1887

Abstract

Apoptosis has been shown to be induced and downregulated by the Hantaan virus (HTNV) nucleocapsid (N) protein. To address these conflicting data, expression of the p53 protein, one of the key molecules involved in apoptosis, was assessed in the presence of the N protein in A549 and HeLa cells. The amount of p53, increased by drug treatment, was reduced when cells were infected with HTNV or transfected with an expression vector of the HTNV N protein. When cells were treated with a proteasome inhibitor (MG132) or an MDM2 antagonist (Nutlin-3), expression was not reduced in N protein-overexpressed cells. We concluded that the HTNV N protein ubiquitinates and degrades p53 MDM2-dependently. Here we report downregulation of p53 expression through a post-translational mechanism: MDM2-dependent ubiquitination and degradation by the HTNV N protein. These results indicate that N protein-dependent p53 degradation through the ubiquitin proteasome system is one of the anti-apoptotic mechanisms employed by HTNV.

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2013-11-01
2019-10-18
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References

  1. Alff P. J., Gavrilovskaya I. N., Gorbunova E., Endriss K., Chong Y., Geimonen E., Sen N., Reich N. C., Mackow E. R.. ( 2006;). The pathogenic NY-1 hantavirus G1 cytoplasmic tail inhibits RIG-I- and TBK-1-directed interferon responses. . J Virol 80:, 9676–9686. [CrossRef][PubMed]
    [Google Scholar]
  2. Ferecatu I., Rincheval V., Mignotte B., Vayssiere J. L.. ( 2009;). Tickets for p53 journey among organelles. . Front Biosci (Landmark Ed) 14:, 4214–4228. [CrossRef][PubMed]
    [Google Scholar]
  3. Hinds P. W., Finlay C. A., Frey A. B., Levine A. J.. ( 1987;). Immunological evidence for the association of p53 with a heat shock protein, hsc70, in p53-plus-ras-transformed cell lines. . Mol Cell Biol 7:, 2863–2869.[PubMed]
    [Google Scholar]
  4. Kang J. I., Park S. H., Lee P. W., Ahn B. Y.. ( 1999;). Apoptosis is induced by hantaviruses in cultured cells. . Virology 264:, 99–105. [CrossRef][PubMed]
    [Google Scholar]
  5. Kaukinen P., Vaheri A., Plyusnin A.. ( 2003;). Non-covalent interaction between nucleocapsid protein of Tula hantavirus and small ubiquitin-related modifier-1, SUMO-1. . Virus Res 92:, 37–45. [CrossRef][PubMed]
    [Google Scholar]
  6. Kinpe D. M., Howley P. M., Field B. N.. ( 2001;). Fields Virology. Philadelphia:: Lippincott-Raven;.
    [Google Scholar]
  7. Klingström J., Hardestam J., Stoltz M., Zuber B., Lundkvist A., Linder S., Ahlm C.. ( 2006;). Loss of cell membrane integrity in puumala hantavirus-infected patients correlates with levels of epithelial cell apoptosis and perforin. . J Virol 80:, 8279–8282. [CrossRef][PubMed]
    [Google Scholar]
  8. Lee B. H., Yoshimatsu K., Maeda A., Ochiai K., Morimatsu M., Araki K., Ogino M., Morikawa S., Arikawa J.. ( 2003;). Association of the nucleocapsid protein of the Seoul and Hantaan hantaviruses with small ubiquitin-like modifier-1-related molecules. . Virus Res 98:, 83–91. [CrossRef][PubMed]
    [Google Scholar]
  9. Li X. D., Mäkelä T. P., Guo D., Soliymani R., Koistinen V., Vapalahti O., Vaheri A., Lankinen H.. ( 2002;). Hantavirus nucleocapsid protein interacts with the Fas-mediated apoptosis enhancer Daxx. . J Gen Virol 83:, 759–766.[PubMed]
    [Google Scholar]
