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 kinase PKR plays an important role in protein synthesis by modulating the phosphorylation of the alpha-subunit of eukaryotic initiation fact 2 (eIF-2 alpha). In addition to translational control, PKR has been implicated in several signaling pathways leading to gene transcription. For example, PKR induces I kappa B alpha kinase (IKK) activity and I kappa B alpha phosphorylation leading to the induction of NF-kappa B-mediated gene transcription. Recent findings suggested that NF-kappa B activation by PKR does not require the catalytic activity of the kinase. Here, we provide novel evidence that induction of IKK and NF-kappa B activities proceeds independently of the dsRNA-binding properties of PKR and also verify the kinase-free role of PKR in this 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 the amount of the mutant PKR proteins expressed in cells. These data strongly support an indirect role of PKR in I kappa B alpha phosphorylation by modulating IKK activity through pathways that do not utilize the enzymatic and dsRNA-binding properties of PKR.
Ishii
T
T
Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada.
Kwon
H
H
Hiscott
J
J
Mosialos
G
G
Koromilas
A E
AE
D016475:3T3 Cells; D000818:Animals; D002384:Catalysis; D002471:Cell Transformation, Neoplastic; D004247:DNA / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D051550:I-kappa B Kinase; D007372:Interferons / Q000494:pharmacology*; D051379:Mice; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012330:RNA, Double-Stranded / Q000378:metabolism*; D015533:Transcriptional Activation; D019892:eIF-2 Kinase / Q000502:physiology*
D016328:NF-kappa B; D012330:RNA, Double-Stranded; D004247:DNA; D007372:Interferons; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase; C496559:CHUK protein, human; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases