Old target new approach: an alternate NF-kappaB activation pathway via translation inhibition.

Activation of the transcription factor NF-kappaB is a highly regulated multi-level process. The critical step during activation is the release from its inhibitor IkappaB, which as any other protein is under the direct influence of translation regulation. In this review, we summarize in detail the current understanding of the impact of translational regulation on NF-kappaB activation. We illustrate a newly developed mechanism of eIF2alpha kinase-mediated IkappaB depletion and subsequent NF-kappaB activation. We also show that the classical NF-kappaB activation pathways occur simultaneously with, and are complemented by, translational down regulation of the inhibitor molecule IkappaB, the importance of one or the other being shifted in accordance with the type and magnitude of the stressing agent or stimuli.