Molecular basis for the exploitation of nuclear mRNA export by influenza A virus

Abstract

Influenza A virus replicates in the cell nucleus and has evolved at least two mechanisms to exploit the host nuclear mRNA export pathway. First, we show that a key influenza virulence factor NS1 blocks nuclear export of host mRNAs. We identify the direct target of NS1 as the mRNA export receptor complex, NXF1‐NXT1, which is the principal receptor mediating docking and translocation of mRNAs through the nuclear pore complex via interactions with nucleoporins. We determined the crystal structure of NS1 in complex with NXF1‐NXT1 at 3.8 Å resolution. The structure reveals that NS1 prevents binding of NXF1‐NXT1 to nucleoporins, thereby inhibiting mRNA export through the nuclear pore complex into the cytoplasm for translation. Second, packaging of influenza virus genome has been suggested to require the mRNA export factor UAP56 through interaction with the influenza NP protein, but the mechanism remains elusive. Our biochemical characterization of the NP‐UAP56 interaction suggests that UAP56 primes NP for engaging with viral RNA. Together, our studies uncover the molecular basis of how influenza A virus targets nuclear mRNA export to inhibit host gene expression and promote viral proliferation.Support or Funding InformationNIH R01 GM113874, R01 AI125524, and R35 GM133743