1887

Abstract

During infection, the influenza A virus non-structural protein 1 (NS1) interacts with a diverse range of viral and cellular factors to antagonize host antiviral defences and promote viral replication. Here, I review the structural basis for some of these functions and discuss the emerging view that NS1 cannot simply be regarded as a ‘static’ protein with a single structure. Rather, the dynamic property of NS1 to adopt various quaternary conformations is critical for its multiple activities. Understanding NS1 plasticity, and the mechanisms governing this plasticity, will be essential for assessing both fundamental protein function and the consequences of strain-dependent polymorphisms in this important virulence factor.

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2014-10-01
2019-11-18
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References

  1. Aramini J. M., Ma L. C., Zhou L., Schauder C. M., Hamilton K., Amer B. R., Mack T. R., Lee H. W., Ciccosanti C. T.. & other authors ( 2011;). Dimer interface of the effector domain of non-structural protein 1 from influenza A virus: an interface with multiple functions. . J Biol Chem 286:, 26050–26060. [CrossRef][PubMed]
    [Google Scholar]
  2. Aramini J. M., Hamilton K., Ma L. C., Swapna G. V., Leonard P. G., Ladbury J. E., Krug R. M., Montelione G. T.. ( 2014;). (19)F NMR reveals multiple conformations at the dimer interface of the nonstructural protein 1 effector domain from influenza A virus. . Structure 22:, 515–525. [CrossRef][PubMed]
    [Google Scholar]
  3. Ayllon J., Russell R. J., García-Sastre A., Hale B. G.. ( 2012;). Contribution of NS1 effector domain dimerization to influenza A virus replication and virulence. . J Virol 86:, 13095–13098. [CrossRef][PubMed]
    [Google Scholar]
  4. Bornholdt Z. A., Prasad B. V.. ( 2006;). X-ray structure of influenza virus NS1 effector domain. . Nat Struct Mol Biol 13:, 559–560. [CrossRef][PubMed]
    [Google Scholar]
  5. Bornholdt Z. A., Prasad B. V.. ( 2008;). X-ray structure of NS1 from a highly pathogenic H5N1 influenza virus. . Nature 456:, 985–988. [CrossRef][PubMed]
    [Google Scholar]
  6. Carrillo B., Choi J. M., Bornholdt Z. A., Sankaran B., Rice A. P., Prasad B. V.. ( 2014;). The influenza A virus protein NS1 displays structural polymorphism. . J Virol 88:, 4113–4122. [CrossRef][PubMed]
    [Google Scholar]
  7. Chen G., Liu C. H., Zhou L., Krug R. M.. ( 2014;). Cellular DDX21 RNA helicase inhibits influenza A virus replication but is counteracted by the viral NS1 protein. . Cell Host Microbe 15:, 484–493. [CrossRef][PubMed]
    [Google Scholar]
  8. Cheng A., Wong S. M., Yuan Y. A.. ( 2009;). Structural basis for dsRNA recognition by NS1 protein of influenza A virus. . Cell Res 19:, 187–195. [CrossRef][PubMed]
    [Google Scholar]
  9. Chien C. Y., Tejero R., Huang Y., Zimmerman D. E., Ríos C. B., Krug R. M., Montelione G. T.. ( 1997;). A novel RNA-binding motif in influenza A virus non-structural protein 1. . Nat Struct Biol 4:, 891–895. [CrossRef][PubMed]
    [Google Scholar]
  10. Chien C. Y., Xu Y., Xiao R., Aramini J. M., Sahasrabudhe P. V., Krug R. M., Montelione G. T.. ( 2004;). Biophysical characterization of the complex between double-stranded RNA and the N-terminal domain of the NS1 protein from influenza A virus: evidence for a novel RNA-binding mode. . Biochemistry 43:, 1950–1962. [CrossRef][PubMed]
