Latent CSN-CRL complexes are crucial for curcumin-induced apoptosis and recruited during adipogenesis to lipid droplets via small GTPase RAB18

The COP9 signalosome (CSN) and cullin-RING ubiquitin ligases (CRLs) form latent CSN-CRL complexes detectable in cells. We demonstrate that the CSN variants CSNCSN7A and CSNCSN7B preferentially bind to CRL3 or CRL4A and CRL4B, respectively. Interestingly, the interacting protein ubiquitin-specific protease 15 exclusively binds to latent CSNCSN7A-CRL3, while p27(KIP) attaches to latent CSNCSN7B-CRL4A complex. Inhibition of deneddylation by CSN5i-3 or neddylation by MLN4924 do not impede the formation of latent complexes. Latent CSNCSN7A-CRL3 and latent CSNCSN7B-CRL4A/B particles are essential for specific cellular functions. We found that curcumin-induced cell death requires latent CSNCSN7B-CRL4A. Knockout of (CSN7B) in HeLa cells leads to resistance against curcumin. Remarkably, the small GTPase RAB18 recruits latent CSNCSN7A-CRL3 complex to lipid droplets (LDs), where CRL3 is activated by neddylation, an essential event for LD formation during adipogenesis. Knockdown of (CSN7A) or RAB18 or destabilization of latent complexes by cutting off (CSN7A) C-terminal 201-275 amino acids blocks adipogenesis.

Automated summary

The COP9 signalosome and cullin-RING ubiquitin ligases form latent CSN-CRL complexes detectable in cells. CSN7A and CSN7B variants preferentially bind to CRL3 and CRL4A/B, respectively. Specific cellular functions require latent CSN7A-CRL3 and CSN7B-CRL4A/B particles, with curcumin-induced cell death requiring latent CSN7B-CRL4A.