COP9 signalosome explained

COP9 (Constitutive photomorphogenesis 9) signalosome (CSN) is a protein complex with isopeptidase activity. It catalyses the hydrolysis of NEDD8 protein from the cullin subunit of Cullin-RING ubiquitin ligases (CRL). Therefore, it is responsible for CRL deneddylation – at the same time, it is able to bind denedyllated cullin-RING complex and retain them in deactivated form. COP9 signalosome thus serves as a sole deactivator of CRLs.^[1] The complex was originally identified in plants,^{[2] [3]} and subsequently found in all eukaryotic organisms including human. ^{[4] [5]} Human COP9 signalosome (total size ~350 kDa) consists of 8 subunits - CSN1, CSN2, CSN3, CSN4, CSN5, CSN6, CSN7 (COPS7A, COPS7B), CSN8. All are essential for full function of the complex and mutation in some of them is lethal in mice.

COP9 signalosome as a drug target for cancer and parasitic infections

Given the essential functions of the COP9 signalosome, the complex has been explored as a target for drug discovery. Preclinical studies showed that inhibiting COP9 resulted in death of cancer cells and medically important parasite.^{[6] [7]}

References

1. Lingaraju. GM. Bunker. RD. Cavadini. S. Hess. D. Hassiepen. U. Renatus. M. Fischer. ES. Thomä. NH. Crystal structure of the human COP9 signalosome.. Nature. 14 August 2014. 512. 7513. 161–5. 25043011. 10.1038/nature13566. 2014Natur.512..161L. 205239748.
2. Wei. Ning. Chamovitz. Daniel A.. Deng. Xing-Wang. Arabidopsis COP9 is a component of a novel signaling complex mediating light control of development. Cell. 78. 1. 1994. 117–124. 0092-8674. 10.1016/0092-8674(94)90578-9. 8033203. 205021135.
3. Chamovitz. Daniel A. Wei. Ning. Osterlund. Mark T. von Arnim. Albrecht G. Staub. Jeffrey M. Matsui. Minami. Deng. Xing-Wang. The COP9 Complex, a Novel Multisubunit Nuclear Regulator Involved in Light Control of a Plant Developmental Switch. Cell. 86. 1. 1996. 115–121. 0092-8674. 10.1016/S0092-8674(00)80082-3. 8689678. free.
4. Seeger. M. A novel protein complex involved in signal transduction possessing similarities to 26S proteasome subunits.. The FASEB Journal. 1 April 1998. 12. 6. 469–478. 9535219. 10.1096/fasebj.12.6.469. free. 25424324.
5. Wei. N. Serino. G. Deng. XW. The COP9 signalosome: more than a protease.. Trends in Biochemical Sciences. December 2008. 33. 12. 592–600. 18926707. 10.1016/j.tibs.2008.09.004.
6. Ghosh . S . Farr . L . Singh . A . Leaton . LA . Padalia . J . Shirley . DA . Sullivan . D . Moonah . S . COP9 signalosome is an essential and druggable parasite target that regulates protein degradation. . PLOS Pathogens . 22 September 2020 . 16 . 9 . e1008952 . 10.1371/journal.ppat.1008952 . 7531848 . 32960936. free .
7. Schlierf . A . Altmann . E . Quancard . J . Jefferson . AB . Assenberg . R . Renatus . M . Jones . M . Hassiepen . U . Schaefer . M . Kiffe . M . Weiss . A . Wiesmann . C . Sedrani . R . Eder . J . Martoglio . B . Targeted inhibition of the COP9 signalosome for treatment of cancer. . Nature Communications . 24 October 2016 . 7 . 13166 . 10.1038/ncomms13166 . 27774986. 5078989 . 2016NatCo...713166S .

Further reading

• Salmena . Leonardo . Hakem . Razqallah . 2013 . From photomorphogenesis to cancer. A CSN journey . Cell Cycle . 12 . 2. 205–206 . 10.4161/cc.23422 . 23287466 . 3575449 .
• Singer . R. . Atar . S. . Atias . O. . Oron . E. . Segal . D. . Hirsch . J. A. . Chamovitz . D. A. . 2014 . Drosophila COP9 signalosome subunit 7 interacts with multiple genomic loci to regulate development . Nucleic Acids Research . 42 . 15. 9761–9770 . 10.1093/nar/gku723 . 25106867 . 4150811.
• Lingaraju . G. M. . Bunker . R. D. . Cavadini . S. . Hess . D. . Hassiepen . U. . Renatus . M. . Nicolas H. Thomä . Thomä . N. H. . 2014 . Crystal structure of the human COP9 signalosome . Nature . 512 . 7513. 161–165 . 10.1038/nature13566 . 25043011. 2014Natur.512..161L . 205239748 .
• Birol . M. . Echalier . A. . Dumas . C. . Padilla . A. . Yang . Y. . Hoh . F. . 2014 . The COP9 Signalosome: Activity and Regulation . Biophysical Journal . 106 . 2. 463a . 10.1016/j.bpj.2013.11.2622 . 2014BpJ...106..463B . free .
• Chamovitz . D. A. . 2009 . Revisiting the COP9 signalosome as a transcriptional regulator . EMBO Reports . 10 . 4. 352–358 . 10.1038/embor.2009.33 . 19305390 . 2672896.
• Stratmann . Johannes W. . Gusmaroli . Giuliana . 2012 . Many jobs for one good cop – The COP9 signalosome guards development and defense . Plant Science . 185–186 . 50–64 . 10.1016/j.plantsci.2011.10.004 . 22325866 .
• Fang . L. . Kaake . R. M. . Patel . V. R. . Yang . Y. . Baldi . P. . Huang . L. . 2012 . Mapping the Protein Interaction Network of the Human COP9 Signalosome Complex Using a Label-free QTAX Strategy . Molecular & Cellular Proteomics. 11 . 5. 138–147 . 10.1074/mcp.M111.016352 . free . 22474085 . 3418852 .