    [Google Scholar]
  11. Das K., Ma L. C., Xiao R., Radvansky B., Aramini J., Zhao L., Marklund J., Kuo R. L., Twu K. Y.. & other authors ( 2008;). Structural basis for suppression of a host antiviral response by influenza A virus. . Proc Natl Acad Sci U S A 105:, 13093–13098. [CrossRef][PubMed]
    [Google Scholar]
  12. de Chassey B., Meyniel-Schicklin L., Aublin-Gex A., Navratil V., Chantier T., André P., Lotteau V.. ( 2013;). Structure homology and interaction redundancy for discovering virus–host protein interactions. . EMBO Rep 14:, 938–944. [CrossRef][PubMed]
    [Google Scholar]
  13. Engel D. A.. ( 2013;). The influenza virus NS1 protein as a therapeutic target. . Antiviral Res 99:, 409–416. [CrossRef][PubMed]
    [Google Scholar]
  14. Hale B. G., Barclay W. S., Randall R. E., Russell R. J.. ( 2008a;). Structure of an avian influenza A virus NS1 protein effector domain. . Virology 378:, 1–5. [CrossRef][PubMed]
    [Google Scholar]
  15. Hale B. G., Batty I. H., Downes C. P., Randall R. E.. ( 2008b;). Binding of influenza A virus NS1 protein to the inter-SH2 domain of p85 suggests a novel mechanism for phosphoinositide 3-kinase activation. . J Biol Chem 283:, 1372–1380. [CrossRef][PubMed]
    [Google Scholar]
  16. Hale B. G., Randall R. E., Ortín J., Jackson D.. ( 2008c;). The multifunctional NS1 protein of influenza A viruses. . J Gen Virol 89:, 2359–2376. [CrossRef][PubMed]
    [Google Scholar]
  17. Hale B. G., Kerry P. S., Jackson D., Precious B. L., Gray A., Killip M. J., Randall R. E., Russell R. J.. ( 2010a;). Structural insights into phosphoinositide 3-kinase activation by the influenza A virus NS1 protein. . Proc Natl Acad Sci U S A 107:, 1954–1959. [CrossRef][PubMed]
    [Google Scholar]
  18. Hale B. G., Steel J., Medina R. A., Manicassamy B., Ye J., Hickman D., Hai R., Schmolke M., Lowen A. C.. & other authors ( 2010b;). Inefficient control of host gene expression by the 2009 pandemic H1N1 influenza A virus NS1 protein. . J Virol 84:, 6909–6922. [CrossRef][PubMed]
    [Google Scholar]
  19. Kerry P. S., Ayllon J., Taylor M. A., Hass C., Lewis A., García-Sastre A., Randall R. E., Hale B. G., Russell R. J.. ( 2011a;). A transient homotypic interaction model for the influenza A virus NS1 protein effector domain. . PLoS ONE 6:, e17946. [CrossRef][PubMed]
    [Google Scholar]
  20. Kerry P. S., Long E., Taylor M. A., Russell R. J.. ( 2011b;). Conservation of a crystallographic interface suggests a role for β-sheet augmentation in influenza virus NS1 multifunctionality. . Acta Crystallogr Sect F Struct Biol Cryst Commun 67:, 858–861. [CrossRef][PubMed]
    [Google Scholar]
  21. Krug R. M., Garcia-Sastre A.. 2013; The NS1 protein: a master regulator of host and viral functions. . In Textbook of Influenza. 2nd edn. pp. 114–132. Edited by Webster R. G., Monto A. S., Braciale T. J., Lamb R. A... Oxford:: John Wiley & Sons;. [CrossRef]
  22. Li W., Noah J. W., Noah D. L.. ( 2011;). Alanine substitutions within a linker region of the influenza A virus non-structural protein 1 alter its subcellular localization and attenuate virus replication. . J Gen Virol 92:, 1832–1842. [CrossRef][PubMed]
    [Google Scholar]
