The Role of Ubiquitin in NF-κB Regulatory Pathways

Nuclear factor kappa enhancer binding protein (NF-kappa B) regulates diverse biological processes including immunity, inflammation, and apoptosis. A vast array of cellular stimuli converges on NF-kappa B, and ubiquitination plays an essential role in the coordination of these signals to regulate NF-kappa B activity. At least three steps in NF-kappa B activation directly involve ubiquitination: proteasomal degradation of inhibitor of NF-kappa B (I kappa B), processing of NF-kappa B precursors, and activation of the transforming growth factor (TGF)-beta-activated kinase (TAK1) and I kappa B kinase (IKK) complexes. In this review, we discuss recent advances in the identification and characterization of ubiquitination and deubiquitination machinery that regulate NF-kappa B. Particular emphasis is given to proteasome-independent functions of ubiquitin, specifically its role in the activation of protein kinase complexes and in coordination of cell survival and apoptosis signals downstream of tumor necrosis factor alpha (TNF alpha).