The C-terminal tail of CSNAP attenuates the CSN complex

Protein degradation is one of the essential mechanisms that enables reshaping of the proteome landscape in response to various stimuli. The largest E3 ubiquitin ligase family that targets proteins to degradation by catalyzing ubiquitination is the cullin-RING ligases (CRLs). Many of the proteins that are regulated by CRLs are central to tumorigenesis and tumor progression, and dysregulation of the CRL family is frequently associated with cancer. The CRL family comprises similar to 300 complexes, all of which are regulated by the COP9 signalosome complex (CSN). Therefore, CSN is considered an attractive target for therapeutic intervention. Research efforts for targeted CSN inhibition have been directed towards inhibition of the complex enzymatic subunit, CSN5. Here, we have taken a fresh approach focusing on CSNAP, the smallest CSN subunit. Our results show that the C-terminal region of CSNAP is tightly packed within the CSN complex, in a groove formed by CSN3 and CSN8. We show that a 16 amino acid C-terminal peptide, derived from this CSN-interacting region, can displace the endogenous CSNAP subunit from the complex. This, in turn, leads to a CSNAP null phenotype that attenuates CSN activity and consequently CRLs function. Overall, our findings emphasize the potential of a CSNAP-based peptide for CSN inhibition as a new therapeutic avenue.

Automated summary

Protein degradation is an essential mechanism for reshaping the proteome in response to stimuli. Cullin-RING ligases (CRLs) are the largest E3 ubiquitin ligase family targeting proteins for degradation. Dysregulation of the CRL family is associated with cancer, making it an attractive target for therapeutic intervention. CSNAP, the smallest subunit of the COP9 signalosome complex (CSN), has been identified as a potential target for CSN inhibition. The results of this study demonstrate that a 16 amino acid peptide derived from CSNAP can displace the subunit from the CSN complex, attenuating its activity and suggesting a new therapeutic avenue.