The COP9 signalosome variants CSNCSN7A and CSNCSN7B form complexes with specific CRLs which are targets of autophagy

COP9 signalosome (CSN) is a representative of the ZOMES complexes, which further consist of the 26S proteasome LID and the eukaryotic translation initiation factor 3 (eIF3), key players in proteostasis. Whereas the eIF3 complex has a role in general translation initiation, the LID, as part of the regulatory particle of the 26S proteasome, is the main cellular proteolytic machinery, specifically degrades ubiquitylated substrates. Interestingly, CSN is associated with the production of ubiquitylated substrates. Contrary to its paralogous complexes, CSN appears as variants. Our interest mainly lies in the variants CSNCSN7A and CSNCSN7B. The CSN variants form stable complexes with cullin-RING-ubiquitin ligases (CRLs). While CSNCSN7A preferentially interacts with CRL3, CSNCSN7B binds to CRL4A. CSNCSN7A-CRL3 and CSNCSN7B-CRL4A complexes are stored in human cells as latent complexes. During adipogenesis in LiSa-2 model preadipocytes, the complexes are integrated into different functions. CSNCSN7A-CRL3 complexes are recruited by rat sarcoma-related small GTPase 18 to the membrane of lipid droplets, where they are neddylated. CSNCSN7B-CRL4A complexes lose their substrate receptor and stop degrading p27, causing cell cycle arrest necessary for adipogenesis. The C-terminal approximately 60 amino acids of CSN7A and CSN7B are essential for the specific binding to CRLs. Without C-termini, CSNCSN7A1-200 and CSNCSN7B1-200 lose CRL3 or CRL4A and their function. CSN-CRL complexes are degraded by a selective macroautophagic pathway. In the presence of the specific inhibitor CSN5i-3, the appearance of ubiquitylated CSN-CRL complexes was detected in cells. Nonfunctioning CSN-CRL particles are fixed as cargo before forming vesicles as autophagosomes following degradation via lysosome.