Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Perspective
  • Published:

The COP9 signalosome: an assembly and maintenance platform for cullin ubiquitin ligases?

Nature Cell Biology volume 5, pages 1029–1033 (2003)Cite this article

Abstract

The COP9 signalosome (CSN) is a highly conserved protein complex implicated in diverse biological functions that involve ubiquitin-mediated proteolysis. Paradoxically, conserved enzymatic activities associated with CSN inhibit cullin ubiquitin ligase activity in vitro, whereas mutational analysis suggests that CSN promotes cullin-dependent proteolysis in vivo. This apparent paradox can be resolved in a model that proposes CSN-mediated cullin inhibition is a prerequisite for the proper assembly and maintenance of active cullin ubiquitin ligase complexes.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Three modes of SCF assembly and maintenance.

Similar content being viewed by others

References

  1. Wei, N., Chamovitz, D.A. & Deng, X.W. Arabidopsis COP9 is a component of a novel signaling complex mediating light control of development. Cell 78, 117–124 (1994).

    Article  CAS  Google Scholar 

  2. Chamovitz, D.A. et al. The COP9 complex, a novel multisubunit nuclear regulator involved in light control of a plant developmental switch. Cell 86, 115–121 (1996).

    Article  CAS  Google Scholar 

  3. Wei, N. et al. The COP9 complex is conserved between plants and mammals and is related to the 26S proteasome regulatory complex. Curr. Biol. 8, 919–922 (1998).

    Article  CAS  Google Scholar 

  4. Seeger, M. et al. A novel protein complex involved in signal transduction possessing similarities to 26S proteasome subunits. FASEB J. 12, 469–478 (1998).

    Article  CAS  Google Scholar 

  5. Freilich, S. et al. The COP9 signalosome is essential for development of Drosophila melanogaster. Curr. Biol. 9, 1187–1190 (1999).

    Article  CAS  Google Scholar 

  6. Mundt, K.E. et al. The COP9–signalosome complex is conserved in fission yeast and has a role in S phase. Curr. Biol. 9, 1427–1430 (1999).

    Article  CAS  Google Scholar 

  7. Mundt, K.E., Liu, C. & Carr, A.M. Deletion mutants in COP9/signalosome subunits in fission yeast Schizosaccharomyces pombe display distinct phenotypes. Mol. Biol. Cell 13, 493–502 (2002).

    Article  CAS  Google Scholar 

  8. Zhou, C. et al. The fission yeast COP9–signalosome is involved in cullin modification by ubiquitin-related Ned8p. BMC Biochemistry 2, 7 (2001).

    Article  CAS  Google Scholar 

  9. Wee, S., Hetfeld, B., Dubiel, W. & Wolf, D.A. Conservation of the COP9–signalosome in budding yeast. BMC Genetics 3:15 (2002).

  10. Maytal-Kivity, V., Piran, R., Pick, E., Hofmann, K. & Glickman, M.H. COP9 signalosome components play a role in the mating pheromone response of S. cerevisiae. EMBO Rep. 3, 1215–1221 (2002).

    Article  CAS  Google Scholar 

  11. Busch, S., Eckert, S.E., Krappmann, S. & Braus, G.H. The COP9 signalosome is an essential regulator of development in the filamentous fungus Aspergillus nidulans. Mol. Microbiol. 49, 717–730 (2003).

    Article  CAS  Google Scholar 

  12. Pintard, L. et al. Neddylation and deneddylation of CUL-3 is required to target MEI-1/katanin for degradation at the meiosis-to-mitosis transition in C. elegans. Curr. Biol. 13, 911–921 (2003).

    Article  CAS  Google Scholar 

  13. Glickman, M.H. et al. A subcomplex of the proteasome regulatory particle required for ubiquitin-conjugate degradation and related to the COP9-signalosome and eIF3. Cell 94, 615–623 (1998).

    Article  CAS  Google Scholar 

  14. Wei, N. & Deng, X.W. Characterization and purification of the mammalian COP9 complex, a conserved nuclear regulator initially identified as a repressor of photomorphogenesis in higher plants. Photochem. Photobiol. 68, 237–241 (1998).

    Article  CAS  Google Scholar 

  15. Hofmann, K. & Bucher, P. The PCI domain: a common theme in three multiprotein complexes. Trends Biochem. Sci. 23, 204–205 (1998).

    Article  CAS  Google Scholar 

  16. Schwechheimer, C. & Deng, X.W. COP9 signalosome revisited: a novel mediator of protein degradation. Trends Cell Biol. 11, 420–426 (2001).

    Article  CAS  Google Scholar 

  17. Bech-Otschir, D., Seeger, M. & Dubiel, W. The COP9 signalosome: at the interface between signal transduction and ubiquitin-dependent proteolysis. J. Cell Sci. 115, 467–473 (2002).

