Phosphorylation meets ubiquitination:: The control of NF-κB activity

NF-kappa B (nuclear factor-kappa B) 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-kappa B 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 reprogramming of gene expression. NF-kappa B is normally sequestered in the cytoplasm of nonstimulated cells and consequently must be translocated into the nucleus to function. The subcellular location of NF-kappa B is controlled by a family of inhibitory proteins, I kappa Bs, which bind NF-kappa B and mask its nuclear localization signal, thereby preventing nuclear uptake. Exposure of cells to a variety of extracellular stimuli leads to the rapid phosphorylation, ubiquitination, and ultimately proteolytic degradation of I kappa B, which frees NF-kappa B to translocate to the nucleus where it regulates gene transcription. NF-kappa B 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 understanding the details of the signaling pathways that regulate NF-kappa B activity, particularly those responding to the proinflammatory cytokines tumor necrosis factor-alpha and interleukin-1. The multisubunit I kappa B kinase (IKK) responsible for inducible I kappa B phosphorylation is the point of convergence for most NF-KB-activating stimuli. IKK contains two catalytic subunits, IKK alpha and IKK beta, both of which are able to correctly phosphorylate I kappa B. Gene knockout studies have shed light on the very different physiological functions of IKK alpha and IKK beta. After phosphorylation, the IKK phosphoacceptor sites on I kappa B serve as an essential part of a specific recognition site for E3RS(I kappa B/beta-TrCP), SCF-type E3 ubiquitin ligase, thereby explaining how IKK controls I kappa B ubiquitination and degradation. A variety of other signaling events, including phosphorylation of NF-kappa B, hyperphosphorylation of IKK, induction of I kappa B synthesis, and the processing of NF-kappa B precursors, provide additional mechanisms that modulate the level and duration of NF-kappa B activity.