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 p88(rIPK). This leads to recruitment of a tetrameric protein complex consisting of p88(rIPK), the inhibitor of PKR p58(IPK) 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 cells genetically deficient in MK2 or MK3 genes as well as in highly proliferating tumor cells, in which expression of MKs was diminished by specific small interfering RNA. Accordingly, knockdown of MKs resulted in enhanced phosphorylation of PKR and its substrate eIF2α.
Luig
Christina
C
Institute of Molecular Virology, Westfälische-Wilhelms-University, D-48149 Münster, Germany.
Köther
Katharina
K
Dudek
Sabine Eva
SE
Gaestel
Matthias
M
Hiscott
John
J
Wixler
Viktor
V
Ludwig
Stephan
S
D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D055786:Gene Knockout Techniques; D006801:Humans; D009980:Influenza A virus / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D020798:Two-Hybrid System Techniques; D014779:Virus Replication; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors*; D000099190:MAP-Kinase-Activated Kinase 2
D017931:DNA Primers; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase; D000099190:MAP-Kinase-Activated Kinase 2; C098416:MAP-kinase-activated kinase 3