Apoptosis

, Volume 13, Issue 2, pp 187–195

The COP9 signalosome-mediated deneddylation is stimulated by caspases during apoptosis

Authors

  • Bettina K. J. Hetfeld
    • Department of Surgery, Division of Molecular BiologyCharité - Universitätsmedizin Berlin
  • Andreas Peth
    • Department of Surgery, Division of Molecular BiologyCharité - Universitätsmedizin Berlin
  • Xiao-Ming Sun
    • MRC Toxicology Unit, Hodgkin BuildingUniversity of Leicester
  • Peter Henklein
    • Institute of BiochemistryCharité - Universitätsmedizin Berlin
  • Gerald M. Cohen
    • MRC Toxicology Unit, Hodgkin BuildingUniversity of Leicester
    • Department of Surgery, Division of Molecular BiologyCharité - Universitätsmedizin Berlin
Original Paper

DOI: 10.1007/s10495-007-0164-7

Cite this article as:
Hetfeld, B.K.J., Peth, A., Sun, X. et al. Apoptosis (2008) 13: 187. doi:10.1007/s10495-007-0164-7

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.

Keywords

COP9 signalosomeDeneddylationCaspasesApoptosisUbiquitinRbx1

Copyright information

© Springer Science+Business Media, LLC 2007