Archives of Virology

, Volume 153, Issue 9, pp 1677–1684

GTPase activity is not essential for the interferon-inducible MxA protein to inhibit the replication of hepatitis B virus

  • Zhijian Yu
  • Zhanhui Wang
  • Jinjun Chen
  • Hui Li
  • Zhanzhou Lin
  • Fan Zhang
  • Yuanping Zhou
  • Jinlin Hou
Original Article

Abstract

Multiple studies have established that GTPase activity is critical for MxA to act against RNA viruses. Recently, it was shown that MxA can also restrict the replication of hepatitis B virus (HBV), a DNA virus, but the requirements for GTPase activity in inhibition of HBV by MxA remain unknown. Here, we report that GTPase-defective mutants (K83A, T103A, and L612K) can downregulate extracellullar HBsAg and HBeAg and reduce the expression of extra- and intracellular HBV DNA in HepG2 cells to levels similar to that achieved by wild-type MxA. Furthermore, TMxA and T103, two nuclear forms of wild-type MxA and a GTPase-defective mutant (T103A) could only slightly decrease the expression of extra- and intracellular HBV DNA in HepG2 cells. In conclusion, GTPase activity is not essential for MxA protein to inhibit HBV replication, and MxA may have only a minimal effect on the replicative cycle of HBV in the nucleus.

