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DDX50 inhibits the replication of dengue virus 2 by upregulating IFN-β production

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Abstract

Dengue virus (DENV) infects approximately 390 million people per year, and each of the four DENV serotypes (DENV-1, DENV-2, DENV-3, and DENV-4) is capable of causing infection. At present, there is no antiviral drug available for the treatment of DENV. Several DExD/H-box helicases have been shown to be involved in the antiviral immune response or viral replication. In the present study, we investigated the role of DDX50 in DENV-2 RNA replication. Our data showed that the level of DENV-2 RNA increased in DDX50 knockdown cells during an early stage of viral infection and decreased in DDX50-overexpressing cells. DDX50, in conjunction with RIG-I and MDA5, upregulated the production of IFN-β in infected cells through an additive effect on the IFN-β promoter. Furthermore, transcription of several IFN-stimulated genes was increased in DDX50-overexpressing cells infected with DENV-2. These results provide evidence that DDX50 negatively regulates DENV-2 replication during the early stages of infection by inducing IFN-β production.

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References

  1. Guzman MG, Harris E (2015) Dengue. The Lancet 385(9966):453–465

    Article  Google Scholar 

  2. Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow AW, Moyes CL, Drake JM, Brownstein JS, Hoen AG, Sankoh O (2013) The global distribution and burden of dengue. Nature 496(7446):504–507

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Whitehorn J, Simmons CP (2011) The pathogenesis of dengue. Vaccine 29(42):7221–7228

    Article  CAS  PubMed  Google Scholar 

  4. Cologna R, Armstrong PM, Rico-Hesse R (2005) Selection for virulent dengue viruses occurs in humans and mosquitoes. J Virol 79(2):853–859. doi:10.1128/JVI.79.2.853-859.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Martin J, Hermida L (2016) Dengue vaccine: an update on recombinant subunit strategies. Acta virologica 60(1):3–14

    Article  CAS  PubMed  Google Scholar 

  6. Goubau D, Deddouche S, e Sousa CR (2013) Cytosolic sensing of viruses. Immunity 38(5):855–869

    Article  CAS  PubMed  Google Scholar 

  7. Takeuchi O, Akira S (2010) Pattern recognition receptors and inflammation. Cell 140(6):805–820

    Article  CAS  PubMed  Google Scholar 

  8. Levy DE, Marie IJ, Durbin JE (2011) Induction and function of type I and III interferon in response to viral infection. Curr Opin Virol 1(6):476–486. doi:10.1016/j.coviro.2011.11.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Fang J, Kubota S, Yang B, Zhou N, Zhang H, Godbout R, Pomerantz RJ (2004) A DEAD box protein facilitates HIV-1 replication as a cellular co-factor of Rev. Virology 330(2):471–480

    Article  CAS  PubMed  Google Scholar 

  10. Zhang Z, Kim T, Bao M, Facchinetti V, Jung SY, Ghaffari AA, Qin J, Cheng G, Liu Y-J (2011) DDX1, DDX21, and DHX36 helicases form a complex with the adaptor molecule TRIF to sense dsRNA in dendritic cells. Immunity 34(6):866–878

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Ariumi Y (2014) Multiple functions of DDX3 RNA helicase in gene regulation, tumorigenesis, and viral infection. Front Genet 5:423

    Article  PubMed  PubMed Central  Google Scholar 

  12. Soulat D, Bürckstümmer T, Westermayer S, Goncalves A, Bauch A, Stefanovic A, Hantschel O, Bennett KL, Decker T, Superti-Furga G (2008) The DEAD-box helicase DDX3X is a critical component of the TANK-binding kinase 1-dependent innate immune response. The EMBO journal 27(15):2135–2146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Yoo J-S, Takahasi K, Ng CS, Ouda R, Onomoto K, Yoneyama M, Lai JC, Lattmann S, Nagamine Y, Matsui T (2014) DHX36 enhances RIG-I signaling by facilitating PKR-mediated antiviral stress granule formation. PLoS Pathog 10(3):e1004012

    Article  PubMed  PubMed Central  Google Scholar 

  14. Miyashita M, Oshiumi H, Matsumoto M, Seya T (2011) DDX60, a DEXD/H box helicase, is a novel antiviral factor promoting RIG-I-like receptor-mediated signaling. Mol Cell Biol 31(18):3802–3819

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Oshiumi H, Miyashita M, Okamoto M, Morioka Y, Okabe M, Matsumoto M, Seya T (2015) DDX60 is involved in RIG-I-dependent and independent antiviral responses, and its function is attenuated by virus-induced EGFR activation. Cell Rep 11(8):1193–1207

    Article  CAS  PubMed  Google Scholar 

  16. Valdez BC, Perlaky L, Henning D (2002) Expression, cellular localization, and enzymatic activities of RNA helicase II/Guβ. Exp Cell Res 276(2):249–263

    Article  CAS  PubMed  Google Scholar 

  17. Chen G, Liu C-H, Zhou L, Krug RM (2014) Cellular DDX21 RNA helicase inhibits influenza A virus replication but is counteracted by the viral NS1 protein. Cell Host Microbe 15(4):484–493

