The COP9 signalosome inhibits Cullin-RING E3 ubiquitin ligases independently of its deneddylase activity

Abstract

The COP9 signalosome inhibits the activity of Cullin-RING E3 ubiquitin ligases by removing Nedd8 modifications from their Cullin subunits. Neddylation renders these complexes catalytically active, but deneddylation is also necessary for them to exchange adaptor subunits and avoid auto-ubiquitination. Although deneddylation is thought to be the primary function of the COP9 signalosome, additional activities have been ascribed to some of its subunits. We recently showed that COP9 subunits protect the transcriptional repressor and tumor suppressor Capicua from two distinct modes of degradation. Deneddylation by the COP9 signalosome inactivates a Cullin 1 complex that ubiquitinates Capicua following its phosphorylation by MAP kinase in response to Epidermal Growth Factor Receptor signaling. The CSN1b subunit also stabilizes unphosphorylated Capicua to control its basal level, independently of the deneddylase function of the complex. Here we further examine the importance of deneddylation for COP9 functions in vivo. We use an uncleavable form of Nedd8 to show that preventing deneddylation does not reproduce the effects of loss of COP9. In contrast, in the presence of COP9, conjugation to uncleavable Nedd8 renders Cullins unable to promote the degradation of their substrates. Our results suggest that irreversible neddylation prolongs COP9 binding to and inhibition of Cullin-based ubiquitin ligases.

CSN1 facilitates proliferation and migration of hepatocellular carcinoma cells by upregulating cyclin A2 expression

“…MPN in CSN6 may serve as a structural scaffold or play a regulatory function ( 16 , 19 , 20 ). Previous studies have confirmed that CSN inhibits the ubiquitin-dependent degradation of numerous tumor-related proteins ( 21 – 23 ), such as P27, P53, E3 ubiquitin-protein ligase Mdm2, Smad7, Runt-related transcription factor 3, DNA-binding protein inhibitor ID-1, S-phase kinase-associated protein 2 and hypoxia-inducible factor 1 ( 14 ), indicating that CSN plays an important role in tumorigenesis. In particular, CSN5 or CSN6 overexpression has been detected in numerous types of cancer, such as myeloma, lung cancer and breast cancer ( 24 , 25 ).…”

“…MPN in CSN6 may serve as a structural scaffold or play a regulatory function (16,19,20). Previous studies have confirmed that CSN inhibits the ubiquitin-dependent degradation of numerous tumor-related proteins (21)(22)(23), such as P27, P53, E3 ubiquitin-protein ligase Mdm2, Smad7, Runt-related…”

COP9 signalosome complex subunit-7-mediated regulation of cAMP levels contributes to autophagic degradation and pathogenesis of rice blast fungusMagnaporthe oryzae

“…Generally, the COP9-signalosome complex facilitates the termination of ubiquitination by decoupling neddylases from the Cullen protein (Suisse et al, 2018).…”

“…The copyright holder for this preprint (which this version posted May 1, 2023. ; https://doi.org/10.1101/2023.04.25.538259 doi: bioRxiv preprint displacement of Nedd8 or deneddylation triggered by CSN-SCF interaction results in the termination of Cullin-dependent ubiquitination. Deneddylation is an essential biochemical process that effectively prevents auto-ubiquitination by coordinating interactions between substrates and substrate adaptor subunits of the SCF complex (Suisse et al, 2018).…”