Ubiquitin:: tool and target for intracellular NF-κB inhibitors

The transcription factor nuclear factor-kappa B (NF-kappa B) has a pivotal role in initiating inflammation and raising an effective immune response. Because NF-kappa B activation depends on ubiquitination, cells have developed ubiquitin (Ub)-mediated strategies for inhibiting NF-kappa B activation and preventing excessive inflammation. Recent findings concerning tumor necrosis factor (TNF) receptor and toll-like receptor (TLR)-interleukin-1 (IL-1) receptor signalling pathways show that Ub can be a tool as well as a target for NF-kappa B inhibitory proteins, either by labelling specific signalling proteins for proteasome-dependent degradation or by serving as a target for specific de-ubiquitinating enzymes that prevent the formation of pertinent signalling complexes. Interfering with ubiquitination therefore seems to be a versatile means for regulating NF-kappa B activity, indicating that studies of Ub-mediated signalling might hold the key for developing new therapeutic strategies for inflammatory disease.