It takes two to tango: IκBs, the multifunctional partners of NF-κB

The inhibitory IkappaB proteins have been discovered as fundamental regulators of the inducible transcription factor nuclear factor-κB (NF-κB). As a generally excepted model, stimulus-dependent destruction of inhibitory IκBs and processing of precursor molecules, both promoted by components of the signal integrating IκB kinase complex, are the key events for the release of various NF-κB/Rel dimers and subsequent transcriptional activation. Intense research of more than 20 years provides evidence that the extending family of IkappaBs act not simply as reversible inhibitors of NF-κB activation but rather as a complex regulatory module, which assures feedback regulation of the NF-κB system and either can inhibit or promote transcriptional activity in a stimulus-dependent manner. Thus, IκB and NF-κB/Rel family proteins establish a complex interrelationship that allows modulated NF-κB-dependent transcription, tailored to the physiological environment.