Abstract
Previous studies have shown that mycophenolic acid (MPA) has an anti-HCV activity. However, the mechanism of MPA-mediated inhibition of HCV replication remains to be determined. This study investigated whether MPA has an effect on autophagy, a cellular machinery required for HCV replication, thereby, inhibits HCV replication in Huh7 cells. MPA treatment of Huh7 cells could suppress autophagy, evidenced by decreased LC3B-II level and conversion of LC3B-I to LC3B-II, decreased autophagosome formation, and increased p62 level compared to MPA-untreated cells. Tunicamycin treatment or HCV infection could induce cellular autophagy, however, MPA also exhibited its inhibitory effect on tunicamycin- or HCV infection-induced autophagy. The expression of three autophagy-related genes, Atg3, Atg5, and Atg7 were identified to be inhibited by MPA treatment. Over-expression of these genes could partly recover HCV replication inhibited by MPA; however, silencing their expression by siRNAs could enhance the inhibitory effect of MPA on HCV. Collectively, these results reveal that suppression of autophagy by MPA plays a role in its anti-HCV activity. Down-regulating the expression of three autophagy-related genes by MPA involves in its antiviral mechanism.
Highlights
Cyclosporine in organ transplantations as well as treatments for acute rejection[9,10]
The inhibition concentration of mycophenolic acid (MPA) is in the range of 0.1 μg/mL to 6 μg/mL, and the inhibitory effect of MPA on Hepatitis C virus (HCV) replication is in a dose-dependent manner
On the contrary, decreased p62 levels were observed (Fig. 6c,d). These results indicate that overexpression of ATG3, ATG5 or ATG7 enhances cellular autophagy, along with partially restores HCV replication inhibited by MPA treatment
Summary
Cyclosporine in organ transplantations as well as treatments for acute rejection[9,10]. The general antiviral mechanisms of MPA are believed to involve in two aspects, guanosine depletion and enhancement of interferon (IFN)-stimulated genes (ISGs) expression[21,22]. Both mechanisms could not fully explain the inhibitory effect on HCV replication by MPA22,23, suggesting that other mechanisms be involved. A number of autophagy-related proteins, including Beclin 1, LC3, Atg4B, Atg[5], Atg[7] and Atg[12], have been identified to be required for productive HCV infection[24,25,26,27] These proteins are beneficial for HCV replication, through modulating the onset of translation of incoming HCV RNA or contributing to HCV particle assembly and/or secretion[24,25,26,27,28]. We investigated whether MPA blocks the autophagy in human hepatoma cells, thereby, inhibits HCV infection/replication in cells
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