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Journal of Virology, November 2004, p. 11574-11582, Vol. 78, No. 21
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.21.11574-11582.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

The N- and C-Terminal Domains of the NS1 Protein of Influenza B Virus Can Independently Inhibit IRF-3 and Beta Interferon Promoter Activation

Nicola R. Donelan,1,2 Bianca Dauber,3 Xiuyan Wang,1,2,{dagger} Christopher F. Basler,1 Thorsten Wolff,3 and Adolfo García-Sastre1*

Department of Microbiology,1 Microbiology Graduate School Training Program, Mount Sinai School of Medicine, New York, New York,2 Robert Koch-Institut, Berlin, Germany3

Received 30 March 2004/ Accepted 10 June 2004

The NS1 proteins of influenza A and B viruses (A/NS1 and B/NS1 proteins) have only ~20% amino acid sequence identity. Nevertheless, these proteins show several functional similarities, such as their ability to bind to the same RNA targets and to inhibit the activation of protein kinase R in vitro. A critical function of the A/NS1 protein is the inhibition of synthesis of alpha/beta interferon (IFN-{alpha}/ß) during viral infection. Recently, it was also found that the B/NS1 protein inhibits IFN-{alpha}/ß synthesis in virus-infected cells. We have now found that the expression of the B/NS1 protein complements the growth of an influenza A virus with A/NS1 deleted. Expression of the full-length B/NS1 protein (281 amino acids), as well as either its N-terminal RNA-binding domain (amino acids 1 to 93) or C-terminal domain (amino acids 94 to 281), in the absence of any other influenza B virus proteins resulted in the inhibition of IRF-3 nuclear translocation and IFN-ß promoter activation. A mutational analysis of the truncated B/NS1(1-93) protein showed that RNA-binding activity correlated with IFN-ß promoter inhibition. In addition, a recombinant influenza B virus with NS1 deleted induces higher levels of IRF-3 activation, as determined by its nuclear translocation, and of IFN-{alpha}/ß synthesis than wild-type influenza B virus. Our results support the hypothesis that the NS1 protein of influenza B virus plays an important role in antagonizing the IRF-3- and IFN-induced antiviral host responses to virus infection.

* Corresponding author. Mailing address: Department of Microbiology, Box 1124, Mount Sinai School of Medicine, 1 Gustave L. Levy Pl., New York, NY 10029. Phone: (212) 241-7769. Fax: (212) 534-1684. E-mail: adolfo.garcia-sastre{at}mssm.edu.

{dagger} Present address: Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06520.

Journal of Virology, November 2004, p. 11574-11582, Vol. 78, No. 21
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.21.11574-11582.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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