Home LiteratureArticle Details
PMID: 11483732 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S.

Influenza virus ns1 protein induces apoptosis in cultured cells.

Journal of virology ·Vol. 75 ·No. 17 ·2001-09-00 ·Pages 7875-81

Schultz-Cherry S, Dybdahl-Sissoko N, Neumann G, Kawaoka Y, Hinshaw VS

Abstract

The importance of influenza viruses as worldwide pathogens in humans, domestic animals, and poultry is well recognized. Discerning how influenza viruses interact with the host at a cellular level is crucial for a better understanding of viral pathogenesis. Influenza viruses induce apoptosis through mechanisms involving the interplay of cellular and viral factors that may depend on the cell type. However, it is unclear which viral genes induce apoptosis. In these studies, we show that the expression of the nonstructural (NS) gene of influenza A virus is sufficient to induce apoptosis in MDCK and HeLa cells. Further studies showed that the multimerization domain of the NS1 protein but not the effector domain is required for apoptosis. However, this mutation is not sufficient to inhibit apoptosis using whole virus.

MeSH Terms
Animals Apoptosis Cell Line Dogs HeLa Cells Humans Kidney/cytology Mutation Orthomyxoviridae/genetics,physiology Plasmids/genetics Reassortant Viruses/genetics,physiology Transfection Viral Nonstructural Proteins/chemistry,genetics,metabolism
Chemicals
INS1 protein, influenza virus Viral Nonstructural Proteins
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Schultz-Cherry S
Southeast Poultry Research Laboratory, Agricultural Research Service, U.S. Department of Agriculture, Athens, Georgia 30605, USA. sschultz@seprl.usda.gov
Dybdahl-Sissoko N
Neumann G
Kawaoka Y
Hinshaw V S
References (71)
71 references, click to expand
  1. The influenza virus NS1 protein: a novel inhibitor of pre-mRNA splicing.
    Genes Dev. 1994 Aug 1;8(15):1817-28 PMID: 7958859
  2. Deregulated expression of E2F-1 induces S-phase entry and leads to apoptosis.
    Mol Cell Biol. 1994 Dec;14(12):8166-73 PMID: 7969153
  3. TGF-beta 1 and cyclic AMP promote apoptosis in resting human B lymphocytes.
    J Immunol. 1995 Feb 15;154(4):1634-43 PMID: 7836748
  4. Tight control of gene expression in mammalian cells by tetracycline-responsive promoters.
    Proc Natl Acad Sci U S A. 1992 Jun 15;89(12):5547-51 PMID: 1319065
  5. Binding of influenza A virus NS1 protein to dsRNA in vitro.
    J Gen Virol. 1992 Dec;73 ( Pt 12):3325-9 PMID: 1469370
  6. Anhydrotetracycline, a novel effector for tetracycline controlled gene expression systems in eukaryotic cells.
    Nucleic Acids Res. 1993 Sep 11;21(18):4411-2 PMID: 8415012
  7. Induction of programmed cell death (apoptosis) by influenza virus infection in tissue culture cells.
    J Gen Virol. 1993 Nov;74 ( Pt 11):2347-55 PMID: 7504071
  8. E1A 12S in the absence of E1B or other cooperating oncogenes enables cells to overcome apoptosis.
    Oncogene. 1993 Dec;8(12):3289-96 PMID: 8247531
  9. Influenza virus NS1 protein inhibits pre-mRNA splicing and blocks mRNA nucleocytoplasmic transport.
    EMBO J. 1994 Feb 1;13(3):704-12 PMID: 8313914
  10. Apoptosis in viral infections.
    Adv Virus Res. 1995;45:1-60 PMID: 7793322
  11. The choice of alternative 5' splice sites in influenza virus M1 mRNA is regulated by the viral polymerase complex.
    Proc Natl Acad Sci U S A. 1995 Jul 3;92(14):6324-8 PMID: 7541537
  12. Transcription stimulation of the Fas-encoding gene by nuclear factor for interleukin-6 expression upon influenza virus infection.
    J Biol Chem. 1995 Jul 28;270(30):18007-12 PMID: 7543095
  13. The influenza virus NS1 protein forms multimers in vitro and in vivo.
    Virology. 1995 Oct 1;212(2):422-8 PMID: 7571411
  14. Potential roles of apoptosis in viral pathogenesis.
    Am J Respir Crit Care Med. 1995 Oct;152(4 Pt 2):S20-4 PMID: 7551407
  15. In vivo induction of apoptosis by influenza virus.
    J Gen Virol. 1995 Nov;76 ( Pt 11):2869-73 PMID: 7595397
  16. The influenza virus NS1 protein binds to a specific region in human U6 snRNA and inhibits U6-U2 and U6-U4 snRNA interactions during splicing.
    RNA. 1995 May;1(3):304-16 PMID: 7489502
  17. Binding of the influenza virus NS1 protein to double-stranded RNA inhibits the activation of the protein kinase that phosphorylates the elF-2 translation initiation factor.
