P HOSPHORYLATION M EETS U BIQUITINATION : The Control of NF-jB Activity
NF-κB (nuclear factor-κB) is a collective name for inducible dimeric transcription factors composed of members of the Rel family of DNA-binding proteins that recognize a common sequence motif. NF-κB is found in essentially all cell types and is involved in activation of an exceptionally large number of genes in response to infections, inflammation, and other stressful situations requiring rapid reprogram- ming of gene expression. NF-κB is normally sequestered in the cytoplasm of nonsti- mulated cells and consequently must be translocated into the nucleus to function. The subcellular location of NF-κB is controlled by a family of inhibitory proteins, IκBs, which bind NF-κB and mask its nuclear localization signal, thereby preventing nuclear uptake. Exposure of cells to a variety of extracellular stimuli leads to the rapid phos- phorylation, ubiquitination, and ultimately proteolytic degradation of IjB, which frees NF-κB to translocate to the nucleus where it regulates gene transcription. NF-κB activation represents a paradigm for controlling the function of a regulatory protein via ubiquitination-dependent proteolysis, as an integral part of a phosphorylation- based signaling cascade. Recently, considerable progress has been made in under- standing the details of the signaling pathways that regulate NF-κBactivity, particularly those responding to the proinflammatory cytokines tumor necrosis factor-? and inter- leukin-1. The multisubunit IjB kinase (IKK) responsible for inducible IjB phos- phorylation is the point of convergence for most NF-jB–activating stimuli. IKK contains two catalytic subunits, IKK? and IKKb, both of which are able to correctly phosphorylate IjB. Gene knockout studies have shed light on the very different physiological functions of IKK? and IKKb. After phosphorylation, the IKK phos- phoacceptor sites on IjB serve as an essential part of a specific recognition site for E3RSIjB/b-TrCP, an SCF-type E3 ubiquitin ligase, thereby explaining how IKK controls IjB ubiquitination and degradation. A variety of other signaling events, including phosphorylation of NF-jB, hyperphosphorylation of IKK, induction of IjB synthesis, and the processing of NF-jBprecursors, provide additional mechanisms that modulate the level and duration of NF-B activity.