Abstract
The interferon-inducible dynamin-like GTPase myxovirus resistance protein A (MxA) exhibits activity against multiple viruses. However, its role in the life cycle of hepatitis C virus (HCV) is unclear, and the mechanisms underlying the anti-HCV activity of MxA require further investigation. In this study, we demonstrated that exogenous MxA expression in the Huh7 and Huh7.5.1 hepatoma cell lines significantly decreased the levels of HCV RNA and core proteins, whereas MxA knockdown exerted the opposite effect. MxA-mediated inhibition of HCV replication was found to involve the JAK-STAT pathway: STAT1 phosphorylation and the expression of IFN-stimulated genes (ISGs) such as guanylate-binding protein 1 and 2'-5'-oligoadenylate synthetase 1 were augmented by MxA overexpression and reduced by endogenous MxA silencing. Treatment with the JAK inhibitor ruxolitinib abrogated the MxA-mediated suppression of HCV replication and activation of the JAK-STAT pathway. Additionally, transfection with an MxA mutant with disrupted GTP-binding consensus motifs abrogated activation of the JAK-STAT pathway and resistance to HCV replication. This study shows that MxA inhibits HCV replication by activating the JAK-STAT signaling pathway through a mechanism involving its GTPase function.