  10. Li X. D., Kukkonen S., Vapalahti O., Plyusnin A., Lankinen H., Vaheri A.. ( 2004;). Tula hantavirus infection of Vero E6 cells induces apoptosis involving caspase 8 activation. . J Gen Virol 85:, 3261–3268. [CrossRef][PubMed]
    [Google Scholar]
  11. Li X. D., Lankinen H., Putkuri N., Vapalahti O., Vaheri A.. ( 2005;). Tula hantavirus triggers pro-apoptotic signals of ER stress in Vero E6 cells. . Virology 333:, 180–189. [CrossRef][PubMed]
    [Google Scholar]
  12. Maeda A., Lee B. H., Yoshimatsu K., Saijo M., Kurane I., Arikawa J., Morikawa S.. ( 2003;). The intracellular association of the nucleocapsid protein (NP) of hantaan virus (HTNV) with small ubiquitin-like modifier-1 (SUMO-1) conjugating enzyme 9 (Ubc9). . Virology 305:, 288–297. [CrossRef][PubMed]
    [Google Scholar]
  13. Markotic A., Hensley L., Geisbert T., Spik K., Schmaljohn C.. ( 2003;). Hantaviruses induce cytopathic effects and apoptosis in continuous human embryonic kidney cells. . J Gen Virol 84:, 2197–2202. [CrossRef][PubMed]
    [Google Scholar]
  14. Mir M. A., Panganiban A. T.. ( 2004;). Trimeric hantavirus nucleocapsid protein binds specifically to the viral RNA panhandle. . J Virol 78:, 8281–8288. [CrossRef][PubMed]
    [Google Scholar]
  15. Nam J. H., Hwang K. A., Yu C. H., Kang T. H., Shin J. Y., Choi W. Y., Kim I. B., Joo Y. R., Cho H. W., Park K. Y.. ( 2003;). Expression of interferon inducible genes following Hantaan virus infection as a mechanism of resistance in A549 cells. . Virus Genes 26:, 31–38. [CrossRef][PubMed]
    [Google Scholar]
  16. Ontiveros S. J., Li Q., Jonsson C. B.. ( 2010;). Modulation of apoptosis and immune signaling pathways by the Hantaan virus nucleocapsid protein. . Virology 401:, 165–178. [CrossRef][PubMed]
    [Google Scholar]
  17. Rang A.. ( 2010;). Modulation of innate immune responses by hantaviruses. . Crit Rev Immunol 30:, 515–527. [CrossRef][PubMed]
    [Google Scholar]
  18. Rotter V.. ( 1983;). p53, a transformation-related cellular-encoded protein, can be used as a biochemical marker for the detection of primary mouse tumor cells. . Proc Natl Acad Sci U S A 80:, 2613–2617. [CrossRef][PubMed]
    [Google Scholar]
  19. Schönrich G., Rang A., Lütteke N., Raftery M. J., Charbonnel N., Ulrich R. G.. ( 2008;). Hantavirus-induced immunity in rodent reservoirs and humans. . Immunol Rev 225:, 163–189. [CrossRef][PubMed]
    [Google Scholar]
  20. Severson W. E., Xu X., Jonsson C. B.. ( 2001;). cis-Acting signals in encapsidation of Hantaan virus S-segment viral genomic RNA by its N protein. . J Virol 75:, 2646–2652. [CrossRef][PubMed]
    [Google Scholar]
  21. Shim S. H., Park M. S., Moon S., Park K. S., Song J. W., Song K. J., Baek L. J.. ( 2011;). Comparison of innate immune responses to pathogenic and putative non-pathogenic hantaviruses in vitro. . Virus Res 160:, 367–373. [CrossRef][PubMed]
    [Google Scholar]
  22. van Regenmortel M., Fauquet C., Bishop D., Carstens E., Estes M., Lemon S., Maniloff J., Mayo M., McGeoch D.. & other authors ( 2000;). Virus Taxonomy: The Classification and Nomenclature of Viruses. San Diego:: Academic Press;.
    [Google Scholar]
  23. Vogelstein B., Lane D., Levine A. J.. ( 2000;). Surfing the p53 network. . Nature 408:, 307–310. [CrossRef][PubMed]
    [Google Scholar]
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