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MAP kinase‐activated protein kinases 2 and 3 are required for influenza A virus propagation and act via inhibition of PKR
Author(s) -
Luig Christina,
Köther Katharina,
Dudek Sabine Eva,
Gaestel Matthias,
Hiscott John,
Wixler Viktor,
Ludwig Stephan
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.10-158766
Subject(s) - protein kinase r , eif 2 kinase , protein kinase a , biology , kinase , interferon , virology , antiviral protein , microbiology and biotechnology , virus , mitogen activated protein kinase kinase , cyclin dependent kinase 2 , rna , biochemistry , gene
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, C., Köther, K., Dudek, S. E., Gaestel, M., Hiscott, J., Wixler, V., Ludwig, S. MAP kinase‐activated protein kinases 2 and 3 are required for influenza A virus propagation and act via inhibition of PKR. FASEB J. 24, 4068–4077 (2010). www.fasebj.org