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Inhibition of retinoic acid-inducible gene I-mediated induction of beta interferon by the NS1 protein of influenza A virus.
Title | Inhibition of retinoic acid-inducible gene I-mediated induction of beta interferon by the NS1 protein of influenza A virus. |
Publication Type | Journal Article |
Year of Publication | 2007 |
Authors | Mibayashi, M, Martinez-Sobrido, L, Loo, Y-M, Cárdenas, WB, Gale, M, García-Sastre, A |
Journal | J Virol |
Volume | 81 |
Issue | 2 |
Pagination | 514-24 |
Date Published | 2007 Jan |
ISSN | 0022-538X |
Keywords | Adaptor Proteins, Signal Transducing, Animals, Cell Line, Cercopithecus aethiops, DEAD-box RNA Helicases, Gene Expression Regulation, Humans, Influenza A virus, Interferon Regulatory Factor-3, Interferon-beta, Promoter Regions, Genetic, RNA, Double-Stranded, RNA, Viral, Vero Cells, Viral Nonstructural Proteins |
Abstract | 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-beta) induction. However, many viruses are known to encode viral products that inhibit IFN-beta production. In the case of influenza A virus, the viral nonstructural protein 1 (NS1) prevents the induction of the IFN-beta promoter by inhibiting the activation of transcription factors, including IRF-3, involved in IFN-beta 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-beta 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-beta. This inhibition was apparent even when a mutant RIG-I that is constitutively activated (in the absence of dsRNA) was used to trigger IFN-beta 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-beta 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-beta. |
DOI | 10.1128/JVI.01265-06 |
Alternate Journal | J. Virol. |
PubMed ID | 17079289 |