Phosphorylation meets ubiquitination: The control of NF-kappa B activity

NF-kappa B (nuclear factor-kappa B) is a collective name for inducible dime ric transcription factors composed of members of the Rel family of DNA-bind ing proteins that recognize a common sequence motif. NF-kappa B is found in essentially all cell types and is involved in activation of an exceptional ly 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 subcel lular location of NF-kappa B is controlled by a family of inhibitory protei ns, I kappa Bs, which bind NF-kappa B and mask its nuclear localization sig nal, thereby preventing nuclear uptake. Exposure of cells to a variety of e xtracellular stimuli leads to the rapid phosphorylation, ubiquitination, an d ultimately proteolytic degradation of I kappa B, which frees NF-kappa B t o translocate to the nucleus where it regulates gene transcription. NF-kapp a B activation represents a paradigm for controlling the function of a regu latory protein via ubiquitination-dependent proteolysis, as an integral par t of a phosphorylation-based signaling cascade. Recently, considerable prog ress has been made in understanding the details of the signaling pathways t hat regulate NF-kappa B activity, particularly those responding to the proi nflammatory cytokines tumor necrosis factor-alpha and interleukin-1. The mu ltisubunit I kappa B kinase (IKK) responsible for inducible I kappa B phosp horylation is the point of convergence for most NF-KB-activating stimuli. I KK contains two catalytic subunits, IKK alpha and IKK beta, both of which a re able to correctly phosphorylate I kappa B. Gene knockout studies have sh ed light on the very different physiological functions of IKK alpha and IKK beta. After phosphorylation, the IKK phosphoacceptor sites on I kappa B se rve 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 contro ls I kappa B ubiquitination and degradation. A variety of other signaling e vents, including phosphorylation of NF-kappa B, hyperphosphorylation of IKK , induction of I kappa B synthesis, and the processing of NF-kappa B precur sors, provide additional mechanisms that modulate the level and duration of NF-kappa B activity.