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Interferon-inducible protein Mx1 inhibits influenza virus by interfering with functional viral ribonucleoprotein complex assembly

Judith Verhelst (UGent) , Eef Parthoens (UGent) , Bert Schepens (UGent) , Walter Fiers and Xavier Saelens (UGent)
(2012) JOURNAL OF VIROLOGY. 86(24). p.13445-13455
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Abstract
Mx1 is a GTPase that is part of the antiviral response induced by type I and type III interferons in the infected host. It inhibits influenza virus infection by blocking viral transcription and replication, but the molecular mechanism is not known. Polymerase basic protein 2 (PB2) and nucleoprotein (NP) were suggested to be the possible target of Mx1, but a direct interaction between Mx1 and any of the viral proteins has not been reported. We investigated the interplay between Mx1, NP, and PB2 to identify the mechanism of Mx1's antiviral activity. We found that Mx1 inhibits the PB2-NP interaction, and the strength of this inhibition correlated with a decrease in viral polymerase activity. Inhibition of the PB2-NP interaction is an active process requiring enzymatically active Mx1. We also demonstrate that Mx1 interacts with the viral proteins NP and PB2, which indicates that Mx1 protein has a direct effect on the viral ribonucleoprotein complex. In a minireplicon system, avian-like NP from swine virus isolates was more sensitive to inhibition by murine Mx1 than NP from human influenza A virus isolates. Likewise, murine Mx1 displaced avian NP from the viral ribonucleoprotein complex more easily than human NP. The stronger resistance of the A/H1N1 pandemic 2009 virus against Mx1 also correlated with reduced inhibition of the PB2-NP interaction. Our findings support a model in which Mx1 interacts with the influenza ribonucleoprotein complex and interferes with its assembly by disturbing the PB2-NP interaction.
Keywords
VESICULAR STOMATITIS-VIRUS, A VIRUS, RNA-POLYMERASE, MUTATIONAL ANALYSIS, ANTIVIRAL ACTIVITY, NUCLEAR IMPORT, GENE-PRODUCT, PA PROTEIN, RESISTANCE, MICE

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Citation

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Chicago
Verhelst, Judith, Eef Parthoens, Bert Schepens, Walter Fiers, and Xavier Saelens. 2012. “Interferon-inducible Protein Mx1 Inhibits Influenza Virus by Interfering with Functional Viral Ribonucleoprotein Complex Assembly.” Journal of Virology 86 (24): 13445–13455.
APA
Verhelst, Judith, Parthoens, E., Schepens, B., Fiers, W., & Saelens, X. (2012). Interferon-inducible protein Mx1 inhibits influenza virus by interfering with functional viral ribonucleoprotein complex assembly. JOURNAL OF VIROLOGY, 86(24), 13445–13455.
Vancouver
1.
Verhelst J, Parthoens E, Schepens B, Fiers W, Saelens X. Interferon-inducible protein Mx1 inhibits influenza virus by interfering with functional viral ribonucleoprotein complex assembly. JOURNAL OF VIROLOGY. 2012;86(24):13445–55.
MLA
Verhelst, Judith, Eef Parthoens, Bert Schepens, et al. “Interferon-inducible Protein Mx1 Inhibits Influenza Virus by Interfering with Functional Viral Ribonucleoprotein Complex Assembly.” JOURNAL OF VIROLOGY 86.24 (2012): 13445–13455. Print.
@article{3077225,
  abstract     = {Mx1 is a GTPase that is part of the antiviral response induced by type I and type III interferons in the infected host. It inhibits influenza virus infection by blocking viral transcription and replication, but the molecular mechanism is not known. Polymerase basic protein 2 (PB2) and nucleoprotein (NP) were suggested to be the possible target of Mx1, but a direct interaction between Mx1 and any of the viral proteins has not been reported. We investigated the interplay between Mx1, NP, and PB2 to identify the mechanism of Mx1's antiviral activity. We found that Mx1 inhibits the PB2-NP interaction, and the strength of this inhibition correlated with a decrease in viral polymerase activity. Inhibition of the PB2-NP interaction is an active process requiring enzymatically active Mx1. We also demonstrate that Mx1 interacts with the viral proteins NP and PB2, which indicates that Mx1 protein has a direct effect on the viral ribonucleoprotein complex. In a minireplicon system, avian-like NP from swine virus isolates was more sensitive to inhibition by murine Mx1 than NP from human influenza A virus isolates. Likewise, murine Mx1 displaced avian NP from the viral ribonucleoprotein complex more easily than human NP. The stronger resistance of the A/H1N1 pandemic 2009 virus against Mx1 also correlated with reduced inhibition of the PB2-NP interaction. Our findings support a model in which Mx1 interacts with the influenza ribonucleoprotein complex and interferes with its assembly by disturbing the PB2-NP interaction.},
  author       = {Verhelst, Judith and Parthoens, Eef and Schepens, Bert and Fiers, Walter and Saelens, Xavier},
  issn         = {0022-538X},
  journal      = {JOURNAL OF VIROLOGY},
  keywords     = {VESICULAR STOMATITIS-VIRUS,A VIRUS,RNA-POLYMERASE,MUTATIONAL ANALYSIS,ANTIVIRAL ACTIVITY,NUCLEAR IMPORT,GENE-PRODUCT,PA PROTEIN,RESISTANCE,MICE},
  language     = {eng},
  number       = {24},
  pages        = {13445--13455},
  title        = {Interferon-inducible protein Mx1 inhibits influenza virus by interfering with functional viral ribonucleoprotein complex assembly},
  url          = {http://dx.doi.org/10.1128/JVI.01682-12},
  volume       = {86},
  year         = {2012},
}

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