Regulation of NF-κB by ubiquitination

The nuclear factor κ enhancer binding protein (NF-κB) family of transcription factors regulates the expression of a large array of genes involved in diverse cellular processes including inflammation, immunity and cell survival. Activation of NF-κB requires ubiquitination, a highly conserved and versatile modification that can regulate cell signaling through both proteasome dependent and independent mechanisms. Studies in the past few years have provided new insights into the mechanisms underlying regulation of NF-κB by ubiquitination, including the involvement of multiple linkages of ubiquitin, the essential role of ubiquitin binding, and the function of unanchored polyubiquitin chains. In this review, we will focus on recent advances in understanding the role of ubiquitination in NF-κB regulation in various pathways.

► Polyubiquitination activates TAK1 and IKK through proteasome-independent mechanisms. ► Unanchored ubiquitin chains have signaling functions in NF-κB activation by cytokines and viruses. ► Microbial pathogens can sabotage host defense by hijacking the ubiquitin system to repress NF-κB signaling. ► A20 can inhibit NF-κB through noncatalytic mechanisms. ► Ubiquitin sensors and quantitative mass spectrometry are useful tools to dissect the mechanism of ubiquitin signaling.