InterPro domain: IPR033859

CSN6 (COP9 signalosome subunit 6; COP9 subunit 6; MOV34 homolog, 34 kD; MEROPS identifier M67.972) is one of the eight subunits of COP9 signalosome. CSN6 is an MPN-domain protein that directly interacts with the MPN+-domain subunit CSN5 [ 1 ]. It is cleaved during apoptosis by activated caspases. CSN6 processing occurs in CSN/CRL (cullin-RING Ub ligase) complexes and is followed by the cleavage of Rbx1, the direct interaction partner of CSN6 [ 2 ]. CSN6 cleavage enhances CSN-mediated deneddylating activity (i.e. cleavage of ubiquitin-like protein Nedd8 (neural precursor cell expressed, developmentally downregulated 8)) in the cullin 1 in cells [ 3 ]. The cleavage of Rbx1 and increased deneddylation of cullins inactivate CRLs and presumably stabilize pro-apoptotic factors for final apoptotic steps. While CSN6 shows a typical MPN metalloprotease fold, it lacks the canonical JAMM motif, and therefore does not show catalytic isopeptidase activity.

The COP9 signalosome (CSN) is a conserved protein complex that regulates the ubiquitin (Ubl) conjugation pathway by mediating the deneddylation of the cullin subunits of SCF-type E3 ligase complexes [ 4 ], which leads to a decrease in Ubl ligase activity of SCF-type complexes such as SCF, CSA or DDB2 [ 5 ]. Protein kinases CK2 and D, which phosphorylate proteins such as cJun and p53 resulting in their degradation by the ubiquitin-26S proteasome system, also binds to CSN [ 6 , 7 ]. The mammalian CSN typically consistis of eight subunits designated CSN1-CSN8. The fission yeast possesses a smaller version of the CSN, consisting only of six subunits, whereas a more distant CSN-like complex has been described in Saccharomyces cerevisiae [ 8 ].

1. The crystal structure of the MPN domain from the COP9 signalosome subunit CSN6. FEBS Lett. 586, 1147-53
2. The subunit CSN6 of the COP9 signalosome is cleaved during apoptosis. J. Biol. Chem. 282, 12557-65
3. The COP9 signalosome-mediated deneddylation is stimulated by caspases during apoptosis. Apoptosis 13, 187-95
4. Promotion of NEDD-CUL1 conjugate cleavage by COP9 signalosome. Science 292, 1382-5
5. The ubiquitin ligase activity in the DDB2 and CSA complexes is differentially regulated by the COP9 signalosome in response to DNA damage. Cell 113, 357-67
6. Protein kinase CK2 and protein kinase D are associated with the COP9 signalosome. EMBO J. 22, 1302-12
7. COP9 signalosome-specific phosphorylation targets p53 to degradation by the ubiquitin system. EMBO J. 20, 1630-9
8. The COP9 signalosome: more than a protease. Trends Biochem. Sci. 33, 592-600