Abstract
Hepatitis C virus (HCV) is associated with various liver diseases. Chronic HCV infection is characterized by an abnormal host immune response. Therefore, it is speculated that to suppress HCV, a well-regulated host immune response is necessary. 2-O-methylhonokiol was identified by the screening of anti-HCV compounds using Renilla luciferase assay in Huh 7.5/Con 1 genotype 1b replicon cells. Here, we investigated the mechanism by which 2-O-methylhonokiol treatment inhibits HCV replication using real-time PCR. Our data shows that treatment with 2-O-methylhonokiol activated innate immune responses via nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) pathway. Additionally, the immunoprecipitation result shows that treatment with 2-O-methylhonokiol augmented tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6) by preventing p62 from binding to TRAF6, resulting in reduced autophagy caused by HCV. Finally, we reproduced our data with the conditioned media from 2-O-methylhonokiol-treated cells. These findings strongly suggest that 2-O-methylhonokiol enhances the host immune response and suppresses HCV replication via TRAF6-mediated NF-kB activation.
Highlights
As a result of repeated quantitative analysis of Hepatitis C virus (HCV) replication, it was confirmed that 2-O-methylhonokiol inhibited HCV replication by more than 50% relative to that in equal volume DMSO-treated cells (Figure 1b)
We found that the physical binding of p62 and TRAF6 was abolished by 2-O-methylhonokiol treatment, especially at 48 h, suggesting that treatment with 2-O-methylhonokiol may decrease autophagy (Figure 4c)
We found that HCV replication was inhibited by activation of the TRAF6-mediated nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) by inhibiting depletion of the TRAF6, which became autophagic degradation by p62 in HCV replication
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Hepatitis C virus (HCV) infection causes chronic liver diseases such as liver cirrhosis and liver cancer [1]. There are a total of seven genotypes of HCV [2], which include separate genotypes that are infected by race [3]. HCV genotype 1 has the highest incidence in the world of 46.2% [4]. Of the 53% of genotype 1 cases for which the subtype was specified, 99% were subtypes 1a and 1b ((31% and 68%), respectively) [4]
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