    CAS  PubMed  Google Scholar 

  18. Seeger, M., Gordon, C. & Dubiel, W. Protein stability: the COP9 signalosome gets in on the act. Curr. Biol. 11, R643–R646 (2001).

    Article  CAS  Google Scholar 

  19. Groisman, R. et al. The ubiquitin ligase activity in the DDB2 and CSA complexes is differentially regulated by the COP9 signalosome in response to DNA damage. Cell 113, 357–367 (2003).

    Article  CAS  Google Scholar 

  20. Doronkin, S., Djagaeva, I. & Beckendorf, S.K. The COP9 signalosome promotes degradation of Cyclin E during early Drosophila oogenesis. Dev. Cell 4, 699–710 (2003).

    Article  CAS  Google Scholar 

  21. Zhou, C. et al. Fission Yeast COP9–Signalosome suppresses cullin activity through recruitment of the deubiquitylating enzyme Ubp12p. Mol. Cell 11, 927–938 (2003).

    Article  CAS  Google Scholar 

  22. Liu, C. et al. Cop9–signalosome subunits and Pcu4 regulate ribonucleotide reductase by both checkpoint-dependent and -independent mechanisms. Genes Dev. 17, 1130–1140 (2003).

    Article  CAS  Google Scholar 

  23. Kleemann, R. et al. Intracellular action of the cytokine MIF to modulate AP-1 activity and the cell cycle through Jab1. Nature 408, 211–216 (2000).

    Article  CAS  Google Scholar 

  24. Tomoda, K. et al. The cytoplasmic shuttling and subsequent degradation of p27Kip1 mediated by Jab1/CSN5 and the COP9 signalosome complex. J. Biol. Chem. 277, 2302–2310 (2002).

    Article  CAS  Google Scholar 

  25. Osterlund, M.T., Ang, L.H. & Deng, X.W. The role of COP1 in repression of Arabidopsis photomorphogenic development. Trends Cell Biol. 9, 113–118 (1999).

    Article  CAS  Google Scholar 

  26. Osterlund, M.T., Hardtke, C.S., Wei, N. & Deng, X.W. Targeted destabilization of HY5 during light-regulated development of Arabidopsis. Nature 405, 462–466 (2000).

    Article  CAS  Google Scholar 

  27. Bech-Otschir, D. et al. COP9 signalosome-specific phosphorylation targets p53 to degradation by the ubiquitin system. EMBO J. 20, 1630–1639 (2001).

    Article  CAS  Google Scholar 

  28. Naumann, M., Bech-Otschir, D., Huang, X., Ferrell, K. & Dubiel, W. COP9 signalosome-directed c-Jun activation/stabilization is independent of JNK. J. Biol. Chem. 274, 35297–35300 (1999).

    Article  CAS  Google Scholar 

  29. Uhle, S. et al. Protein kinase CK2 and protein kinase D are associated with the COP9 signalosome. EMBO J. 22, 1302–1312 (2003).

    Article  CAS  Google Scholar 

  30. Lyapina, S. et al. Promotion of NEDD8–CUL1 conjugate cleavage by COP9 signalosome. Science 292, 1382–1385 (2001).

    Article  CAS  Google Scholar 

  31. Schwechheimer, C. et al. Interactions of the COP9 signalosome with the E3 ubiquitin ligase SCFTIRI in mediating auxin response. Science 292, 1379–1382 (2001).

    Article  CAS  Google Scholar 

  32. Yang, X. et al. The COP9 signalosome inhibits p27(kip1) degradation and impedes G1–S phase progression via deneddylation of SCF Cul1. Curr. Biol. 12, 667–672 (2002).

    Article  CAS  Google Scholar 

  33. Deshaies, R.J. SCF and Cullin/Ring H2-based ubiquitin ligases. Annu. Rev. Cell Dev. Biol. 15, 435–467 (1999).

    Article  CAS  Google Scholar 

  34. Sun, Y., Wilson, M.P. & Majerus, P.W. Inositol 1,3,4-Trisphosphate 5/6-kinase associates with the COP9 signalosome by binding to CSN1. J. Biol. Chem. 277, 45759–45764 (2002).

    Article  CAS  Google Scholar 

  35. Cope, G. et al. Role of predicted metalloprotease motif of Jab1/Csn5 in cleavage of NEDD8 from CUL1. Science 298, 608–611 (2002).

    Article  CAS  Google Scholar 

  36. Maytal-Kivity, V., Reis, N., Hofmann, K. & Glickman, M.H. MPN+, a putative catalytic motif found in a subset of MPN domain proteins from eukaryotes and prokaryotes, is critical for Rpn11 function. BMC Biochem. 3, 28 (2002).

