The PB2 subunit of the influenza virus RNA polymerase affects virulence by interacting with MAVS and inhibiting IFN-{beta} expression.
http://www.ncbi.nlm.nih.gov/pubmed/20538852
Graef KM, Vreede FT, Lau YF, McCall AW, Carr SM, Subbarao K, Fodor E.
Laboratory of Infectious Diseases, NIAID, NIH, Bethesda, MD 20892, USA; Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK; and Medical Countermeasures (Biological) Laboratory, DMERI, DSO National Laboratories, Singapore 117510.
Abstract
The PB2 subunit of the influenza virus RNA polymerase is a major virulence determinant of influenza viruses. However the molecular mechanisms involved remain unknown. It was previously shown that the PB2 protein, in addition to its nuclear localization, also accumulates in the mitochondria. Here, we demonstrate that the PB2 protein interacts with the mitochondrial antiviral signaling protein, MAVS (also known as IPS-1, VISA, or Cardif), and inhibits MAVS-mediated IFN-beta expression.
In addition, we show that PB2 proteins of influenza viruses differ in their abilities to associate with the mitochondria. In particular, the PB2 proteins of seasonal human influenza viruses localize to the mitochondria while PB2 proteins of avian influenza viruses are non-mitochondrial. This difference in localization is caused by a single amino acid polymorphism in the PB2 mitochondrial targeting signal. In order to address the functional significance of the mitochondrial localization of the PB2 protein in vivo, we have generated two recombinant human influenza viruses encoding either mitochondrial or non-mitochondrial PB2 proteins. We found that the difference in the mitochondrial localization of the PB2 proteins does not affect the growth of these viruses in cell culture. However, the virus encoding the non-mitochondrial PB2 protein induces higher levels of IFN-beta and, in an animal model, is attenuated compared to the isogenic virus encoding a mitochondrial PB2. Overall this study implicates the PB2 protein in the regulation of host antiviral innate immune pathways and suggests an important role for the mitochondrial association of the PB2 protein in determining virulence.
PMID: 20538852 [PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/20538852
Graef KM, Vreede FT, Lau YF, McCall AW, Carr SM, Subbarao K, Fodor E.
Laboratory of Infectious Diseases, NIAID, NIH, Bethesda, MD 20892, USA; Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK; and Medical Countermeasures (Biological) Laboratory, DMERI, DSO National Laboratories, Singapore 117510.
Abstract
The PB2 subunit of the influenza virus RNA polymerase is a major virulence determinant of influenza viruses. However the molecular mechanisms involved remain unknown. It was previously shown that the PB2 protein, in addition to its nuclear localization, also accumulates in the mitochondria. Here, we demonstrate that the PB2 protein interacts with the mitochondrial antiviral signaling protein, MAVS (also known as IPS-1, VISA, or Cardif), and inhibits MAVS-mediated IFN-beta expression.
In addition, we show that PB2 proteins of influenza viruses differ in their abilities to associate with the mitochondria. In particular, the PB2 proteins of seasonal human influenza viruses localize to the mitochondria while PB2 proteins of avian influenza viruses are non-mitochondrial. This difference in localization is caused by a single amino acid polymorphism in the PB2 mitochondrial targeting signal. In order to address the functional significance of the mitochondrial localization of the PB2 protein in vivo, we have generated two recombinant human influenza viruses encoding either mitochondrial or non-mitochondrial PB2 proteins. We found that the difference in the mitochondrial localization of the PB2 proteins does not affect the growth of these viruses in cell culture. However, the virus encoding the non-mitochondrial PB2 protein induces higher levels of IFN-beta and, in an animal model, is attenuated compared to the isogenic virus encoding a mitochondrial PB2. Overall this study implicates the PB2 protein in the regulation of host antiviral innate immune pathways and suggests an important role for the mitochondrial association of the PB2 protein in determining virulence.
PMID: 20538852 [PubMed - as supplied by publisher]
