Archives of Virology

, Volume 163, Issue 6, pp 1429–1438 | Cite as

Myxovirus resistance protein A inhibits hepatitis C virus replication through JAK-STAT pathway activation

  • Hailong Wang
  • Xiu Xin
  • Mingzhen Wang
  • Lingling Han
  • Jiadai Li
  • Yao Hao
  • Congyi Zheng
  • Chao Shen
Original Article


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.

Compliance with ethical standards

Conflict of interests

The authors declare that they have no competing interests.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.


  1. 1.
    Aly HH, Shimotohno K, Hijikata M, Seya T (2012) In vitro models for analysis of the hepatitis C virus life cycle. Microbiol Immunol 56:1–9CrossRefPubMedGoogle Scholar
  2. 2.
    Blindenbacher A, Duong FH, Hunziker L, Stutvoet ST, Wang X, Terracciano L, Moradpour D, Blum HE, Alonzi T, Tripodi M, La Monica N, Heim MH (2003) Expression of hepatitis c virus proteins inhibits interferon alpha signaling in the liver of transgenic mice. Gastroenterology 124:1465–1475CrossRefPubMedGoogle Scholar
  3. 3.
    Chen Q, Denard B, Huang H, Ye J (2013) Epigenetic silencing of antiviral genes renders clones of Huh-7 cells permissive for hepatitis C virus replication. J Virol 87:659–665CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Cheng JC, Yeh YJ, Huang YH, Liang KH, Chang ML, Lin CY, Yeh CT (2012) Hepatic expression of MxA and OAS1 in an ex vivo liver slice assay independently predicts treatment outcomes in chronic hepatitis C. J Viral Hepat 19:154–162CrossRefGoogle Scholar
  5. 5.
    Feld JJ, Foster GR (2016) Second generation direct-acting antivirals—do we expect major improvements? J Hepatol 65:130–142CrossRefGoogle Scholar
  6. 6.
    Frese M, Pietschmann T, Moradpour D, Haller O, Bartenschlager R (2001) Interferon-α inhibits hepatitis C virus subgenomic RNA replication by an MxA-independent pathway. J Gen Virol 82:723–733CrossRefPubMedGoogle Scholar
  7. 7.
    Gale M Jr, Foy EM (2005) Evasion of intracellular host defence by hepatitis C virus. Nature 436:939–945CrossRefPubMedGoogle Scholar
  8. 8.
    Haller O, Kochs G (2011) Human MxA protein: an interferon-induced dynamin-like GTPase with broad antiviral activity. J Interferon Cytokine Res 31:79–87CrossRefPubMedGoogle Scholar
  9. 9.
    Haller O, Staeheli P, Schwemmle M, Kochs G (2015) Mx GTPases: dynamin-like antiviral machines of innate immunity. Trends Microbiol 23:154–163CrossRefPubMedGoogle Scholar
  10. 10.
    Hamdi N, El-Akel W, El-Serafy M, Esmat G, Sarrazin C, Abdelaziz AI (2012) Transcriptional response of MxA, PKR and SOCS3 to interferon-based therapy in HCV genotype 4-infected patients and contribution of p53 to host antiviral response. Intervirology 55:210–218CrossRefPubMedGoogle Scholar
  11. 11.
    Heim MH, Moradpour D, Blum HE (1999) Expression of hepatitis C virus proteins inhibits signal transduction through the Jak-STAT pathway. J Virol 73:8469–8475PubMedPubMedCentralGoogle Scholar
  12. 12.
    Hilgenfeldt EG, Schlachterman A, Firpi RJ (2015) Hepatitis C: treatment of difficult to treat patients. World J Hepatol 7:1953–1963CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Itsui Y, Sakamoto N, Kurosaki M, Kanazawa N, Tanabe Y, Koyama T, Takeda Y, Nakagawa M, Kakinuma S, Sekine Y, Maekawa S, Enomoto N, Watanabe M (2006) Expressional screening of interferon-stimulated genes for antiviral activity against hepatitis C virus replication. J Viral Hepat 13:690–700CrossRefPubMedGoogle Scholar
  14. 14.
    Lan KH, Lan KL, Lee WP, Sheu ML, Chen MY, Lee YL, Yen SH, Chang FY, Lee SD (2007) HCV NS5A inhibits interferon-alpha signaling through suppression of STAT1 phosphorylation in hepatocyte-derived cell lines. J Hepatol 46:759–767CrossRefPubMedGoogle Scholar
  15. 15.
    Moradpour D, Penin F, Rice CM (2007) Replication of hepatitis C virus. Nat Rev Microbiol 5:453–463CrossRefPubMedGoogle Scholar
  16. 16.
    Petruzziello A, Marigliano S, Loquercio G, Cozzolino A, Cacciapuoti C (2016) Global epidemiology of hepatitis C virus infection: An up-date of the distribution and circulation of hepatitis C virus genotypes. World J Gastroenterol 22:7824–7840CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Pitossi F, Blank A, Schroder A, Schwarz A, Hussi P, Schwemmle M, Pavlovic J, Staeheli P (1993) A functional GTP-binding motif is necessary for antiviral activity of Mx proteins. J Virol 67:6726–6732PubMedPubMedCentralGoogle Scholar
