1887

Abstract

In the present work we investigated the importance of the Raf/MEK/ERK signalling pathway in the multiplication of the arenavirus Junín (JUNV) in monkey and human cell cultures. We established that JUNV induces a biphasic activation of ERK and we proved that a specific inhibitor of the ERK pathway, U0126, impairs viral replication. Furthermore, U0126 exerted inhibitory action against the arenaviruses Tacaribe and Pichinde. Moreover, treatment with known ERK activators such as phorbol 12-myristate 13-acetate and serum increased viral yields whereas ERK silencing by small interfering RNAs caused the inhibition of viral multiplication. Therefore, activation of the Raf/MEK/ERK signalling pathway is required to ensure efficient JUNV replication and may constitute a host target for the development of novel effective therapeutic strategies to deal with arenavirus infections.

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2014-04-01
2019-11-20
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References

  1. Abkhezr M. , Keramati A. R. , Ostad S. N. , Davoodi J. , Ghahremani M. H. . ( 2010; ). The time course of Akt and ERK activation on XIAP expression in HEK 293 cell line. . Mol Biol Rep 37:, 2037–2042. [CrossRef] [PubMed]
    [Google Scholar]
  2. Bowick G. C. , McAuley A. J. . ( 2011; ). Meta-analysis of high-throughput datasets reveals cellular responses following hemorrhagic fever virus infection. . Viruses 3:, 613–619. [CrossRef] [PubMed]
    [Google Scholar]
  3. Bowick G. C. , Fennewald S. M. , Scott E. P. , Zhang L. , Elsom B. L. , Aronson J. F. , Spratt H. M. , Luxon B. A. , Gorenstein D. G. , Herzog N. K. . ( 2007; ). Identification of differentially activated cell-signaling networks associated with Pichinde virus pathogenesis by using systems kinomics. . J Virol 81:, 1923–1933. [CrossRef] [PubMed]
    [Google Scholar]
  4. Chang M. S. , Chen B. C. , Yu M. T. , Sheu J. R. , Chen T. F. , Lin C. H. . ( 2005; ). Phorbol 12-myristate 13-acetate upregulates cyclooxygenase-2 expression in human pulmonary epithelial cells via Ras, Raf-1, ERK, and NF-κB, but not p38 MAPK, pathways. . Cell Signal 17:, 299–310. [CrossRef] [PubMed]
    [Google Scholar]
  5. Droebner K. , Pleschka S. , Ludwig S. , Planz O. . ( 2011; ). Antiviral activity of the MEK-inhibitor U0126 against pandemic H1N1v and highly pathogenic avian influenza virus in vitro and in vivo . . Antiviral Res 92:, 195–203. [CrossRef] [PubMed]
    [Google Scholar]
  6. Emonet S. F. , de la Torre J. C. , Domingo E. , Sevilla N. . ( 2009; ). Arenavirus genetic diversity and its biological implications. . Infect Genet Evol 9:, 417–429. [CrossRef] [PubMed]
    [Google Scholar]
  7. García C. C. , Sepúlveda C. S. , Damonte E. B. . ( 2011; ). Novel therapeutic targets for arenavirus hemorrhagic fevers. . Future Virol 6:, 27–44. [CrossRef]
    [Google Scholar]
  8. Gómez R. M. , Jaquenod de Giusti C. , Sanchez Vallduvi M. M. , Frik J. , Ferrer M. F. , Schattner M. . ( 2011; ). Junín virus. A XXI century update. . Microbes Infect 13:, 303–311. [CrossRef] [PubMed]
    [Google Scholar]
  9. Gretton S. , Hughes M. , Harris M. . ( 2010; ). Hepatitis C virus RNA replication is regulated by Ras–Erk signalling. . J Gen Virol 91:, 671–680. [CrossRef] [PubMed]
    [Google Scholar]
  10. Howard C. R. , Buchmeier M. J. . ( 1983; ). A protein kinase activity in lymphocytic choriomeningitis virus and identification of the phosphorylated product using monoclonal antibody. . Virology 126:, 538–547. [CrossRef] [PubMed]
