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PMID:17079289

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Citation

Mibayashi, M, Martínez-Sobrido, L, Loo, YM, Cárdenas, WB, Gale, M Jr and García-Sastre, A (2007) Inhibition of retinoic acid-inducible gene I-mediated induction of beta interferon by the NS1 protein of influenza A virus. J. Virol. 81:514-24

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.

Links

PubMed PMC1797471 Online version:10.1128/JVI.01265-06

Keywords

Adaptor Proteins, Signal Transducing/genetics; Adaptor Proteins, Signal Transducing/metabolism; Animals; Cell Line; Cercopithecus aethiops; DEAD-box RNA Helicases/genetics; DEAD-box RNA Helicases/metabolism; Gene Expression Regulation; Humans; Influenza A virus/metabolism; Influenza A virus/pathogenicity; Interferon Regulatory Factor-3/genetics; Interferon Regulatory Factor-3/metabolism; Interferon-beta/antagonists & inhibitors; Interferon-beta/biosynthesis; Promoter Regions, Genetic; RNA, Double-Stranded/genetics; RNA, Double-Stranded/metabolism; RNA, Viral/genetics; RNA, Viral/metabolism; Vero Cells; Viral Nonstructural Proteins/immunology; Viral Nonstructural Proteins/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:DDX58

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P03496

F

Seeded From UniProt

complete

HUMAN:DDX58

involved_in

GO:0051091: positive regulation of DNA-binding transcription factor activity

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:Q14653)

Seeded From UniProt

complete

I72A2:NS1

involved_in

GO:0019056: modulation by virus of host transcription

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

I72A2:NS1

enables

GO:0003725: double-stranded RNA binding

ECO:0000304: author statement supported by traceable reference used in manual assertion

F

Seeded From UniProt

complete

I72A2:NS1

involved_in

GO:0052170: suppression by symbiont of host innate immune response

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

I72A2:NS1

involved_in

GO:0052038: modulation by symbiont of host intracellular transport

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

I72A2:NS1

involved_in

GO:0046775: suppression by virus of host cytokine production

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

I34A1:NS1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O95786

F

Seeded From UniProt

complete

HUMAN:IRF3

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:IRF3

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:DDX58

involved_in

GO:0051091: positive regulation of DNA-binding transcription factor activity

ECO:0000314: direct assay evidence used in manual assertion

P

has_regulation_target:(UniProtKB:Q14653)

Seeded From UniProt

complete

HUMAN:DDX58

involved_in

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:DDX58

involved_in

GO:0032728: positive regulation of interferon-beta production

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:DDX58

involved_in

GO:0009597: detection of virus

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:DDX58

enables

GO:0003725: double-stranded RNA binding

ECO:0000304: author statement supported by traceable reference used in manual assertion

F

Seeded From UniProt

complete

HUMAN:IFIH1

involved_in

GO:0032728: positive regulation of interferon-beta production

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

HUMAN:IFIH1

involved_in

GO:0032727: positive regulation of interferon-alpha production

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

HUMAN:IFIH1

involved_in

GO:0009597: detection of virus

ECO:0000304: author statement supported by traceable reference used in manual assertion

P

Seeded From UniProt

complete

HUMAN:IFIH1

enables

GO:0003725: double-stranded RNA binding

ECO:0000304: author statement supported by traceable reference used in manual assertion

F

Seeded From UniProt

complete

HUMAN:IRF3

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:IRF3

part_of

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete


See also

References

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