Figure 1.

A working model for the role of the COP9 signalosome (CSN) in the regulation of the catalytic dynamic of Cullin-RING ligases (CRLs). (A) Under normal condition, the CSN holocomplex formed by eight unique protein subunits (CSN1 through CSN8) removes the Nedd8 from the neddylated Cullin, thereby inactivates and dissembles the CRL that has completed ubiquitinating a substrate protein (Substrate-1) recruited by substrate receptor 1 (SR1), allowing for the formation of a new CRL with a new SR (SR2) to recruit a new substrate (Substrate-2) for ubiquitination. (B) Defect in the formation of the CSN holocomplex, such as depletion of a subunit due to genetic mutation, may increase the abundance of certain species of minicomplexes composed of some of the CSN subunits but reduces or loses the deneddylase activity, impairing Cullin deneddylation; Cullin deneddylation by the CSN can also be inhibited by small molecules (e.g., CSN5i-3). When Cullin deneddylation is lost, the exchange of SRs in CRLs will be compromised, and as a result, the catalytic dynamic of CRLs will be stalled, leading to autoubiquitination and destruction of CRL components (e.g., SR).