    Article  Google Scholar 

  37. Yao, T. & Cohen, R.E. A cryptic protease couples deubiquitination and degradation by the proteasome. Nature 419, 403–407 (2002).

    Article  CAS  Google Scholar 

  38. Wang, X. et al. The COP9 signalosome interacts with SCF(UFO) and participates in Arabidopsis flower development. Plant Cell 15, 1071–1082 (2003).

    Article  CAS  Google Scholar 

  39. Feng, S. et al. The COP9 signalosome interacts physically with SCF COI1 and modulates jasmonate responses. Plant Cell 15, 1083–1094 (2003).

    Article  CAS  Google Scholar 

  40. Zhou, P. & Howley, P.M. Ubiquitination and degradation of the substrate recognition subunits of SCF ubiquitin-protein ligases. Mol. Cell 2, 571–580 (1998).

    Article  CAS  Google Scholar 

  41. Galan, J.M. & Peter, M. Ubiquitin-dependent degradation of multiple F-box proteins by an autocatalytic mechanism. Proc. Natl Acad. Sci. USA 96, 9124–9129 (1999).

    Article  CAS  Google Scholar 

  42. Kamura, T., Brower, C.S., Conaway, R.C. & Conaway, J.W. A molecular basis for stabilization of the Von Hippel-Lindau (VHL) tumor suppressor protein by components of the VHL ubiquitin ligase. J. Biol. Chem. 277, 30388–30393 (2002).

    Article  CAS  Google Scholar 

  43. Rouillon, A., Barbey, R., Patton, E.E., Tyers, M. & Thomas, D. Feedback-regulated degradation of the transcriptional activator Met4 is triggered by the SCF(Met30)complex. EMBO J. 19, 282–294 (2000).

    Article  CAS  Google Scholar 

  44. Wirbelauer, C. et al. The F-box protein Skp2 is a ubiquitylation target of a Cul1-based core ubiquitin ligase complex: evidence for a role of Cul1 in the suppression of Skp2 expression in quiescent fibroblasts. EMBO J. 19, 5362–5375 (2000).

    Article  CAS  Google Scholar 

  45. Geyer, R., Wee, S., Anderson, S., Yates, J.R.I. & Wolf, D.A. BTB/POZ domain proteins are putative substrate adaptors for cullin 3 ubiquitin ligases. Mol. Cell 12, 783–790 (2003).

    Article  CAS  Google Scholar 

  46. Liu, J., Furukawa, M., Matsumoto, T. & Xiong, Y. NEDD8 modification of CUL1 dissociates p120(CAND1), an inhibitor of CUL1-SKP1 binding and SCF ligases. Mol. Cell 10, 1511–1518 (2002).

    Article  CAS  Google Scholar 

  47. Oshikawa, K. et al. Preferential interaction of TIP120A with Cul1 that is not modified by NEDD8 and not associated with Skp1. Biochem. Biophys. Res. Commun. 303, 1209–1216 (2003).

    Article  CAS  Google Scholar 

  48. Zheng, J. et al. CAND1 binds to unneddylated CUL1 and regulates the formation of SCF ubiquitin E3 ligase complex. Mol. Cell 10, 1519–1526 (2002).

    Article  CAS  Google Scholar 

  49. Hwang, J.W., Min, K.W., Tamura, T.A. & Yoon, J.B. TIP120A associates with unneddylated cullin 1 and regulates its neddylation. FEBS Lett. 541, 102–108 (2003).

    Article  CAS  Google Scholar 

  50. Min, K.W. et al. TIP120A Associates with cullins and modulates ubiquitin ligase activity. J. Biol. Chem. 278, 15905–15910 (2003).

    Article  CAS  Google Scholar 

  51. Peng, Z. et al. Evidence for a physical association of the COP9 signalosome, the proteasome, and specific SCF E3 ligases in vivo. Curr. Biol. 13, R504–R505 (2003).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We wish to thank R. J. Deshaies for comments on the manuscript and for his generous support and mentorship. Work in the authors' laboratory is funded by the National Institute of General Medical Sciences and the National Institute of Environmental Health Sciences.

Author information

Authors and Affiliations

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

    Dieter A. Wolf, Chunshui Zhou & Susan Wee

Authors
  1. Dieter A. Wolf
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chunshui Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Susan Wee
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dieter A. Wolf.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wolf, D., Zhou, C. & Wee, S. The COP9 signalosome: an assembly and maintenance platform for cullin ubiquitin ligases?. Nat Cell Biol 5, 1029–1033 (2003). https://doi.org/10.1038/ncb1203-1029

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb1203-1029

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing