Abstract
The MxA protein belongs to the family of dynamin-like, large GTPases and exerts antiviral activity against a variety of RNA and DNA viruses, including influenza A (IAV). MxA restricts infection with zoonotic avian IAV, while human IAV have adapted and exhibit a largely resistant phenotype. Recent evidence reveals that the resistance phenotype of human IAV segregates with a discrete cluster of surface-exposed amino acids in the nucleoprotein (NP) of human IAV, indicating that MxA targets NP. Thus, we addressed the question whether MxA has to form a stable complex with NP to interfere with its function. Co-immunoprecipitation experiments with cytoplasmic extracts of cells either infected with IAV or ectopically transfected with plasmids encoding NP revealed that interaction of MxA and NP was only detected when MxA was expressed in its dimeric form. As expected, MxA bound to NP of all Mx-sensitive avian strains tested, while the NP of a human MxA-resistant IAV strain derived from the 1918 IAV (H1N1) strain did not bind. Intriguingly, the NP from the MxA-resistant human pandemic H1N1 (2009) strain still exhibited pronounced binding to MxA. However, the resistance-associated amino acids in NP differ between these two human two strains, suggesting that MxA binding to NP is required but not sufficient for activity. Hence, we currently map the amino acids of NP from sensitive and resistant strains responsible for binding and/or susceptibilities to MxA exploiting their differences in binding-capacities and sensitivity to MxA.
Published Version
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