed	IFN-λ4 potently blocks IFN-α signalling by ISG15 and USP18 in hepatitis C virus infection
title_sort	ifn-λ4 potently blocks ifn-α signalling by isg15 and usp18 in hepatitis c virus infection
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/00500f4a1f294b1196287c799b731f7a
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IFN-λ4 potently blocks IFN-α signalling by ISG15 and USP18 in hepatitis C virus infection

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