The COP9 signalosome-mediated deneddylation is stimulated by caspases during apoptosis.
In concert with the ubiquitin (Ub) proteasome system (UPS) the COP9 signalosome (CSN) controls the stability of cellular regulators. The CSN interacts with cullin-RING Ub ligases (CRLs) consisting of a specific cullin, a RING protein as Rbx1 and substrate recognition proteins. The Ub-like protein Nedd8 is covalently linked to cullins and removed by the CSN-mediated deneddylation. Cycles of neddylation and deneddylation regulate CRLs. Apoptotic stimuli cause caspase-dependent modifications of the UPS. However, little is known about the CSN during apoptosis. We demonstrate in vitro and in vivo that CSN6 is cleaved most effectively by caspase 3 at D23 after 2-3 h of apoptosis induced by anti-Fas-Ab or etoposide. CSN6 processing occurs in CSN-CRL complexes and is followed by the cleavage of Rbx1, the direct interaction partner of CSN6. Caspase-dependent cutting of Rbx1 is accompanied by decrease of neddylated proteins in Jurkat T cells. Another functional consequence of CSN6 cleavage is the enhancement of CSN-mediated deneddylating activity causing deneddylation of cullin 1 in cells. The CSN-associated deubiquitinating as well as kinase activity remained unchanged in presence of active caspase 3. The cleavage of Rbx1 and increased deneddylation of cullins inactivate CRLs and presumably stabilize pro-apoptotic factors for final apoptotic steps.
Department of Surgery, Division of Molecular Biology, Charité - Universitätsmedizin Berlin, Monbijoustr. 2, 10117 Berlin, Germany.
Bettina K J
BK
Hetfeld
Andreas
A
Peth
Xiao-Ming
XM
Sun
Peter
P
Henklein
Gerald M
GM
Cohen
Wolfgang
W
Dubiel
D017209:Apoptosis; D000075686:COP9 Signalosome Complex; D002352:Carrier Proteins / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D044842:Cullin Proteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D046912:Multiprotein Complexes / Q000378:metabolism*; D010447:Peptide Hydrolases / Q000378:metabolism*; D011994:Recombinant Proteins; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
D002352:Carrier Proteins; D044842:Cullin Proteins; D046912:Multiprotein Complexes; C479529:RBX1 protein, human; D011994:Recombinant Proteins; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D010447:Peptide Hydrolases; D000075686:COP9 Signalosome Complex; D020169:Caspases