Activation of the I kappa B alpha kinase (IKK) complex by double-stranded RNA-binding defective and catalytic inactive mutants of the interferon-inducible protein kinase PKR

The interferon (IFN)-inducible double stranded (ds) RNA-activated protein k inase PKR plays an important role in protein synthesis by modulating the ph osphorylation of the alpha -subunit of eukaryotic initiation fact 2 (eIF-2 alpha), In addition to translational control, PKR has been implicated in se veral signaling pathways leading to gene transcription. For example, PKR in duces I kappaB alpha kinase (IKK) activity and I kappaB alpha phosphorylati on leading to the induction of NF-kappaB-mediated gene transcription. Recen t findings suggested that NF-kappaB activation by PKR does not require the catalytic activity of the kinase, Here, we provide novel evidence that indu ction of IKK and NF-kappaB activities proceeds independently of the dsRNA-b inding properties of PKR and also verify the kinase-free role of PKR in thi s process. We also show that the effects of PKR mutants on IKK and NF-kappa B activation are independent of cell transformation but are dependent on th e amount of the mutant PKR proteins expressed in cells. These data strongly support an indirect role of PKR in I kappaB alpha phosphorylation by modul ating IKK activity through pathways that do not utilize the enzymatic and d sRNA-binding properties of PKR.