Myxovirus resistance protein A inhibits hepatitis C virus replication through JAK-STAT pathway activation
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.
We thank Prof. Qingzhen Liu (College of Life Science, Wuhan University, China) for helpful comments and critical reading of the manuscript. We are also grateful to Dr. Xinwen Chen, Dr. Takaji Wakita, and Dr. Huang Zan for generously providing reagents. This work was supported by the National Natural Sciences Foundation of China (No. 31370185), the National Basic Research Program of China (No. 2011CB504800), the National Infrastructure of Natural Resources for Science and Technology Program (No.2011-572) to Prof. C Zheng, and the National Science and Technology Infrastructure Grant NSTI-CR15 and NSTI-CR16 to Dr. Chao Shen.
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Conflict of interests
The authors declare that they have no competing interests.
This article does not contain any studies with human participants or animals performed by any of the authors.
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