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Dong Y, Ye W, Yang J, Han P, Wang Y, Ye C, Weng D, Zhang F, Xu Z, Lei Y (2016) DDX21 translocates from nucleus to cytoplasm and stimulates the innate immune response due to dengue virus infection. Biochem Biophys Res Commun 473(2):648–653

    Article  CAS  PubMed  Google Scholar 

  19. Westermarck J, Weiss C, Saffrich R, Kast J, Musti AM, Wessely M, Ansorge W, Séraphin B, Wilm M, Valdez BC (2002) The DEXD/H-box RNA helicase RHII/Gu is a co-factor for c-Jun-activated transcription. EMBO J 21(3):451–460

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Childs K, Stock N, Ross C, Andrejeva J, Hilton L, Skinner M, Randall R, Goodbourn S (2007) mda-5, but not RIG-I, is a common target for paramyxovirus V proteins. Virology 359(1):190–200

    Article  CAS  PubMed  Google Scholar 

  21. Li J, Liu K, Liu Y, Xu Y, Zhang F, Yang H, Liu J, Pan T, Chen J, Wu M (2013) Exosomes mediate the cell-to-cell transmission of IFN-[alpha]-induced antiviral activity. Nat Immunol 14(8):793–803

    Article  CAS  PubMed  Google Scholar 

  22. Gao D, Yang Y-K, Wang R-P, Zhou X, Diao F-C, Li M-D, Zhai Z-H, Jiang Z-F, Chen D-Y (2009) REUL is a novel E3 ubiquitin ligase and stimulator of retinoic-acid-inducible gene-I. PloS One 4(6):e5760

    Article  PubMed  PubMed Central  Google Scholar 

  23. Li G, Feng T, Pan W, Shi X, Dai J (2015) DEAD-box RNA helicase DDX3X inhibits DENV replication via regulating type one interferon pathway. Biochem Biophys Res Commun 456(1):327–332

    Article  CAS  PubMed  Google Scholar 

  24. Parvatiyar K, Zhang Z, Teles RM, Ouyang S, Jiang Y, Iyer SS, Zaver SA, Schenk M, Zeng S, Zhong W (2012) The helicase DDX41 recognizes the bacterial secondary messengers cyclic di-GMP and cyclic di-AMP to activate a type I interferon immune response. Nat Immunol 13(12):1155–1161

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Schneider WM, Chevillotte MD, Rice CM (2014) Interferon-stimulated genes: a complex web of host defenses. Ann Rev Immunol 32:513

    Article  CAS  Google Scholar 

  26. Green AM, Beatty PR, Hadjilaou A, Harris E (2014) Innate immunity to dengue virus infection and subversion of antiviral responses. J Mol Biol 426(6):1148–1160

    Article  CAS  PubMed  Google Scholar 

  27. Amaya M, Brooks-Faulconer T, Lark T, Keck F, Bailey C, Raman V, Narayanan A (2016) Venezuelan equine encephalitis virus non-structural protein 3 (nsP3) interacts with RNA helicases DDX1 and DDX3 in infected cells. Antivir Res 131:49–60. doi:10.1016/j.antiviral.2016.04.008

    Article  CAS  PubMed  Google Scholar 

  28. Goubau D, van der Veen AG, Chakravarty P, Lin R, Rogers N, Rehwinkel J, Deddouche S, Rosewell I, Hiscott J, Reis ESC (2015) Mouse superkiller-2-like helicase DDX60 is dispensable for type I IFN induction and immunity to multiple viruses. Eur J Immunol 45(12):3386–3403. doi:10.1002/eji.201545794

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Schoggins JW (2014) Interferon-stimulated genes: roles in viral pathogenesis. Curr Opin Virol 6:40–46

    Article  CAS  PubMed  Google Scholar 

  30. Jiang D, Weidner JM, Qing M, Pan X-B, Guo H, Xu C, Zhang X, Birk A, Chang J, Shi P-Y (2010) Identification of five interferon-induced cellular proteins that inhibit west nile virus and dengue virus infections. J Virol 84(16):8332–8341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hishiki T, K-i Arimoto, Shimotohno K, Igarashi T, Vasudevan SG, Suzuki Y, Yamamoto N (2014) Interferon-mediated ISG15 conjugation restricts dengue virus 2 replication. Biochem Biophys Res Commun 448(1):95–100

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (no. 31370193).

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Correspondence to Yingfeng Lei or Fanglin Zhang.

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The authors have no conflicts of interest to declare.

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P. Han, W. Ye, X. Lv contributed equally to this article.

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Han, P., Ye, W., Lv, X. et al. DDX50 inhibits the replication of dengue virus 2 by upregulating IFN-β production. Arch Virol 162, 1487–1494 (2017). https://doi.org/10.1007/s00705-017-3250-3

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  • DOI: https://doi.org/10.1007/s00705-017-3250-3

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