Signal integration via PKR.
The vital role of interferons (IFNs) as mediators of innate immunity is well established. It has recently become apparent that one of the pivotal proteins in mediating the antiviral activity of IFNs, the double-stranded RNA (dsRNA)-activated protein kinase (PKR), also functions as a signal transducer in the proinflammatory response to different agents. PKR is a member of a small family of kinases that are activated by extracellular stresses and that phosphorylate the alpha subunit of protein synthesis initiation factor eIF-2, thereby inhibiting protein synthesis. The activation of PKR during infection by viral dsRNA intermediates results in the inhibition of viral replication. PKR also mediates the activation of signal transduction pathways by proinflammatory stimuli, including bacterial lipopolysaccharide (LPS), tumor necrosis factor alpha (TNF-alpha), and interleukin 1 (IL-1). PKR is a component of the inhibitor of kappaB (IkappaB) kinase complex and plays either a catalytic or structural role in the activation of IkappaB kinase, depending on the stimulus. The activities of the stress-activated protein kinases p38 and c-Jun NH(2)-terminal kinase (JNK) are also regulated by PKR in a pathway that leads to the production of proinflammatory cytokines. This review will focus on the role of PKR in nuclear factor kappa B (NF-kappaB) and mitogen-activated protein kinase (MAPK) pathways, because these have been the subjects of a series of publications over the past year that have reported conflicting findings. Although the conflicts may not be resolved in this review, suggestions are made for experiments that could lead to a clearer understanding of the mechanisms involved.
Williams
B R
BR
The author is in the Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA. williab@ccf.org
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D006801:Humans; D012330:RNA, Double-Stranded / Q000502:physiology; D011971:Receptors, Immunologic / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D019892:eIF-2 Kinase / Q000502:physiology*
D012330:RNA, Double-Stranded; D011971:Receptors, Immunologic; D019892:eIF-2 Kinase