MAP kinase-activated protein kinases 2 and 3 are required for influenza A virus propagation and act via inhibition of PKR

Influenza viruses have to overcome the type I interferon induced antiviral response to successfully propagate in target cells. A major antiviral factor induced by interferons is the protein kinase R (PKR) that is further activated by dsRNA and phosphorylates the eukaryotic initiation factor 2 (eIF2α). This results in inhibition of protein translation thereby limiting viral replication. Here we describe a novel mechanism by which influenza A viruses escape the antiviral action of PKR. We demonstrate that the mitogen-activated protein kinase-activated protein kinases (MAPKAPKs) MK2 and MK3 are activated on virus infection and, in their active form, directly interact with the repressor of the inhibitor of PKR p88rIPK. This leads to recruitment of a tetrameric protein complex consisting of p88rIPK, the inhibitor of PKR p58IPK and PKR itself, and finally results in inhibition of the kinase. The importance of MKs for influenza virus propagation was further underscored by demonstrating reduced viral progeny in c...