Glycogen synthase kinase 3β enhances hepatitis C virus replication by supporting miR-122

  • Hepatitis C virus (HCV) infection is associated with alterations in host lipid and insulin signaling cascades, which are partially explained by a dependence of the HCV life cycle on key molecules in these metabolic pathways. Yet, little is known on the role in the HCV life cycle of glycogen synthase kinase 3 (GSK3), one of the most important kinases in cellular metabolism. Therefore, the impact of GSK3 on the HCV life cycle was assessed in human hepatoma cell lines harboring subgenomic genotype 1b and 2a replicons or producing cell culture-derived HCV genotype 2a by exposure to synthetic GSK3 inhibitors, GSK3 gene silencing, overexpression of GSK3 constructs and immunofluorescence analyses. In addition, the role of GSK3 in hepatitis E virus (HEV) replication was investigated to assess virus specificity of the observed findings. We found that both inhibition of GSK3 function by synthetic inhibitors as well as silencing of GSK3β gene expression resulted in a decrease of HCV replication and infectious particle production, whereas silencing of the GSK3α isoform had no relevant effect on the HCV life cycle. Conversely, overexpression of GSK3β resulted in enhanced HCV replication. In contrast, GSK3β had no effect on replication of subgenomic HEV replicon. The pro-viral effect of GSK3β on HCV replication was mediated by supporting expression of microRNA-122 (miR-122), a micro-RNA which is mandatory for wild-type HCV replication, as GSK3 inhibitors suppressed miR-122 levels and as inhibitors of GSK3 had no antiviral effect on a miR-122-independent HCV mutant. In conclusion, we have identified GSK3β is a novel host factor supporting HCV replication by maintaining high levels of hepatic miR-122 expression.

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Author:Maged Saleh, Sabrina Rüschenbaum, Christoph Welsch, Stefan ZeuzemORCiDGND, Darius Moradpour, Jérôme Gouttenoire, Christian M. Lange
Pubmed Id:
Parent Title (English):Frontiers in microbiology
Publisher:Frontiers Media
Place of publication:Lausanne
Contributor(s):Shiu-Wan Chan
Document Type:Article
Year of Completion:2018
Date of first Publication:2018/11/27
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2019/03/05
Tag:GSK3α; GSK3β; hepatitis E virus; host-targeting antivirals; insulin resistance; miR-122
Issue:Art. 2949
Page Number:10
First Page:1
Last Page:10
Copyright © 2018 Saleh, Rüschenbaum, Welsch, Zeuzem, Moradpour, Gouttenoire and Lange. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0