Seminars

The transcription factor NF-κB exerts crucial functions in the regulation of innate and adaptive immune responses, wound healing and tissue maintenance and in the development of immune cells. The integral component of the NF-κB system, the IκB kinases (IKK) phosphorylate IκB, thereby tagging it for subsequent ubiquitinylation and proteolytic destruction, this enables DNA-binding NF-κB dimers to enter the nucleus and to program gene expression. Many components of the NF-κB activation pathway have been identified in the recent years, and the functional relevance of the involved signaling proteins was revealed by pharmacological inhibition, siRNA-mediated knockdown or by the analysis of genetically altered mice. Importantly, an involvement of the COP9 signalosome (CSN) in the regulation of NF-κB has been discovered recently in our lab. The CSN is a conserved multiprotein complex, which mainly functions in the control of proteolysis and disease. The CSN regulates the assembly and activity of cullin-RING ubiquitin-ligases (CRLs). The CSN comprise eight subunits with an intrinsic metalloprotease activity, which removes the covalent conjugated regulatory protein Nedd8 from CRLs. In addition, CSN-associated deubiquitinylases (DUBs) affect basal and signal-induced CRL-dependent control of molecules in the NF-κB system.