Beyond IκBs: alternative regulation of NF‐KB activity

The transcription factor nuclear factor-kappa B (NF-kappaB) is a crucial regulator of many physiological and patho-physiological processes, including control of the adaptive and innate immune responses, inflammation, proliferation, tumorigenesis, and apoptosis. Thus, the tight regulation of NF-kappaB activity within a cell is extremely important. The central mechanism of NF-kappaB regulation is the signal-induced proteolytic degradation of a family of cytoplasmic inhibitors of NF-kappaB, the IkappaBs. However, with the discovery of an IkappaB-independent noncanonical or "alternative" pathway of NF-kappaB activation, the importance of other regulatory mechanisms responsible for the fine-tuning of NF-kappaB became clear. Post-translational modification, especially phosphorylation, of the Rel proteins, of which dimeric NF-kappaB is composed, are such alternative regulatory mechanisms. The best analyzed example is RelA phosphorylation, which takes place at specific amino acids resulting in distinct functional changes of this gene regulatory protein. The interaction of NF-kappaB with other proteins such as glucocorticoid receptors is very important for the regulation of NF-kappaB activity. Recently, exciting new concepts of IkappaB-independent NF-kappaB control like dimer exchange and nucleolar sequestration of RelA have been described, indicating that many aspects of NF-kappaB control are waiting to be discovered.