The COP9 signalosome-mediated deneddylation is stimulated by caspases during apoptosis |
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Authors: | Bettina K J Hetfeld Andreas Peth Xiao-Ming Sun Peter Henklein Gerald M Cohen Wolfgang Dubiel |
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Institution: | 1.Department of Surgery, Division of Molecular Biology,Charité - Universit?tsmedizin Berlin,Berlin,Germany;2.MRC Toxicology Unit, Hodgkin Building,University of Leicester,Leicester,UK;3.Institute of Biochemistry,Charité - Universit?tsmedizin Berlin,Berlin,Germany |
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Abstract: | 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.
Bettina K. J. Hetfeld and Andreas Peth contributed equally. |
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Keywords: | COP9 signalosome Deneddylation Caspases Apoptosis Ubiquitin Rbx1 |
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