  18. 18.
    Saito T, Gale M Jr (2007) Principles of intracellular viral recognition. Curr Opin Immunol 19:17–23CrossRefPubMedGoogle Scholar
  19. 19.
    Samuel CE (2001) Antiviral actions of interferons. Clin Microbiol Rev 14:778–809 (table of contents) CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Shaker OG, Abdel-Rahim MT, Bayoumi ST (2015) Gene polymorphisms of IL-10 and MxA in responders and non-responders to interferon therapy in HCV Egyptian patients genotype 4. Cell Biochem Biophys 71:617–625CrossRefPubMedGoogle Scholar
  21. 21.
    Shi XZ, Jiao BH, Chen YZ, Li SL, Chen LM (2017) MxA is a positive regulator of type I IFN signaling in HCV infection. J Med Virol 89:2173–2180CrossRefPubMedGoogle Scholar
  22. 22.
    Stevenson NJ, Murphy AG, Bourke NM, Keogh CA, Hegarty JE, O’Farrelly C (2011) Ribavirin enhances IFN-alpha signalling and MxA expression: a novel immune modulation mechanism during treatment of HCV. PLoS One 6:e27866CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Suzuki F, Arase Y, Suzuki Y, Tsubota A, Akuta N, Hosaka T, Someya T, Kobayashi M, Saitoh S, Ikeda K, Kobayashi M, Matsuda M, Takagi K, Satoh J, Kumada H (2004) Single nucleotide polymorphism of the MxA gene promoter influences the response to interferon monotherapy in patients with hepatitis C viral infection. J Viral Hepat 11:271–276CrossRefPubMedGoogle Scholar
  24. 24.
    Takaoka A, Yanai H (2006) Interferon signalling network in innate defence. Cell Microbiol 8:907–922CrossRefPubMedGoogle Scholar
  25. 25.
    Thomas E, Gonzalez VD, Li Q, Modi AA, Chen W, Noureddin M, Rotman Y, Liang TJ (2012) HCV infection induces a unique hepatic innate immune response associated with robust production of type III interferons. Gastroenterology 142:978–988CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Verhelst J, Parthoens E, Schepens B, Fiers W, Saelens X (2012) Interferon-inducible protein Mx1 inhibits influenza virus by interfering with functional viral ribonucleoprotein complex assembly. J Virol 86:13445–13455CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Verhelst J, Hulpiau P, Saelens X (2013) Mx proteins: antiviral gatekeepers that restrain the uninvited. Microbiol Mol Biol Rev 77:551–566CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Xiong W, Yang J, Wang M, Wang H, Rao Z, Zhong C, Xin X, Mo L, Yu S, Shen C, Zheng C (2015) Vinexin beta interacts with hepatitis C virus NS5A, modulating its hyperphosphorylation to regulate viral propagation. J Virol 89:7385–7400CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Xu G, Xin X, Zheng C (2013) GPS2 is required for the association of NS5A with VAP-A and hepatitis C virus replication. PLoS One 8:e78195CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Yamauchi S, Takeuchi K, Chihara K, Honjoh C, Kato Y, Yoshiki H, Hotta H, Sada K (2016) STAT1 is essential for the inhibition of hepatitis C virus replication by interferon-lambda but not by interferon-alpha. Sci Rep 6:38336CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Yuan B, Fang H, Shen C, Zheng C (2015) Expression of porcine Mx1 with FMDV IRES enhances the antiviral activity against foot-and-mouth disease virus in PK-15 cells. Arch Virol 160:1989–1999CrossRefPubMedGoogle Scholar
  32. 32.
    Zhang L, Jilg N, Shao RX, Lin W, Fusco DN, Zhao H, Goto K, Peng LF, Chen WC, Chung RT (2011) IL28B inhibits hepatitis C virus replication through the JAK-STAT pathway. J Hepatol 55:289–298CrossRefPubMedGoogle Scholar
  33. 33.
    Zhao LJ, He SF, Liu Y, Zhao P, Bian ZQ, Qi ZT (2016) Inhibition of STAT Pathway Impairs Anti-Hepatitis C Virus Effect of Interferon Alpha. Cell Physiol Biochem Int J Exp Cell Physiol Biochem Pharmacol 40:77–90CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Austria, part of Springer Nature 2018

Authors and Affiliations

  • Hailong Wang
    • 1
  • Xiu Xin
    • 1
  • Mingzhen Wang
    • 1
  • Lingling Han
    • 1
  • Jiadai Li
    • 1
  • Yao Hao
    • 1
  • Congyi Zheng
    • 1
    • 2
  • Chao Shen
    • 1
    • 2
  1. 1.State Key Laboratory of Virology, School of Life SciencesWuhan UniversityWuhanPeople’s Republic of China
  2. 2.China Center for Type Culture CollectionWuhan UniversityWuhanChina

Personalised recommendations