Stiftung Tierärztliche Hochschule Hannover (TiHo)

Alternative interaction sites in the influenza A virus nucleoprotein mediate viral escape from the importin-α7 mediated nuclear import pathway

Resa-Infante, Patricia ORCID; Bonet, Jaume; Thiele, Swantje; Alawi, Malik; Stanelle-Bertram, Stephanie; Tuku, Berfin; Beck, Sebastian; Oliva, Baldo; Gabriel, Gülsah GND

Influenza A viruses are able to adapt to restrictive conditions due to their high mutation rates. Importin-α7 is a component of the nuclear import machinery required for avian-mammalian adaptation and replicative fitness in human cells. Here, we elucidate the mechanisms by which influenza A viruses may escape replicative restriction in the absence of importin-α7. To address this question, we assessed viral evolution in mice lacking the importin-α7 gene. We show that three mutations in particular occur with high frequency in the viral nucleoprotein (NP) protein (G102R, M105K and D375N) in a specific structural area upon in vivo adaptation. Moreover, our findings suggest that the adaptive NP mutations mediate viral escape from importin-α7 requirement likely due to the utilization of alternative interaction sites in NP beyond the classical nuclear localization signal. However, viral escape from importin-α7 by mutations in NP is, at least in part, associated with reduced viral replication highlighting the crucial contribution of importin-α7 to replicative fitness in human cells.

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Resa-Infante, P., Bonet, J., Thiele, S., Alawi, M., Stanelle-Bertram, S., Tuku, B., Beck, S., Oliva, B., Gabriel, G., 2019. Alternative interaction sites in the influenza A virus nucleoprotein mediate viral escape from the importin-α7 mediated nuclear import pathway. FEBS journal 286, 3374–3388. https://doi.org/10.1111/febs.14868
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