Influenza Virus Protein PB1-F2 Inhibits the Induction of Type I Interferon by Binding to MAVS and Decreasing Mitochondrial Membrane Potential
| Autor: | Balaji Manicassamy, Peter Palese, Zsuzsanna T. Varga, Alesha Grant |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Vesicle-associated membrane protein 8
animal structures viruses Immunology Virulence Biology medicine.disease_cause Microbiology Virus Cell Line Viral Proteins Influenza A Virus H1N1 Subtype Interferon Virology Protein Interaction Mapping medicine Influenza A virus Humans Adaptor Proteins Signal Transducing Immune Evasion HSPA9 Membrane Potential Mitochondrial virus diseases Signal transducing adaptor protein biochemical phenomena metabolism and nutrition Molecular biology Virus-Cell Interactions Transmembrane domain Insect Science Host-Pathogen Interactions Interferon Type I Protein Binding medicine.drug |
| Zdroj: | Journal of Virology. 86:8359-8366 |
| ISSN: | 1098-5514 0022-538X |
| DOI: | 10.1128/jvi.01122-12 |
| Popis: | PB1-F2 is a small, 87- to 90-amino-acid-long protein encoded by the +1 alternate open reading frame of the PB1 gene of most influenza A virus strains. It has been shown to contribute to viral pathogenicity in a host- and strain-dependent manner, and we have previously discovered that a serine at position 66 (66S) in the PB1-F2 protein increases virulence of the 1918 and H5N1 pandemic viruses. Recently, we have shown that PB1-F2 inhibits the induction of type I interferon (IFN) at the level of the MAVS adaptor protein. However, the molecular mechanism for the IFN antagonist function of PB1-F2 has remained unclear. In the present study, we demonstrated that the C-terminal portion of the PB1-F2 protein binds to MAVS in a region that contains the transmembrane domain. Strikingly, PB1-F2 66S was observed to bind to MAVS more efficiently than PB1-F2 66N. We also tested the effect of PB1-F2 on the IFN antagonist functions of the polymerase proteins PB1, PB2, and PA and observed enhanced IFN inhibition by the PB1 and PB2 proteins in combination with PB1-F2 but not by the PA protein. Using a flow cytometry-based assay, we demonstrate that the PB1-F2 protein inhibits MAVS-mediated IFN synthesis by decreasing the mitochondrial membrane potential (MMP). Interestingly, PB1-F2 66S affected the MMP more efficiently than wild-type PB1-F2. In summary, the results of our study identify the molecular mechanism by which the influenza virus PB1-F2 N66S protein increases virulence. |
| Databáze: | OpenAIRE |
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