CSN facilitates Cullin–RING ubiquitin ligase function by counteracting autocatalytic adapter instability

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.

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“…In addition, the CSN is associated with a deubiquitinating enzyme called USP15 and with kinases such as CK2 and PKD [30,31,39].…”

Section: Caspase Cleavage Of Csn6 Is Accompanied By Cleavage Of Rbx1mentioning

confidence: 99%

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

et al. 2007

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“…Multiple studies from a range of organisms have shown that CSN interacts with Cullin-RING E3s and that proper E3 function is dependent on CSN and more specifically on CSN5-mediated deneddylation Schwechheimer et al, 2001;Schwechheimer, 2004). Some recent studies suggest that deneddylation is required for E3 subunit stability or E3 complex assembly (Hetfeld et al, 2005;Wee et al, 2005;Wu et al, 2005;Bornstein et al, 2006). Furthermore, it has been proposed that CSN is part of a proteasome-related complex (Peng et al, 2001(Peng et al, , 2003.…”

Section: Introductionmentioning

confidence: 99%

Characterization of theVIER F-BOX PROTEINEGenes fromArabidopsisReveals Their Importance for Plant Growth and Development

et al. 2007

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E3 ubiquitin ligases (E3s) target proteins for degradation by the 26S proteasome. In SKP1/CDC53/F-box protein–type E3s, substrate specificity is conferred by the interchangeable F-box protein subunit. The vast majority of the 694 F-box proteins encoded by the Arabidopsis thaliana genome remain to be understood. We characterize the VIER F-BOX PROTEINE (VFB; German for FOUR F-BOX PROTEINS) genes from Arabidopsis that belong to subfamily C of the Arabidopsis F-box protein superfamily. This subfamily also includes the F-box proteins TRANSPORT INHIBITOR RESPONSE1 (TIR1)/AUXIN SIGNALING F-BOX (AFB) proteins and EIN3 BINDING F-BOX proteins, which regulate auxin and ethylene responses, respectively. We show that loss of VFB function causes delayed plant growth and reduced lateral root formation. We find that the expression of a number of auxin-responsive genes and the activity of DR5:β-glucuronidase, a reporter for auxin reponse, are reduced in the vfb mutants. This finding correlates with an increase in the abundance of an AUXIN/INDOLE-3-ACETIC ACID repressor. However, we also find that auxin responses are not affected in the vfb mutants and that a representative VFB family member, VFB2, cannot functionally complement the tir1-1 mutant. We therefore exclude the possibility that VFBs are functional orthologs of TIR1/AFB proteins.

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“…Even though deneddylation inactivates CRLs in vitro [18][19][20] , the CSN promotes ubiquitin ligase activity in vivo in various organisms 17,21,22 . This paradoxical behaviour can at least partially be explained by the fact that in cells constitutively neddylated complexes ubiquitylate their own subunits, leading to autodegradation 23 .…”

mentioning

confidence: 99%

CSN- and CAND1-dependent remodelling of the budding yeast SCF complex

et al. 2013

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Cullin-RING ligases (CRLs) are ubiquitin E3 enzymes with variable substrate-adaptor and -receptor subunits. All CRLs are activated by modification of the cullin subunit with the ubiquitin-like protein Nedd8 (neddylation). The protein CAND1 (Cullin-associated-Nedd8-dissociated-1) also promotes CRL activity, even though it only interacts with inactive ligase complexes. The molecular mechanism underlying this behaviour remains largely unclear. Here, we find that yeast SCF (Skp1-Cdc53-F-box) Cullin-RING complexes are remodelled in a CAND1-dependent manner, when cells are switched from growth in fermentable to non-fermentable carbon sources. Mechanistically, CAND1 promotes substrate adaptor release following SCF deneddylation by the COP9 signalosome (CSN). CSN-or CAND1-mutant cells fail to release substrate adaptors. This delays the formation of new complexes during SCF reactivation and results in substrate degradation defects. Our results shed light on how CAND1 regulates CRL activity and demonstrate that the cullin neddylationdeneddylation cycle is not only required to activate CRLs, but also to regulate substrate specificity through dynamic substrate adaptor exchange.

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CSN facilitates Cullin–RING ubiquitin ligase function by counteracting autocatalytic adapter instability

Cited by 168 publications

References 27 publications

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

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

Characterization of theVIER F-BOX PROTEINEGenes fromArabidopsisReveals Their Importance for Plant Growth and Development

CSN- and CAND1-dependent remodelling of the budding yeast SCF complex

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