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IFN-?4 potently blocks IFN-? signalling by ISG15 and USP18 in hepatitis C virus infection.

ABSTRACT: Genetic polymorphisms in IFNL4 have been shown to predict responses to IFN-?-based therapy in hepatitis C virus (HCV)-infected patients. The IFNL4-?G genotype, which encodes functional IFN-?4 protein, is associated with a poor treatment response. In the present study, we investigated the induction and biological effects of IFN-?4 in HCV-infected hepatocytes and their association with responsiveness to IFN-?. We also studied the effects of direct-acting antiviral (DAA) treatment on IFN-?4 expression and IFN-? responsiveness. HCV infection induced IFN-?4 expression at mRNA and protein levels in primary human hepatocytes (PHHs). In hepatoma cells, IFNL4 gene transfection or recombinant IFN-?4 protein treatment robustly increased the protein levels of ISG15 and USP18 in an IFNLR1-dependent manner and potently blocked IFN-? signalling. The ISG15/USP18-mediated IFN-? unresponsiveness was demonstrated by transfection of siRNAs targeting ISG15 and/or USP18. This potent IFN-?4 effect was related to prolonged ISG expression after IFNL4 gene transfection. DAA treatment of HCV-infected PHHs reduced the expression of IFN-?s, including IFN-?4, and restored IFN-? responsiveness. These results demonstrate that virus-induced IFN-?4 potently blocks IFN-? signalling by inducing high protein levels of ISG15 and USP18. Moreover, the data clearly demonstrate that DAA therapy restores IFN-? responsiveness in HCV-infected cells.

SUBMITTER: Sung PS

PROVIDER: S-EPMC5476576 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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

Sung Pil Soo PS Hong Seon-Hui SH Chung Jae-Hee JH Kim Sojeong S Park Su-Hyung SH Kim Ho Min HM Yoon Seung Kew SK Shin Eui-Cheol EC

Scientific reports 20170619 1

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 express ...[more]

PMID: 28630501

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Project description:The interferon (IFN)-stimulated gene product 15 (ISG15) represents an ubiquitin-like protein (Ubl), which in a process termed ISGylation can be covalently linked to target substrates via a cascade of E1, E2, and E3 enzymes. Furthermore, ISG15 exerts functions in its free form both, as an intracellular and as a secreted protein. In agreement with its role as a type I IFN effector, most functions of ISG15 and ISGylation are linked to the anti-pathogenic response. However, also key roles in other cellular processes such as protein translation, cytoskeleton dynamics, exosome secretion, autophagy or genome stability and cancer were described. Ubiquitin-specific protease 18 (USP18) constitutes the major ISG15 specific protease which counteracts ISG15 conjugation. Remarkably, USP18 also functions as a critical negative regulator of the IFN response irrespective of its enzymatic activity. Concordantly, lack of USP18 function causes fatal interferonopathies in humans and mice. The negative regulatory function of USP18 in IFN signaling is regulated by various protein-protein interactions and its stability is controlled via proteasomal degradation. The broad repertoire of physiological functions and regulation of ISG15 and USP18 offers a variety of potential intervention strategies which might be of therapeutic use. Due to the high mutation rates of pathogens which are often species specific and constantly give rise to a variety of immune evasion mechanisms, immune effector systems are under constant evolutionarily pressure. Therefore, it is not surprising that considerable differences in ISG15 with respect to function and sequence exist even among closely related species. Hence, it is essential to thoroughly evaluate the translational potential of results obtained in model organisms especially for therapeutic strategies. This review covers existing and conceptual assay systems to target and identify modulators of ISG15, ISGylation, USP18 function, and protein-protein interactions within this context. Strategies comprise mouse models for translational perspectives, cell-based and biochemical assays as well as chemical probes.

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IFN-?4 potently blocks IFN-? signalling by ISG15 and USP18 in hepatitis C virus infection.

Publications

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

Similar Datasets

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