Alternative interaction sites in the influenza A virus nucleoprotein mediate viral escape from the importin‐α7 mediated nuclear import pathway. (25th May 2019)

• Record Type: Journal Article
• Authors: Resa‐Infante, Patricia; Bonet, Jaume; Thiele, Swantje; Alawi, Malik; Stanelle‐Bertram, Stephanie; Tuku, Berfin; Beck, Sebastian; Oliva, Baldo; Gabriel, Gülsah
• Is Part Of: FEBS journal. Volume 286:Number 17(2019)
• Page Start: 3374
• Page End: 3388
• Publication Date: 2019-05-25
• Subjects: host–pathogen interaction -- influenza virus -- nuclear transport -- protein–protein interaction -- virus evolution; Biochemistry -- Periodicals; Molecular biology -- Periodicals; Pathology, Molecular -- Periodicals; 572
• DOI: 10.1111/febs.14868
• Languages: English
• ISSNs: 1742-464X

Abstract

Abstract : 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. Abstract : Influenza A virus replication in human cells is regulated by a complex interplay of various cellular factors. In this study, we show that escape from the influenza A virus replication‐promoting factor importin‐α7 is enabled by accelerated virus evolution. Herein, adaptive mutations in the viral nucleoprotein occur that may partially restore influenza A virus replication in human cells.