The COP9 signalosome: A versatile regulatory hub of Cullin-RING ligases

The multisubunit architecture of the COP9 signalosome (CSN) implements an extraordinary yet general Cullin-RING ubiquitin ligase (CRL) binding mode, which is subject to versatile regulation. Disruption of the catalytic deneddylase function of the CSN induces autodegradation of many CRL substrate receptors whereby some CRLs with distinct substrate receptors remain unaffected. The secondary messenger inositol hexakisphosphate acts as ‘molecular glue’ for certain CSN-CRL complexes and thereby enables their long-term stabilization and stimulus-dependent dissociation. CSN-associated deubiquitinylases and kinases provide additional means to interfere with CRL-mediated protein degradation. The selective CSN5 inhibitor CSN5i-3 blocks CRL deneddylation and has emerged as a promising candidate for cancer therapy and as a valuable research tool. The COP9 signalosome (CSN) is a universal regulator of Cullin-RING ubiquitin ligases (CRLs) – a family of modular enzymes that control various cellular processes via timely degradation of key signaling proteins. The CSN, with its eight-subunit architecture, employs multisite binding of CRLs and inactivates CRLs by removing a small ubiquitin-like modifier named neural precursor cell–expressed, developmentally downregulated 8 (Nedd8). Besides the active site of the catalytic subunit CSN5, two allosteric sites are present in the CSN, one of which recognizes the substrate recognition module and the presence of CRL substrates, and the other of which can ‘glue’ the CSN-CRL complex by recruitment of inositol hexakisphosphate. In this review, we present recent findings on the versatile regulation of CSN-CRL complexes. The COP9 signalosome (CSN) is a universal regulator of Cullin-RING ubiquitin ligases (CRLs) – a family of modular enzymes that control various cellular processes via timely degradation of key signaling proteins. The CSN, with its eight-subunit architecture, employs multisite binding of CRLs and inactivates CRLs by removing a small ubiquitin-like modifier named neural precursor cell–expressed, developmentally downregulated 8 (Nedd8). Besides the active site of the catalytic subunit CSN5, two allosteric sites are present in the CSN, one of which recognizes the substrate recognition module and the presence of CRL substrates, and the other of which can ‘glue’ the CSN-CRL complex by recruitment of inositol hexakisphosphate. In this review, we present recent findings on the versatile regulation of CSN-CRL complexes. enzymes that cleave ubiquitin attached to proteins. a small protein structurally similar to ubiquitin and similarly conjugated to substrate proteins. an inducible transcription factor that controls gene expression in many critical physiological responses such as inflammation, cell death, and oxidative stress. It is involved in the development of cancer. heterobifunctional small molecules containing two protein-binding domains connected by a linker. One domain directs binding to a specific target protein, and the other PROTAC domain recruits an E3 ligase to the target protein, which is then ubiquitinylated for proteasomal degradation. comprise an array of derivatives of molecular oxygen that occur as a normal attribute of aerobic life. Elevated formation of the different reactive oxygen species leads to molecular damage, denoted as oxidative stress. covalent binding of ubiquitin (a 76–amino acid protein) to lysine residues on substrate proteins or itself, which can result in protein monoubiquitinylation or polyubiquitinylation via a cascade of E1 and E2 enzymes, and E3 ligases.