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Journal of Virology, January 2007, p. 514-524, Vol. 81, No. 2
0022-538X/07/$08.00+0     doi:10.1128/JVI.01265-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Inhibition of Retinoic Acid-Inducible Gene I-Mediated Induction of Beta Interferon by the NS1 Protein of Influenza A Virus{triangledown}

Masaki Mibayashi,1 Luis Martínez-Sobrido,1 Yueh-Ming Loo,2 Washington B. Cárdenas,1 Michael Gale Jr.,2 and Adolfo García-Sastre1*

Department of Microbiology, Mount Sinai School of Medicine, New York, New York,1 Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas2

Received 16 June 2006/ Accepted 23 October 2006

The retinoic acid-inducible gene I product (RIG-I) has been identified as a cellular sensor of RNA virus infection resulting in beta interferon (IFN-ß) induction. However, many viruses are known to encode viral products that inhibit IFN-ß production. In the case of influenza A virus, the viral nonstructural protein 1 (NS1) prevents the induction of the IFN-ß promoter by inhibiting the activation of transcription factors, including IRF-3, involved in IFN-ß transcriptional activation. The inhibitory properties of NS1 appear to be due at least in part to its binding to double-stranded RNA (dsRNA), resulting in the sequestration of this viral mediator of RIG-I activation. However, the precise effects of NS1 on the RIG-I-mediated induction of IFN-ß have not been characterized. We now report that the NS1 of influenza A virus interacts with RIG-I and inhibits the RIG-I-mediated induction of IFN-ß. This inhibition was apparent even when a mutant RIG-I that is constitutively activated (in the absence of dsRNA) was used to trigger IFN-ß production. Coexpression of RIG-I, its downstream signaling partner, IPS-1, and NS1 resulted in increased levels of RIG-I and NS1 within an IPS-1-rich, solubilization-resistant fraction after cell lysis. These results suggest that RIG-I, IPS-1, and NS1 become part of the same complex. Consistent with this idea, NS1 was also found to inhibit IFN-ß promoter activation by IPS-1 overexpression. Our results indicate that, in addition to sequestering dsRNA, the NS1 of influenza A virus binds to RIG-I and inhibits downstream activation of IRF-3, preventing the transcriptional induction of IFN-ß.

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

{triangledown} Published ahead of print on 1 November 2006.

Journal of Virology, January 2007, p. 514-524, Vol. 81, No. 2
0022-538X/07/$08.00+0     doi:10.1128/JVI.01265-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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