Abstract
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.
Highlights
Hepatitis C virus is a member of the Flaviviridae family which has a positive-sense single-stranded RNA genome (Lange et al, 2014b)
In view of remarkable associations between Hepatitis C virus (HCV) and metabolic traits, we have investigated the role in the HCV life cycle of glycogen synthase kinase 3 (GSK3), a key kinase in glucose metabolism and numerous other cellular processes
A recent study has shown that HCV functionally regulates miR-122 within hepatocytes, which results in a de-repression of miR-122 target genes in the presence of HCV and which may partially explain the oncogenic potential of chronic hepatitis C (Luna et al, 2015)
Summary
Hepatitis C virus is a member of the Flaviviridae family which has a positive-sense single-stranded RNA genome (Lange et al, 2014b). GSK3, miR-122 and Hepatitis C depends (Lange et al, 2014b) Though most of these host factors are cellular proteins, a liver-specific micro-RNA (miR-122) has been identified which is mandatory for HCV replication and which is (at least partially) responsible for the hepatotropism of this virus (Lange et al, 2014b). While the effects of HCV infection on glucose metabolism are clearly documented in vivo and in vitro, the benefit of these alterations for the virus remains largely unclear (Petta et al, 2010; Negro, 2014), insulin resistance was identified as a negative predictor of outcome of interferon-based therapies (Romero-Gómez et al, 2005; Dai et al, 2009; Grasso et al, 2009; Moucari et al, 2009; Khattab et al, 2010; Fattovich et al, 2011)
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