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.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $18.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
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).
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).
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).
Seeger, M. et al. A novel protein complex involved in signal transduction possessing similarities to 26S proteasome subunits. FASEB J. 12, 469–478 (1998).
Freilich, S. et al. The COP9 signalosome is essential for development of Drosophila melanogaster. Curr. Biol. 9, 1187–1190 (1999).
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).
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).
Zhou, C. et al. The fission yeast COP9–signalosome is involved in cullin modification by ubiquitin-related Ned8p. BMC Biochemistry 2, 7 (2001).
Wee, S., Hetfeld, B., Dubiel, W. & Wolf, D.A. Conservation of the COP9–signalosome in budding yeast. BMC Genetics 3:15 (2002).
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).
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).
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).
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).
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).
Hofmann, K. & Bucher, P. The PCI domain: a common theme in three multiprotein complexes. Trends Biochem. Sci. 23, 204–205 (1998).
Schwechheimer, C. & Deng, X.W. COP9 signalosome revisited: a novel mediator of protein degradation. Trends Cell Biol. 11, 420–426 (2001).
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).
Seeger, M., Gordon, C. & Dubiel, W. Protein stability: the COP9 signalosome gets in on the act. Curr. Biol. 11, R643–R646 (2001).
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).
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).
Zhou, C. et al. Fission Yeast COP9–Signalosome suppresses cullin activity through recruitment of the deubiquitylating enzyme Ubp12p. Mol. Cell 11, 927–938 (2003).
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).
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).
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).
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).
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).
Bech-Otschir, D. et al. COP9 signalosome-specific phosphorylation targets p53 to degradation by the ubiquitin system. EMBO J. 20, 1630–1639 (2001).
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).
Uhle, S. et al. Protein kinase CK2 and protein kinase D are associated with the COP9 signalosome. EMBO J. 22, 1302–1312 (2003).
Lyapina, S. et al. Promotion of NEDD8–CUL1 conjugate cleavage by COP9 signalosome. Science 292, 1382–1385 (2001).
Schwechheimer, C. et al. Interactions of the COP9 signalosome with the E3 ubiquitin ligase SCFTIRI in mediating auxin response. Science 292, 1379–1382 (2001).
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).
Deshaies, R.J. SCF and Cullin/Ring H2-based ubiquitin ligases. Annu. Rev. Cell Dev. Biol. 15, 435–467 (1999).
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).
Cope, G. et al. Role of predicted metalloprotease motif of Jab1/Csn5 in cleavage of NEDD8 from CUL1. Science 298, 608–611 (2002).
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).
Yao, T. & Cohen, R.E. A cryptic protease couples deubiquitination and degradation by the proteasome. Nature 419, 403–407 (2002).
Wang, X. et al. The COP9 signalosome interacts with SCF(UFO) and participates in Arabidopsis flower development. Plant Cell 15, 1071–1082 (2003).
Feng, S. et al. The COP9 signalosome interacts physically with SCF COI1 and modulates jasmonate responses. Plant Cell 15, 1083–1094 (2003).
Zhou, P. & Howley, P.M. Ubiquitination and degradation of the substrate recognition subunits of SCF ubiquitin-protein ligases. Mol. Cell 2, 571–580 (1998).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Min, K.W. et al. TIP120A Associates with cullins and modulates ubiquitin ligase activity. J. Biol. Chem. 278, 15905–15910 (2003).
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).
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.
About this article
COP9 signalosome complex subunit 5, an IFT20 binding partner, is essential to maintain male germ cell survival and acrosome biogenesis†
Biology of Reproduction (2019)
Plasticity of the Cullin-RING Ligase Repertoire Shapes Sensitivity to Ligand-Induced Protein Degradation
Molecular Cell (2019)
Are Inositol Polyphosphates the Missing Link in Dynamic Cullin RING Ligase Regulation by the COP9 Signalosome?
Jab1/COPS5 as a Novel Biomarker for Diagnosis, Prognosis, Therapy Prediction and Therapeutic Tools for Human Cancer
Frontiers in Pharmacology (2018)