  23. Li Y., Chen S., Zhang X., Fu Q., Zhang Z., Shi S., Zhu Y., Gu M., Peng D., Liu X.. ( 2014;). A 20-amino-acid deletion in the neuraminidase stalk and a five-amino-acid deletion in the NS1 protein both contribute to the pathogenicity of H5N1 avian influenza viruses in mallard ducks. . PLoS ONE 9:, e95539. [CrossRef][PubMed]
    [Google Scholar]
  24. Liu J., Lynch P. A., Chien C. Y., Montelione G. T., Krug R. M., Berman H. M.. ( 1997;). Crystal structure of the unique RNA-binding domain of the influenza virus NS1 protein. . Nat Struct Biol 4:, 896–899. [CrossRef][PubMed]
    [Google Scholar]
  25. Long J. X., Peng D. X., Liu Y. L., Wu Y. T., Liu X. F.. ( 2008;). Virulence of H5N1 avian influenza virus enhanced by a 15-nucleotide deletion in the viral nonstructural gene. . Virus Genes 36:, 471–478. [CrossRef][PubMed]
    [Google Scholar]
  26. Min J. Y., Krug R. M.. ( 2006;). The primary function of RNA binding by the influenza A virus NS1 protein in infected cells: Inhibiting the 2′-5′ oligo (A) synthetase/RNase L pathway. . Proc Natl Acad Sci U S A 103:, 7100–7105. [CrossRef][PubMed]
    [Google Scholar]
  27. Nemeroff M. E., Qian X. Y., Krug R. M.. ( 1995;). The influenza virus NS1 protein forms multimers in vitro and in vivo. . Virology 212:, 422–428. [CrossRef][PubMed]
    [Google Scholar]
  28. Noah D. L., Twu K. Y., Krug R. M.. ( 2003;). Cellular antiviral responses against influenza A virus are countered at the posttranscriptional level by the viral NS1A protein via its binding to a cellular protein required for the 3′ end processing of cellular pre-mRNAS. . Virology 307:, 386–395. [CrossRef][PubMed]
    [Google Scholar]
  29. Trapp S., Soubieux D., Marty H., Esnault E., Hoffmann T. W., Chandenier M., Lion A., Kut E., Quéré P.. & other authors ( 2014;). Shortening the unstructured, interdomain region of the non-structural protein NS1 of an avian H1N1 influenza virus increases its replication and pathogenicity in chickens. . J Gen Virol 95:, 1233–1243. [CrossRef][PubMed]
    [Google Scholar]
  30. Wang W., Riedel K., Lynch P., Chien C. Y., Montelione G. T., Krug R. M.. ( 1999;). RNA binding by the novel helical domain of the influenza virus NS1 protein requires its dimer structure and a small number of specific basic amino acids. . RNA 5:, 195–205. [CrossRef][PubMed]
    [Google Scholar]
  31. Wang X., Basler C. F., Williams B. R., Silverman R. H., Palese P., García-Sastre A.. ( 2002;). Functional replacement of the carboxy-terminal two-thirds of the influenza A virus NS1 protein with short heterologous dimerization domains. . J Virol 76:, 12951–12962. [CrossRef][PubMed]
    [Google Scholar]
  32. Xia S., Robertus J. D.. ( 2010;). X-ray structures of NS1 effector domain mutants. . Arch Biochem Biophys 494:, 198–204. [CrossRef][PubMed]
    [Google Scholar]
  33. Xia S., Monzingo A. F., Robertus J. D.. ( 2009;). Structure of NS1A effector domain from the influenza A/Udorn/72 virus. . Acta Crystallogr D Biol Crystallogr 65:, 11–17. [CrossRef][PubMed]
    [Google Scholar]
  34. Yoshida T., Shaw M. W., Young J. F., Compans R. W.. ( 1981;). Characterization of the RNA associated with influenza A cytoplasmic inclusions and the interaction of NS1 protein with RNA. . Virology 110:, 87–97. [CrossRef][PubMed]
    [Google Scholar]
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