Latent CSN-CRL complexes are crucial for curcumin-induced apoptosis and recruited during adipogenesis to lipid droplets via small GTPase RAB18
- iScience. 2023 Mar 22;26(4):106468. doi: 10.1016/j.isci.2023.106468.
- 1. Institute of Experimental Internal Medicine, Medical Faculty, Otto von Guericke University, Leipziger Str. 44, 39120 Magdeburg, Germany.
- 2. School of Pharmaceutical Sciences, State Key Laboratory of Cellular Stress Biology, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiang'an South Road, Xiamen 361102 Fujian, China.
- 3. Multi-Parametric Bioimaging and Cytometry Unit (Confocal Microscopy & Flow Cytometry), Institute of Molecular and Clinical Immunology, Medical Faculty, Otto von Guericke University, Leipziger Str. 44, 39120 Magdeburg, Germany.
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 p27KIP 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.
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Cat. No.Product NameDescriptionTargetResearch Area
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Research Areas: Cancer