Inhibition of retinoic acid-inducible gene I-mediated induction of beta interferon by the NS1 protein of influenza A virus.
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.
Mibayashi
Masaki
M
Department of Microbiology, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, New York, NY 10029, USA.
Martínez-Sobrido
Luis
L
Loo
Yueh-Ming
YM
Cárdenas
Washington B
WB
Gale
Michael
M
García-Sastre
Adolfo
A
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D009980:Influenza A virus / Q000378:metabolism / Q000472:pathogenicity*; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000378:metabolism; D016899:Interferon-beta / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D011401:Promoter Regions, Genetic; D012330:RNA, Double-Stranded / Q000235:genetics / Q000378:metabolism; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism; D011971:Receptors, Immunologic; D014709:Vero Cells; D017361:Viral Nonstructural Proteins / Q000276:immunology* / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C085820:INS1 protein, influenza virus; D050838:Interferon Regulatory Factor-3; C505371:MAVS protein, human; D012330:RNA, Double-Stranded; D012367:RNA, Viral; D011971:Receptors, Immunologic; D017361:Viral Nonstructural Proteins; D016899:Interferon-beta; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases