Double-stranded RNA-dependent protein kinase activates transcription factor NF-κB by phosphorylating IκB

The induction of interferon (IFN) genes by viruses or double-stranded RNA (dsRNA) requires the assembly of a complex set of transcription factors on responsive DNA elements of IFN gene promoters. One of the factors necessary for regulating IFN-β gene transcription is nuclear factor NF-κB, the activation of which is triggered by dsRNA. It has previously been suggested that the dsRNA-activated p68 protein kinase (PKR) may act as an inducer- receptor, transducing the signal from dsRNA to NF-κB through phosphorylation of the inhibitor IκB. We present direct evidence that PKR can phosphorylate IκB-α (MAD-3) and activate NF-κB DNA binding activity in vitro. We further show that dsRNA induces an unusual phosphorylated form of IκB-α. The expression of a transdominant mutant PKR is able to perturb the dsRNA- mediated signaling pathway in vivo, suggesting a role for this kinase in IFN- β gene induction.