Dissecting the mechanism of signaling-triggered nuclear export of newly synthesized influenza virus ribonucleoprotein complexes

Influenza viruses (IV) exploit a variety of signaling pathways. Previous studies showed that the Raf/MEK/ERK pathway is functionally linked to nuclear export of viral ribonucleoprotein (vRNP) complexes, suggesting that vRNP export is a signaling induced event. However, the underlying mechanism remained completely enigmatic. Here we have dissected the unknown molecular steps of signaling-driven vRNP export. We identified RSK1 as downstream target of virus-activated ERK signaling. While RSK2 displays an antiviral role, we demonstrate for the first time a virus-supportive function of RSK1, migrating to the nucleus to phosphorylate NP, the major constituent of vRNPs. This drives association with viral M1 at the chromatin, important for vRNP export. Inhibition or knockdown of MEK, ERK or RSK1 caused impaired vRNP export actions of different RSK isoforms.