The NF-κB Activation Pathway: A Paradigm in Information Transfer from Membrane to Nucleus

Nuclear factor kappa B (NF-κB)/Rel proteins are dimeric, sequence-specific transcription factors involved in the activation of an exceptionally large number of genes in response to inflammation, viral and bacterial infections, and other stressful situations requiring rapid reprogramming of gene expression. In unstimulated cells, NF-κB is sequestered in an inactive form in the cytoplasm bound to inhibitory IκB proteins. Stimulation leads to the rapid phosphorylation, ubiquitinylation, and ultimately proteolytic degradation of IκB, which frees NF-κB to translocate to the nucleus and activate the transcription of its target genes. The multisubunit IκB kinase (IKK) responsible for the inducible phosphorylation of IκB appears to be the initial point of convergence for most stimuli that activate NF-κB. IKK contains two catalytic subunits, IKKα and IKKβ, both of which phosphorylate IκB at sites phosphorylated in vivo. Gene knockout studies indicate that IKKβ is primarily responsible for the activation of NF-κB in response to proinflammatory stimuli, whereas IKKα is essential for keratinocyte differentiation. The activity of IKK is regulated by phosphorylation. IKK contains a regulatory subunit, IKKγ, which is critical for activation of IKK and is postulated to serve as a recognition site for upstream activators. When phosphorylated, the IKK recognition site on IκBα serves as a specific recognition site for the κ-TrCP-like component of a Skp1-Cullin-F-box-type E3 ubiquitin-protein ligase. A variety of other signaling events, including phosphorylation of NF-κB, phosphorylation of IKK, new synthesis of IκBs, and the processing of NF-κB precursors provide mechanisms of modulating the amount and duration of NF-κB activity. The transcription factor nuclear factor kappa B (NF-κB) is a somewhat heterogeneous collection of dimeric DNA-binding proteins composed of subunits that belong to the Rel family and 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 inflammation, viral and bacterial infections, and other stressful situations requiring rapid reprogramming of gene expression. NF-κB is sequestered in the cytoplasm of nonstimulated 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, the IκBs, which noncovalently bind to NF-κB and mask its nuclear localization signal, thereby preventing nuclear uptake. Exposure of cells to various extracellular stimuli leads to the rapid phosphorylation, ubiquitinylation, and ultimately proteolytic degradation of IκB, which frees NF-κB to translocate to the nucleus, where it regulates gene transcription. Recently, considerable progress has been made in understanding the details of the signaling pathways that regulate and mediate inducible IκB degradation, particularly those pathways that respond to the proinflammatory cytokines tumor necrosis factor α (TNF-α) and interleukin-1 (IL-1). The multisubunit IκB kinase (IKK) responsible for the inducible phosphorylation of IκB appears to be the point of convergence for most stimuli that activate NF-κB. IKK contains two catalytic subunits, IKKα and IKKβ, both of which phosphorylate IκB at sites phosphorylated in vivo. However, gene knockout studies have revealed that IKKα and IKKβ have very different physiological functions. After phosphorylation, the IKK phosphoacceptor site on IκBα serves as a specific recognition site for the β-TrCP-like component of a Skp1-Cullin-F-box (SCF)-type E3 ubiquitin-protein ligase, thereby explaining how IKK controls IκB ubiquitinylation and degradation. Various other signaling events, including phosphorylation of NF-κB, phosphorylation of IKK, induction of IκB synthesis, and the processing of NF-κB precursors, provide additional mechanisms that modulate the level and duration of NF-κB activity.