    [Google Scholar]
  11. Huerta-Zepeda A. , Cabello-Gutiérrez C. , Cime-Castillo J. , Monroy-Martínez V. , Manjarrez-Zavala M. E. , Gutiérrez-Rodríguez M. , Izaguirre R. , Ruiz-Ordaz B. H. . ( 2008; ). Crosstalk between coagulation and inflammation during Dengue virus infection. . Thromb Haemost 99:, 936–943.[PubMed]
    [Google Scholar]
  12. Linero F. N. , Scolaro L. A. . ( 2009; ). Participation of the phosphatidylinositol 3-kinase/Akt pathway in Junín virus replication in vitro . . Virus Res 145:, 166–170. [CrossRef] [PubMed]
    [Google Scholar]
  13. Linero F. N. , Sepúlveda C. S. , Giovannoni F. , Castilla V. , García C. C. , Scolaro L. A. , Damonte E. B. . ( 2012; ). Host cell factors as antiviral targets in arenavirus infection. . Viruses 4:, 1569–1591. [CrossRef] [PubMed]
    [Google Scholar]
  14. Ludwig S. . ( 2009; ). Targeting cell signalling pathways to fight the flu: towards a paradigm change in anti-influenza therapy. . J Antimicrob Chemother 64:, 1–4. [CrossRef] [PubMed]
    [Google Scholar]
  15. Luo H. , Yanagawa B. , Zhang J. , Luo Z. , Zhang M. , Esfandiarei M. , Carthy C. , Wilson J. E. , Yang D. , McManus B. M. . ( 2002; ). Coxsackievirus B3 replication is reduced by inhibition of the extracellular signal-regulated kinase (ERK) signaling pathway. . J Virol 76:, 3365–3373. [CrossRef] [PubMed]
    [Google Scholar]
  16. Maeto C. A. , Knott M. E. , Linero F. N. , Ellenberg P. C. , Scolaro L. A. , Castilla V. . ( 2011; ). Differential effect of acute and persistent Junín virus infections on the nucleo-cytoplasmic trafficking and expression of heterogeneous nuclear ribonucleoproteins type A and B. . J Gen Virol 92:, 2181–2190. [CrossRef] [PubMed]
    [Google Scholar]
  17. McLay L. , Ansari A. , Liang Y. , Ly H. . ( 2013; ). Targeting virulence mechanisms for the prevention and therapy of arenaviral hemorrhagic fever. . Antiviral Res 97:, 81–92. [CrossRef] [PubMed]
    [Google Scholar]
  18. Pinto R. , Herold S. , Cakarova L. , Hoegner K. , Lohmeyer J. , Planz O. , Pleschka S. . ( 2011; ). Inhibition of influenza virus-induced NF-κB and Raf/MEK/ERK activation can reduce both virus titers and cytokine expression simultaneously in vitro and in vivo . . Antiviral Res 92:, 45–56. [CrossRef] [PubMed]
    [Google Scholar]
  19. Planz O. . ( 2013; ). Development of cellular signaling pathway inhibitors as new antivirals against influenza. . Antiviral Res 98:, 457–468. [CrossRef] [PubMed]
    [Google Scholar]
  20. Planz O. , Pleschka S. , Ludwig S. . ( 2001; ). MEK-specific inhibitor U0126 blocks spread of Borna disease virus in cultured cells. . J Virol 75:, 4871–4877. [CrossRef] [PubMed]
    [Google Scholar]
  21. Pleschka S. . ( 2008; ). RNA viruses and the mitogenic Raf/MEK/ERK signal transduction cascade. . Biol Chem 389:, 1273–1282. [CrossRef] [PubMed]
    [Google Scholar]
  22. Pleschka S. , Wolff T. , Ehrhardt C. , Hobom G. , Planz O. , Rapp U. R. , Ludwig S. . ( 2001; ). Influenza virus propagation is impaired by inhibition of the Raf/MEK/ERK signalling cascade. . Nat Cell Biol 3:, 301–305. [CrossRef] [PubMed]
    [Google Scholar]
  23. Renukaradhya G. J. , Webb T. J. , Khan M. A. , Lin Y. L. , Du W. , Gervay-Hague J. , Brutkiewicz R. R. . ( 2005; ). Virus-induced inhibition of CD1d1-mediated antigen presentation: reciprocal regulation by p38 and ERK. . J Immunol 175:, 4301–4308.[PubMed] [CrossRef]
    [Google Scholar]