References

  1. 1.
    Staeheli P, Pitossi F, Pavlovic J (1993) Mx proteins: GTPases with antiviral activity. Trends Cell Biol 3:268–272PubMedCrossRefGoogle Scholar
  2. 2.
    Chen MS, Obar RA, Schroeder CC, Austin TW, Poodry CA, Wadsworth SC, Vallee RB (1991) Multiple forms of dynamin are encoded by shibire, a Drosophila gene involved in endocytosis. Nature 351:583–596PubMedCrossRefGoogle Scholar
  3. 3.
    Janzen C, Kochs G, Haller O (2000) A monomeric GTPase-negative MxA mutant with antiviral activity. J Virol 74:8202–8206PubMedCrossRefGoogle Scholar
  4. 4.
    Pitossi F, Blank A, Schröder A, Schwarz A, Hüssi P, Schwemmle M, Pavlovic J, Staeheli P (1993) A functional GTP binding motif is necessary for antiviral activity of Mx proteins. J Virol 67:6726–6732PubMedGoogle Scholar
  5. 5.
    Haller O, Kochs G (2002) Interferon-induced mx proteins: dynamin-like GTPases with antiviral activity. Traffic 3:710–717PubMedCrossRefGoogle Scholar
  6. 6.
    Accola MA, Huang B, Al Masri A, McNiven MA (2002) The antiviral dynamin family member, MxA, tubulates lipids and localizes to the smooth endoplasmic reticulum. J Biol Chem 277:21829–21835PubMedCrossRefGoogle Scholar
  7. 7.
    Haller O, Frese M, Kochs G (1998) Mx proteins: mediators of innate resistance to RNA viruses. Rev Sci Tech 17:220–230PubMedGoogle Scholar
  8. 8.
    Kochs G, Janzen C, Hohenberg H, Haller O (2002) Antivirally active MxA protein sequesters La Crosse virus nucleocapsid protein into perinuclear complexes. Proc Natl Acad Sci USA 99:3154–3159CrossRefGoogle Scholar
  9. 9.
    Gordien E, Rosmorduc O, Peltekian C, Garreau F, Brechot C, Kremsdorf D (2001) Inhibition of hepatitis B virus replication by the interferon-inducible MxA protein. J Virol 75:2684–2691PubMedCrossRefGoogle Scholar
  10. 10.
    Rosmorduc O, Sirma H, Soussan P, Gordien E, Lebon P, Horisberger M, Bréchot C (1999) Inhibition of interferon-inducible MxA protein expression by hepatitis B virus capsid protein. J Gen Virol 80:1253–1262PubMedGoogle Scholar
  11. 11.
    Peltekian C, Gordien E, Garreau F, Meas-Yedid V, Soussan P, Willams V, Chaix ML, Olivo-Marin JC, Bréchot C, Kremsdorf D (2005) Human MxA protein participates to the interferon-related inhibition of hepatitis B virus replication in female transgenic mice. J Hepatol 43:965–972PubMedCrossRefGoogle Scholar
  12. 12.
    Lussier MP, Cayouette S, Lepage PK, Bernier CL, Francoeur N, St-Hilaire M, Pinard M, Boulay G (2005) MxA, a member of the dynamin superfamily, interacts with the ankyrin-like repeat domain of TRPC. J Biol Chem 280:19393–19400PubMedCrossRefGoogle Scholar
  13. 13.
    Ponten A, Sick C, Weeber M, Haller O, Kochs G (1997) Dominant negative mutants of human MxA protein: domains in the carboxy-terminal moiety are important for oligomerization and antiviral activity. J Virol 71:2591–2599PubMedGoogle Scholar
  14. 14.
    Sugiyama M, Tanaka Y, Kato T, Orito E, Ito K, Acharya SK, Gish RG, Kramvis A, Shimada T, Izumi N, Kaito M, Miyakawa Y, Mizokami M (2006) Influence of hepatitis B virus genotypes on the intra- and extracellular expression of viral DNA and antigens. Hepatology 44:915–924PubMedCrossRefGoogle Scholar
  15. 15.
    Sun J, Wang Z, Ma S, Zeng G, Zhou Z, Luo K, Hou J (2005) Clinical and virological characteristics of Lamivudine resistance in chronic hepatitis B patients: a single center experience. J Med Virol 75:391–398PubMedCrossRefGoogle Scholar
  16. 16.
    Zürcher T, Pavlovic J, Staeheli P (1992) Mechanism of human MxA protein action: variants wih changed antiviral properties. EMBO J 11:1657–1661PubMedGoogle Scholar
  17. 17.
    Kochs G, Haller O (1999) GTP-bound human MxA protein interacts with the nucleocapsids of Thogoto virus (Orthomyxoviridae). J Biol Chem 274:4370–4376PubMedCrossRefGoogle Scholar
  18. 18.
    Flohr F, Schneider-Schaulies S, Haller O, Kochs G (1999) The central interactive region of human MxA GTPase is involved in GTPase activation and interaction with viral target structures. FEBS Lett 463:24–28PubMedCrossRefGoogle Scholar
  19. 19.
    Hoenen A, Liu W, Kochs G, Khromykh AA, Mackenzie JM (2007) West Nile virus-induced cytoplasmic membrane structures provide partial protection against the interferon-induced antiviral MxA protein. J Gen Virol 88:3013–3017PubMedCrossRefGoogle Scholar
  20. 20.
    Huang ZM, Yen T (1995) Role of the hepatitis B virus posttranslational regulatory element in export of intronless transcripts. Mol Cell Biol 15:3864–3869PubMedGoogle Scholar
  21. 21.
    Tang KF, Abdullah MP, Yusoff K, Tan WS (2007) Interactions of hepatitis B core antigen and peptide inhibitors. J Med Chem 5:5620–5626CrossRefGoogle Scholar
  22. 22.
    Braun S, Zajakina A, Aleksejeva J, Sharipo A, Bruvere R, Ose V, Pumpens P, Garoff H, Meisel H, Kozlovska T (2007) Proteasomal degradation of core protein variants from chronic hepatitis B patients. J Med Virol 79:1312–1321PubMedCrossRefGoogle Scholar
  23. 23.
    Kochs G, Haller O (1999) Interferon-induced human MxA GTPase blocks nuclear import of Thogoto virus nucleocapsids. Proc Natl Acad Sci USA 96:2082–2086PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Zhijian Yu
    • 1
  • Zhanhui Wang
    • 1
  • Jinjun Chen
    • 1
  • Hui Li
    • 1
  • Zhanzhou Lin
    • 1
  • Fan Zhang
    • 1
  • Yuanping Zhou
    • 1
  • Jinlin Hou
    • 1
    • 2
  1. 1.Department of Infectious DiseasesNanfang Hospital, Nanfang Medical UniversityGuangzhouChina
  2. 2.GuangzhouChina

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