Abstract
The antiviral myxovirus resistance protein 1 (MX1) is an interferon-induced GTPase that plays an important role in the defense of mammalian cells against influenza A viruses. Mouse MX1 interacts with the influenza ribonucleoprotein complexes (vRNPs) and can prevent the interaction between polymerase basic 2 (PB2) and the nucleoprotein (NP) of influenza A viruses. However, it is unclear whether mouse MX1 disrupts the PB2-NP interaction in the context of pre-existing vRNPs or prevents the assembly of new vRNP components. Here, we describe a conditionally active mouse MX1 variant that only exerts antiviral activity in the presence of a small molecule drug. Once activated, this MX1 construct phenocopies the antiviral and NP binding activity of wild type MX1. The interaction between PB2 and NP is disrupted within minutes after the addition of the small molecule activator. These findings support a model in which mouse MX1 interacts with the incoming influenza A vRNPs and inhibits their activity by disrupting the PB2-NP interaction.
Highlights
The myxovirus resistance (MX) genes are evolutionarily conserved in most vertebrates
We showed that the active form of this conditional myxovirus resistance protein 1 (MX1) variant behaves as the wild type protein based on its antiviral activity, nuclear localization, and interaction with NP
Generation of a Conditionally Inactive MX1 Variant That Can Be Rapidly Activated—We previously reported that mouse MX1 can prevent the interaction between the influenza A virus vRNP components polymerase basic 2 (PB2) and NP, which could explain how this protein suppresses influenza A virus replication [14]
Summary
The myxovirus resistance (MX) genes are evolutionarily conserved in most vertebrates. In the presence of F-NLS-FKBP and rapalog, FRB*-MX1 regained antiviral activity in the PR8 minireplicon system to a degree comparable with that of wild type MX1 (Fig. 1B). This suggests that fusion of FRB* to the N terminus of MX1 interferes with the antiviral activity of mouse MX1 by a mechanism that can be reversed in the presence of F-NLS-FKBP by the addition of rapalog.
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