    Virology. 1995 Dec 1;214(1):222-8 PMID: 8525619
  18. bcl-2 alters influenza virus yield, spread, and hemagglutinin glycosylation.
    J Virol. 1996 Jan;70(1):663-6 PMID: 8523590
  19. An amino-terminal polypeptide fragment of the influenza virus NS1 protein possesses specific RNA-binding activity and largely helical backbone structure.
    RNA. 1995 Nov;1(9):948-56 PMID: 8548659
  20. [Mechanism of the induction of apoptosis by influenza virus infection].
    Nihon Rinsho. 1996 Jul;54(7):1836-41 PMID: 8741675
  21. Interaction cloning of NS1-I, a human protein that binds to the nonstructural NS1 proteins of influenza A and B viruses.
    J Virol. 1996 Aug;70(8):5363-72 PMID: 8764047
  22. New approach for inhibiting Rev function and HIV-1 production using the influenza virus NS1 protein.
    Proc Natl Acad Sci U S A. 1996 Aug 20;93(17):8873-7 PMID: 8799120
  23. The RNA-binding and effector domains of the viral NS1 protein are conserved to different extents among influenza A and B viruses.
    Virology. 1996 Sep 1;223(1):41-50 PMID: 8806538
  24. Possible involvement of double-stranded RNA-activated protein kinase in cell death by influenza virus infection.
    J Virol. 1996 Nov;70(11):8128-32 PMID: 8892939
  25. Influenza virus neuraminidase activates latent transforming growth factor beta.
    J Virol. 1996 Dec;70(12):8624-9 PMID: 8970987
  26. Regulation of apoptosis by viral gene products.
    J Virol. 1997 Mar;71(3):1739-46 PMID: 9032302
  27. Programmed cell death in animal development.
    Cell. 1997 Feb 7;88(3):347-54 PMID: 9039261
  28. Characterization of influenza virus-induced death of J774.1 macrophages.
    Exp Cell Res. 1997 Aug 1;234(2):249-58 PMID: 9260892
  29. [Induction of apoptosis by influenza virus infection].
    Uirusu. 1997 Jun;47(1):69-76 PMID: 9290316
  30. A novel RNA-binding motif in influenza A virus non-structural protein 1.
    Nat Struct Biol. 1997 Nov;4(11):891-5 PMID: 9360601
  31. Differential induction of cytotoxicity and apoptosis by influenza virus strains of differing virulence.
    J Gen Virol. 1997 Nov;78 ( Pt 11):2821-9 PMID: 9367368
  32. Viruses and apoptosis.
    Br Med Bull. 1997;53(3):509-21 PMID: 9374034
  33. The influenza virus NEP (NS2 protein) mediates the nuclear export of viral ribonucleoproteins.
    EMBO J. 1998 Jan 2;17(1):288-96 PMID: 9427762
  34. U6atac snRNA, the highly divergent counterpart of U6 snRNA, is the specific target that mediates inhibition of AT-AC splicing by the influenza virus NS1 protein.
    RNA. 1998 Jan;4(1):55-64 PMID: 9436908
  35. Dendritic cells acquire antigen from apoptotic cells and induce class I-restricted CTLs.
    Nature. 1998 Mar 5;392(6671):86-9 PMID: 9510252
  36. Influenza virus NS1 protein interacts with the cellular 30 kDa subunit of CPSF and inhibits 3'end formation of cellular pre-mRNAs.
    Mol Cell. 1998 Jun;1(7):991-1000 PMID: 9651582
  37. Transfectant influenza A viruses with long deletions in the NS1 protein grow efficiently in Vero cells.
    J Virol. 1998 Aug;72(8):6437-41 PMID: 9658085
  38. NS1-Binding protein (NS1-BP): a novel human protein that interacts with the influenza A virus nonstructural NS1 protein is relocalized in the nuclei of infected cells.
    J Virol. 1998 Sep;72(9):7170-80 PMID: 9696811
  39. Influence of host species on the evolution of the nonstructural (NS) gene of influenza A viruses.
    Virus Res. 1998 Jun;55(2):143-56 PMID: 9725667
  40. The role of interferon in influenza virus tissue tropism.
    J Virol. 1998 Nov;72(11):8550-8 PMID: 9765393
  41. Biochemical and genetic evidence for complex formation between the influenza A virus NS1 protein and the interferon-induced PKR protein kinase.
    J Interferon Cytokine Res. 1998 Sep;18(9):757-66 PMID: 9781815
  42. Influenza A virus lacking the NS1 gene replicates in interferon-deficient systems.
    Virology. 1998 Dec 20;252(2):324-30 PMID: 9878611
  43. Role of neuraminidase in influenza virus-induced apoptosis.
    J Gen Virol. 1999 Jan;80 ( Pt 1):137-46 PMID: 9934696
  44. Mutant influenza viruses with a defective NS1 protein cannot block the activation of PKR in infected cells.
    J Virol. 1999 Mar;73(3):2425-33 PMID: 9971827
