Cullin-RING Ligase Regulation by the COP9 Signalosome: Structural Mechanisms and New Physiologic Players

The Cullin-RING E3 ligases (CRLs) are major ubiquitylation machineries regulated by reversible cycles of neddylation and deneddylation. The deneddylase COP9 Signalosome (CSN) terminates CRL catalytic cycle. CSN also provides a docking platform for several kinases and deubiquitinases that might play a role in regulating CRL. Recently, remarkable progress has been made in elucidating the biochemical principles and physiological implications of such exquisite regulation. The cryo-EM structures of CRL-CSN complexes provide the biochemical basis of their cognate interactions and reveal potential regulatory mechanisms during complex disassembly. Moreover, novel players beyond the canonical eight subunits of CSN were identified. This includes CSNAP, a potential 9th CSN subunit with regulatory functions, and the metabolite inositol hexakisphosphate (IP₆), which enhances CRL-CSN complex formation, with IP₆-metabolizing enzymes possibly instilling dynamics to the CRL-CSN system. Here, we review and summarize these new mechanistic insights along with progress in understanding CSN biology based on model organisms with genetically edited CSN subunits.