DOUBLE-STRANDED RNA-DEPENDENT PROTEIN-KINASE ACTIVATES TRANSCRIPTION FACTOR NF-KAPPA-B BY PHOSPHORYLATING I-KAPPA-B

The induction of interferon (IFN) genes by viruses or double-stranded RNA (dsRNA) requires the assembly of a complex set of transcription fa ctors on responsive DNA elements of IFN gene promoters. One of the fac tors necessary for regulating IFN-beta gene transcription is nuclear f actor NF-kappa B, the activation of which is triggered by dsRNA. It ha s previously been suggested that the dsRNA-activated p68 protein kinas e (PKR) may act as an inducer-receptor, transducing the signal from ds RNA to NF-kappa B through phosphorylation of the inhibitor I kappa B. We present direct evidence that PKR can phosphorylate I kappa B-alpha (MAD-3) and activate NF-kappa B DNA binding activity in vitro. We furt her show that dsRNA induces an unusual phosphorylated form of I kappa B-alpha. The expression of a transdominant mutant PKR is able to pertu rb the dsRNA-mediated signaling pathway in vivo, suggesting a role for this kinase in IFN-beta gene induction.