Protein kinase PKR amplification of interferon beta induction occurs through initiation factor eIF-2alpha-mediated translational control.
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McAllister CS, Taghavi N, Samuel CE
Protein kinase PKR amplification of interferon beta induction occurs through initiation factor eIF-2alpha-mediated translational control.
J Biol Chem. 2012 Oct 19;287(43):36384-92. doi: 10.1074/jbc.M112.390039. Epub 2012 Sep 4.
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- 22948139 [ View in PubMed]
- Abstract
The protein kinase PKR is activated by RNA with double-stranded (ds) structure and subsequently impairs translation through phosphorylation of protein synthesis initiation factor eIF-2alpha. PKR also mediates activation of signal transduction pathways leading to interferon beta (IFN-beta) gene induction following virus-infection or RNA transfection. We previously demonstrated in measles virus-infected cells that PKR is required for the maximal induction of IFN-beta gene expression by the interferon promoter stimulator gene 1 (IPS-1) adaptor-dependent cytosolic RNA sensor pathway. While both IPS-1 and PKR are important mediators of IFN-beta induction, with PKR contributing to an enhanced NF-kappaB activation, the mechanism by which PKR enhances NF-kappaB activity and amplifies IFN-beta induction is unresolved. Herein we tested the possibility that PKR could activate signal transduction pathways indirectly through translational control responses. Following transfection with synthetic or natural dsRNAs or infection with measles virus, we observed increased mRNA but decreased protein levels for the inhibitor of NF-kappaB signaling, IkappaB-alpha, that correlated with PKR activation and eIF-2alpha phosphorylation. Importantly, knockdown of PKR increased IkappaB-alpha protein levels and impaired IFN-beta induction. Additionally, inhibition of translation by cycloheximide treatment rescued IFN-beta induction following PKR knockdown but not IPS-1 knockdown. Mutation of eIF-2alpha to prevent phosphorylation also impaired IFN-beta induction in PKR-sufficient virus-infected cells. These results suggest that an eIF-2alpha-dependent translation inhibition mechanism is sufficient to explain the PKR-mediated amplification of IPS-1-dependent IFN-beta induction by foreign RNA.