TAK-ling IKK activation: "Ub" the judge.

Investigation of the signaling events that lead to the activation of the transcription factor nuclear factor kappaB (NF-kappaB) has been a hotbed for the discovery of previously uncharacterized signaling mechanisms. The important role that nondegradative polyubiquitin chains play in these processes is now well recognized; however, precisely how they orchestrate NF-kappaB signaling is still a matter of much controversy. A recent study has challenged the dogmatic view by demonstrating that interleukin-1beta (IL-1beta), a major proinflammatory cytokine, activates two consecutive pathways, the "RING" and "zinc" pathways, to coordinate early and late activation of NF-kappaB, respectively. This study introduces a paradigm shift in the still-evolving mechanism of regulation of NF-kappaB.