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. [1]
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
- ^ a b Lingaraju, GM; Bunker, RD; Cavadini, S; Hess, D; Hassiepen, U; Renatus, M; Fischer, ES; Thomä, NH (14 August 2014). "Crystal structure of the human COP9 signalosome". Nature. 512 (7513): 161–5. Bibcode: 2014Natur.512..161L. doi: 10.1038/nature13566. PMID 25043011. S2CID 205239748.
- ^ Wei, Ning; Chamovitz, Daniel A.; Deng, Xing-Wang (1994). "Arabidopsis COP9 is a component of a novel signaling complex mediating light control of development". Cell. 78 (1): 117–124. doi: 10.1016/0092-8674(94)90578-9. ISSN 0092-8674. PMID 8033203. S2CID 205021135.
- ^ Chamovitz, Daniel A; Wei, Ning; Osterlund, Mark T; von Arnim, Albrecht G; Staub, Jeffrey M; Matsui, Minami; Deng, Xing-Wang (1996). "The COP9 Complex, a Novel Multisubunit Nuclear Regulator Involved in Light Control of a Plant Developmental Switch". Cell. 86 (1): 115–121. doi: 10.1016/S0092-8674(00)80082-3. ISSN 0092-8674. PMID 8689678.
- ^ Seeger, M (1 April 1998). "A novel protein complex involved in signal transduction possessing similarities to 26S proteasome subunits". The FASEB Journal. 12 (6): 469–478. doi: 10.1096/fasebj.12.6.469. PMID 9535219. S2CID 25424324.
- ^ Wei, N; Serino, G; Deng, XW (December 2008). "The COP9 signalosome: more than a protease". Trends in Biochemical Sciences. 33 (12): 592–600. doi: 10.1016/j.tibs.2008.09.004. PMID 18926707.
- ^ Ghosh, S; Farr, L; Singh, A; Leaton, LA; Padalia, J; Shirley, DA; Sullivan, D; Moonah, S (22 September 2020). "COP9 signalosome is an essential and druggable parasite target that regulates protein degradation". PLOS Pathogens. 16 (9): e1008952. doi: 10.1371/journal.ppat.1008952. PMC 7531848. PMID 32960936.
- ^ 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 (24 October 2016). "Targeted inhibition of the COP9 signalosome for treatment of cancer". Nature Communications. 7: 13166. Bibcode: 2016NatCo...713166S. doi: 10.1038/ncomms13166. PMC 5078989. PMID 27774986.
Further reading
- Salmena, Leonardo; Hakem, Razqallah (2013). "From photomorphogenesis to cancer. A CSN journey". Cell Cycle. 12 (2): 205–206. doi: 10.4161/cc.23422. PMC 3575449. PMID 23287466.
- 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. doi: 10.1093/nar/gku723. PMC 4150811. PMID 25106867.
- Lingaraju, G. M.; Bunker, R. D.; Cavadini, S.; Hess, D.; Hassiepen, U.; Renatus, M.; Thomä, N. H. (2014). "Crystal structure of the human COP9 signalosome". Nature. 512 (7513): 161–165. Bibcode: 2014Natur.512..161L. doi: 10.1038/nature13566. PMID 25043011. S2CID 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. Bibcode: 2014BpJ...106..463B. doi: 10.1016/j.bpj.2013.11.2622.
- Chamovitz, D. A. (2009). "Revisiting the COP9 signalosome as a transcriptional regulator". EMBO Reports. 10 (4): 352–358. doi: 10.1038/embor.2009.33. PMC 2672896. PMID 19305390.
- 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. doi: 10.1016/j.plantsci.2011.10.004. PMID 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. doi: 10.1074/mcp.M111.016352. PMC 3418852. PMID 22474085.