  45. 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. 1999 Feb;5(2):195-205 PMID: 10024172
  46. Co-expression of Fas and Fas-ligand on the surface of influenza virus-infected cells.
    Cell Death Differ. 1998 May;5(5):426-31 PMID: 10200492
  47. Recruitment of apoptotic cysteine proteases (caspases) in influenza virus-induced cell death.
    Microbiol Immunol. 1999;43(3):245-52 PMID: 10338194
  48. Generation of influenza A viruses entirely from cloned cDNAs.
    Proc Natl Acad Sci U S A. 1999 Aug 3;96(16):9345-50 PMID: 10430945
  49. Rescue of influenza A virus from recombinant DNA.
    J Virol. 1999 Nov;73(11):9679-82 PMID: 10516084
  50. Acceleration of the G1/S phase transition by expression of cyclins D1 and E with an inducible system.
    Mol Cell Biol. 1994 Mar;14(3):1669-79 PMID: 8114703
  51. The influenza virus NS1 protein is a poly(A)-binding protein that inhibits nuclear export of mRNAs containing poly(A).
    J Virol. 1994 Apr;68(4):2425-32 PMID: 7908060
  52. Apoptosis, oncosis, and necrosis. An overview of cell death.
    Am J Pathol. 1995 Jan;146(1):3-15 PMID: 7856735
  53. Apoptosis in the pathogenesis and treatment of disease.
    Science. 1995 Mar 10;267(5203):1456-62 PMID: 7878464
  54. Viruses and apoptosis.
    Curr Opin Genet Dev. 1995 Feb;5(1):105-11 PMID: 7749317
  55. Activation of the apoptotic Fas antigen-encoding gene upon influenza virus infection involving spontaneously produced beta-interferon.
    Virology. 1995 Jun 1;209(2):288-96 PMID: 7539967
  56. A fatal relationship--influenza virus interactions with the host cell.
    Viral Immunol. 1999;12(3):175-96 PMID: 10532647
  57. Viruses and apoptosis.
    Annu Rev Microbiol. 1999;53:577-628 PMID: 10547702
  58. Genetic engineering of influenza and other negative-strand RNA viruses containing segmented genomes.
    Adv Virus Res. 1999;53:265-300 PMID: 10582103
  59. Virus clearance through apoptosis-dependent phagocytosis of influenza A virus-infected cells by macrophages.
    J Virol. 2000 Apr;74(7):3399-403 PMID: 10708457
  60. Depletion of lymphocytes and diminished cytokine production in mice infected with a highly virulent influenza A (H5N1) virus isolated from humans.
    J Virol. 2000 Jul;74(13):6105-16 PMID: 10846094
  61. Activation of interferon regulatory factor 3 is inhibited by the influenza A virus NS1 protein.
    J Virol. 2000 Sep;74(17):7989-96 PMID: 10933707
  62. Induction of apoptosis by the dsRNA-dependent protein kinase (PKR): mechanism of action.
    Apoptosis. 2000 Apr;5(2):107-14 PMID: 11232238
  63. Infectious influenza A and B virus variants with long carboxyl terminal deletions in the NS1 polypeptides.
    Virology. 1987 Feb;156(2):204-13 PMID: 3811235
  64. Destruction of lymphocytes by a virulent avian influenza A virus.
    J Gen Virol. 1989 Feb;70 ( Pt 2):467-72 PMID: 2732695
  65. Virulent avian influenza A viruses: their effect on avian lymphocytes and macrophages in vivo and in vitro.
    J Gen Virol. 1989 Nov;70 ( Pt 11):2887-95 PMID: 2685173
  66. Nucleocytoplasmic transport: the influenza virus NS1 protein regulates the transport of spliced NS2 mRNA and its precursor NS1 mRNA.
    Genes Dev. 1992 Feb;6(2):255-67 PMID: 1531330
  67. Purification and molecular cloning of the APO-1 cell surface antigen, a member of the tumor necrosis factor/nerve growth factor receptor superfamily. Sequence identity with the Fas antigen.
    J Biol Chem. 1992 May 25;267(15):10709-15 PMID: 1375228
  68. Two functional domains of the influenza virus NS1 protein are required for regulation of nuclear export of mRNA.
    J Virol. 1994 Apr;68(4):2433-41 PMID: 8139028
  69. Apoptosis. Its significance in cancer and cancer therapy.
    Cancer. 1994 Apr 15;73(8):2013-26 PMID: 8156506
  70. Apoptosis: a mechanism of cell killing by influenza A and B viruses.
    J Virol. 1994 Jun;68(6):3667-73 PMID: 8189504
  71. Programmed cell death (apoptosis) in human monocytes infected by influenza A virus.
    Immunobiology. 1994 Feb;190(1-2):175-82 PMID: 8082884
Article Info
Journal
Journal of virology
Abbr.
J Virol
ISSN
0022-538X
Published
2001-09-00
Pages
7875-81
Language
English
Region
United States
NLM ID
0113724
PMCID
PMC115031
Subset
IM
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com