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The influenza virus protein PB1-F2 inhibits the induction of type I interferon at the level of the MAVS adaptor protein

Varga, Zsuzsanna T
Ramos, Irene
Hai, Rong
García-Sastre, Adolfo
Fernandez-Sesma, Ana
Palese, Peter
Published in PLOS pathogens. 2011, vol. 7, no. 6, e1002067
Abstract PB1-F2 is a 90 amino acid protein that is expressed from the +1 open reading frame in the PB1 gene of some influenza A viruses and has been shown to contribute to viral pathogenicity. Notably, a serine at position 66 (66S) in PB1-F2 is known to increase virulence compared to an isogenic virus with an asparagine (66N) at this position. Recently, we found that an influenza virus expressing PB1-F2 N66S suppresses interferon (IFN)-stimulated genes in mice. To characterize this phenomenon, we employed several in vitro assays. Overexpression of the A/Puerto Rico/8/1934 (PR8) PB1-F2 protein in 293T cells decreased RIG-I mediated activation of an IFN-β reporter and secretion of IFN as determined by bioassay. Of note, the PB1-F2 N66S protein showed enhanced IFN antagonism activity compared to PB1-F2 wildtype. Similar observations were found in the context of viral infection with a PR8 PB1-F2 N66S virus. To understand the relationship between NS1, a previously described influenza virus protein involved in suppression of IFN synthesis, and PB1-F2, we investigated the induction of IFN when NS1 and PB1-F2 were co-expressed in an in vitro transfection system. In this assay we found that PB1-F2 N66S further reduced IFN induction in the presence of NS1. By inducing the IFN-β reporter at different levels in the signaling cascade, we found that PB1-F2 inhibited IFN production at the level of the mitochondrial antiviral signaling protein (MAVS). Furthermore, immunofluorescence studies revealed that PB1-F2 co-localizes with MAVS. In summary, we have characterized the anti-interferon function of PB1-F2 and we suggest that this activity contributes to the enhanced pathogenicity seen with PB1-F2 N66S- expressing influenza viruses.
Keywords Adaptor Proteins, Signal Transducing/immunologyAnimalsBone Marrow CellsCells, CulturedDendritic CellsHumansInfluenza A virus/chemistry/immunology/pathogenicityInterferon Type I/biosynthesis/geneticsMiceMutation, MissenseNewcastle disease virusTranscriptional ActivationViral Nonstructural Proteins/geneticsViral Proteins/physiologyVirulence
PMID: 21695240
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VARGA, Zsuzsanna T et al. The influenza virus protein PB1-F2 inhibits the induction of type I interferon at the level of the MAVS adaptor protein. In: PLOS pathogens, 2011, vol. 7, n° 6, p. e1002067. doi: 10.1371/journal.ppat.1002067

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Deposited on : 2015-09-25

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