CSN facilitates Cullin-RING ubiquitin ligase function by counteracting autocatalytic adapter instability.
The COP9 signalosome (CSN) is known to bind cullin-RING ubiquitin ligases (CRLs) and to promote their activity in vivo. The mechanism of this stimulation has remained enigmatic because CSN's intrinsic and associated enzymatic activities paradoxically inhibit CRL activity in vitro. Reconciling this paradox, we show here that Csn5-catalysed cullin (Cul) deneddylation and Ubp12-mediated deubiquitination cooperate in maintaining the stability of labile substrate adapters, thus facilitating CRL function. Various fission-yeast csn and ubp12 deletion mutants have lower levels of the Cul3p adapter Btb3p. This decrease is due to increased autocatalytic, Cul3p-dependent, ubiquitination and the subsequent degradation of Btb3p. The CSN-Ubp12p pathway also maintains the stability of the Cul1p adapter Pop1p, a mechanism required for the efficient destruction of its cognate substrate Rum1p. Emphasizing the physiological importance of this mechanism, we found that the dispensable csn5 and ubp12 genes become essential for viability when adapter recruitment to Cul1p is compromised. Our data suggest that maintenance of adapter stability is a general mechanism of CRL control by the CSN.
Wee
Susan
S
Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA.
Geyer
Rory K
RK
Toda
Takashi
T
Wolf
Dieter A
DA
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000075686:COP9 Signalosome Complex; D002384:Catalysis; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism*; D010450:Endopeptidases / Q000378:metabolism; D046912:Multiprotein Complexes; D010447:Peptide Hydrolases; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012568:Schizosaccharomyces / Q000201:enzymology; D029702:Schizosaccharomyces pombe Proteins / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D044842:Cullin Proteins; D046912:Multiprotein Complexes; D011506:Proteins; D029702:Schizosaccharomyces pombe Proteins; D044767:Ubiquitin-Protein Ligases; D010450:Endopeptidases; D010447:Peptide Hydrolases; D000075686:COP9 Signalosome Complex; C474614:Ubp12 protein, S pombe