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

Apoptosis. 2008 Feb;13(2):187-95. 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis*
  • COP9 Signalosome Complex
  • Carrier Proteins / metabolism*
  • Caspases / metabolism*
  • Cell Line
  • Cullin Proteins / metabolism
  • HeLa Cells
  • Humans
  • Jurkat Cells
  • Multiprotein Complexes / metabolism*
  • Peptide Hydrolases / metabolism*
  • Recombinant Proteins
  • Ubiquitin / metabolism*
  • Ubiquitin-Protein Ligases / metabolism*

Substances

  • Carrier Proteins
  • Cullin Proteins
  • Multiprotein Complexes
  • RBX1 protein, human
  • Recombinant Proteins
  • Ubiquitin
  • Ubiquitin-Protein Ligases
  • Peptide Hydrolases
  • COP9 Signalosome Complex
  • Caspases