Function of the mouse Mx1 protein is inhibited by overexpression of the PB2 protein of influenza virus.
The interferon-induced murine Mx1 protein possesses an intrinsic antiviral activity with selectivity for influenza viruses. Mx1 accumulates in the nucleus and inhibits the replication of influenza virus at the level of primary transcription. Simultaneous overexpression of the three influenza virus polymerase subunits via recombinant vaccinia virus vectors can titrate out the inhibitory action of Mx1 as determined by the amplification of a transfected recombinant viral reporter gene. A low degree of neutralization was also observed, when PB2 was overexpressed alone [Huang, T., Pavlovic, J., Staeheli, P., and Krystal, M. (1992) J. Virol. 66, 4154-4160]. We now employed a much simpler experimental setting which allowed us to directly measure the effect of PB2 on the antiviral activity of Mx1. We stably transfected a cell line derived from an A2G mouse (homozygous for a functional Mx1 gene) with expression vectors coding for cDNAs of the influenza virus polymerase subunits PB1 and PB2 or of the nucleoprotein (NP). Cells coexpressing Mx1 and PB1 or NP remained resistant to influenza virus infection whereas cells coexpressing Mx1 and PB2 became sensitive to influenza virus infection. The degree of neutralization of Mx1 activity by PB2 was dependent on the Mx1 concentration in the cell. Immunofluorescence analysis revealed that the nuclear localization of Mx1 and PB2 overlapped to a great extent. These findings support the view that Mx1 exerts its antiviral activity by interfering with the function of the influenza virus polymerase subunit PB2.
Stranden
A M
AM
Institute of Medical Virology, University of Zürich, Switzerland.
Staeheli
P
P
Pavlovic
J
J
D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism*; D002451:Cell Compartmentation; D005455:Fluorescent Antibody Technique; D019204:GTP-Binding Proteins; D051379:Mice; D064547:Myxovirus Resistance Proteins; D009687:Nuclear Proteins / Q000302:isolation & purification; D019590:Nucleocapsid Proteins; D009698:Nucleoproteins; D011506:Proteins / Q000187:drug effects* / Q000302:isolation & purification; D012324:RNA-Dependent RNA Polymerase; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000494:pharmacology; D014162:Transfection; D014407:Tumor Cells, Cultured; D014758:Viral Core Proteins / Q000096:biosynthesis / Q000494:pharmacology; D014764:Viral Proteins / Q000096:biosynthesis / Q000302:isolation & purification / Q000494:pharmacology*
D000998:Antiviral Agents; C579070:Mx1 protein, mouse; D064547:Myxovirus Resistance Proteins; D009687:Nuclear Proteins; D019590:Nucleocapsid Proteins; D009698:Nucleoproteins; C057027:PB2 protein, Influenzavirus A; D011506:Proteins; D011994:Recombinant Proteins; D014758:Viral Core Proteins; D014764:Viral Proteins; C077346:influenza virus polymerase basic protein 1; D012324:RNA-Dependent RNA Polymerase; D019204:GTP-Binding Proteins