  24. Rojek J. M. , Moraz M. L. , Pythoud C. , Rothenberger S. , Van der Goot F. G. , Campbell K. P. , Kunz S. . ( 2012; ). Binding of Lassa virus perturbs extracellular matrix-induced signal transduction via dystroglycan. . Cell Microbiol 14:, 1122–1134. [CrossRef] [PubMed]
    [Google Scholar]
  25. Sánchez A. , Pifat D. Y. , Kenyon R. H. , Peters C. J. , McCormick J. B. , Kiley M. P. . ( 1989; ). Junin virus monoclonal antibodies: characterization and cross-reactivity with other arenaviruses. . J Gen Virol 70:, 1125–1132. [CrossRef] [PubMed]
    [Google Scholar]
  26. Scherbik S. V. , Brinton M. A. . ( 2010; ). Virus-induced Ca2+ influx extends survival of West Nile virus-infected cells. . J Virol 84:, 8721–8731. [CrossRef] [PubMed]
    [Google Scholar]
  27. Steinmetz R. , Wagoner H. A. , Zeng P. , Hammond J. R. , Hannon T. S. , Meyers J. L. , Pescovitz O. H. . ( 2004; ). Mechanisms regulating the constitutive activation of the extracellular signal-regulated kinase (ERK) signaling pathway in ovarian cancer and the effect of ribonucleic acid interference for ERK1/2 on cancer cell proliferation. . Mol Endocrinol 18:, 2570–2582. [CrossRef] [PubMed]
    [Google Scholar]
  28. Torres N. I. , Castilla V. , Bruttomesso A. C. , Eiras J. , Galagovsky L. R. , Wachsman M. B. . ( 2012a; ). In vitro antiviral activity of dehydroepiandrosterone, 17 synthetic analogs and ERK modulators against herpes simplex virus type 1. . Antiviral Res 95:, 37–48. [CrossRef] [PubMed]
    [Google Scholar]
  29. Torres N. I. , Castilla V. , Wachsman M. B. . ( 2012b; ). DHEA inhibits measles virus through a mechanism independent of its ability to modulate the Raf/MEK/ERK signaling pathway. . Future Virol 7:, 1115–1125. [CrossRef]
    [Google Scholar]
  30. Vela E. M. , Bowick G. C. , Herzog N. K. , Aronson J. F. . ( 2008; ). Genistein treatment of cells inhibits arenavirus infection. . Antiviral Res 77:, 153–156. [CrossRef] [PubMed]
    [Google Scholar]
  31. Verin A. D. , Liu F. , Bogatcheva N. , Borbiev T. , Hershenson M. B. , Wang P. , Garcia J. G. . ( 2000; ). Role of Ras-dependent ERK activation in phorbol ester-induced endothelial cell barrier dysfunction. . Am J Physiol Lung Cell Mol Physiol 279:, L360–L370.[PubMed]
    [Google Scholar]
  32. Wang C. , Zhang H. , Xu F. , Niu Y. , Wu Y. , Wang X. , Peng Y. , Sun J. , Liang L. , Xu P. . ( 2013; ). Substituted 3-benzylcoumarins as allosteric MEK1 inhibitors: design, synthesis and biological evaluation as antiviral agents. . Molecules 18:, 6057–6091. [CrossRef] [PubMed]
    [Google Scholar]
  33. Wong W. R. , Chen Y. Y. , Yang S. M. , Chen Y. L. , Horng J. T. . ( 2005; ). Phosphorylation of PI3K/Akt and MAPK/ERK in an early entry step of enterovirus 71. . Life Sci 78:, 82–90. [CrossRef] [PubMed]
    [Google Scholar]
  34. Yang T. C. , Lai C. C. , Shiu S. L. , Chuang P. H. , Tzou B. C. , Lin Y. Y. , Tsai F. J. , Lin C. W. . ( 2010; ). Japanese encephalitis virus down-regulates thioredoxin and induces ROS-mediated ASK1-ERK/p38 MAPK activation in human promonocyte cells. . Microbes Infect 12:, 643–651. [CrossRef] [PubMed]
    [Google Scholar]
  35. Zampieri C. A. , Fortin J. F. , Nolan G. P. , Nabel G. J. . ( 2007; ). The ERK mitogen-activated protein kinase pathway contributes to Ebola virus glycoprotein-induced cytotoxicity. . J Virol 81:, 1230–1240. [CrossRef] [PubMed]
    [Google Scholar]
  36. Zhao L.-J. , Wang W. , Ren H. , Qi Z.-T. . ( 2013; ). ERK signaling is triggered by hepatitis C virus E2 protein through DC-SIGN. . Cell Stress Chaperones 18:, 495–501. [CrossRef] [PubMed]
    [Google Scholar]
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