Control of Deneddylation by the COP9 Signalosome

The interplay between ubiquitin (Ub) family modifiers creates a regulatory network of Ub family proteins which is essential for cell growth and differentiation. One of the best studied crosstalks between Ub family modifiers is the stimulation of ubiquitination by Nedd8 (neural precursor cell expressed developmentally down regulated 8) modification. The neddylation-deneddylation pathway controls the selective ubiquitination of important cellular regulators targeted for proteolysis by the Ub proteasome system (UPS). In this process the cullin scaffolds of cullin-RING Ub ligases (CRLs) are neddylated, which allosterically activates the transfer of Ub to substrates of the CRLs. A major reaction of the regulatory network is the removal of Nedd8 by the COP9 signalosome (CSN), which converts CRLs into an inactive state. The CSN is a conserved protein complex that interacts with CRLs and possesses an intrinsic metalloprotease with a Jab1/Pad1/MPN+ (JAMM) motif responsible for deneddylation.In the present chapter we focus on the CSN-mediated deneddylation and its biological significance. We summarize latest developments on the mechanism of the CSN and its association with supercomplexes. In addition, data on the regulation of CSN-mediated deneddylation are described. Moreover, dysfunctions of the CSN and their implication in the pathogenesis of diseases are discussed.