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

Nature Cell Biology volume 7, pages 387–391 (2005)Cite this article

Abstract

The COP9 signalosome (CSN) is known to bind cullin-RING ubiquitin ligases (CRLs) and to promote their activity in vivo1,2,3. The mechanism of this stimulation has remained enigmatic because CSN's intrinsic and associated enzymatic activities paradoxically inhibit CRL activity in vitro4,5. 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.

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Figure 1: Effect of CSN–Ubp12p on Cul3p–Btb3p expression and interactions.
Figure 2: Btb3p ubiquitination and stability in csn5 and ubp12 mutants.
Figure 3: Effect of CSN–Ubp12p on the stability of Pop1p and Rum1p.
Figure 4: Analysis of the effects of csn5 and ubp12 on skp1-ts mutants.

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Acknowledgements

We wish to thank S. Moreno for Rum1p antisera; G. Cope and R. Deshaies for csn5 JAMM mutants; and C. Zhou for assistance during much of these studies. This work was supported by NIH grant GM59780 to D.A.W., by grants from Cancer Research UK and the Human Frontier Science Program to T.T., and by the NIEHS Center Grant ES00002 and the NIEHS Training Grant ES07155.

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Authors and Affiliations

  1. Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, 02115, MA, USA

    Susan Wee, Rory K. Geyer & Dieter A. Wolf

  2. Laboratory of Cell Regulation, Cancer Research UK, London Research Institute, Lincoln's Inn Fields Laboratories, London, WC2A 3PX, UK

    Takashi Toda

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  1. Susan Wee
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  2. Rory K. Geyer
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Correspondence to Dieter A. Wolf.

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Supplementary figures 1 and 2; supplementary table 1 (PDF 128 kb)

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Wee, S., Geyer, R., Toda, T. et al. CSN facilitates Cullin–RING ubiquitin ligase function by counteracting autocatalytic adapter instability. Nat Cell Biol 7, 387–391 (2005). https://doi.org/10.1038/ncb1241

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