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Abstract
The COP9 signalosome (CSN) is a central component of the activation and remodelling cycle of cullin-RING E3 ubiquitin ligases (CRLs), the largest enzyme family of the ubiquitin–proteasome system in humans. CRLs are implicated in the regulation of numerous cellular processes, including cell cycle progression and apoptosis, and aberrant CRL activity is frequently associated with cancer. Remodelling of CRLs is initiated by CSN-catalysed cleavage of the ubiquitin-like activator NEDD8 from CRLs. Here we describe CSN5i-3, a potent, selective and orally available inhibitor of CSN5, the proteolytic subunit of CSN. The compound traps CRLs in the neddylated state, which leads to inactivation of a subset of CRLs by inducing degradation of their substrate recognition module. CSN5i-3 differentially affects the viability of tumour cell lines and suppresses growth of a human xenograft in mice. Our results provide insights into how CSN regulates CRLs and suggest that CSN5 inhibition has potential for anti-tumour therapy.
Highlights
The COP9 signalosome (CSN) is a central component of the activation and remodelling cycle of cullin-RING E3 ubiquitin ligases (CRLs), the largest enzyme family of the ubiquitin–proteasome system in humans
Critical steps in the cyclic regulation of CRLs are the activation of CRLs induced by the covalent attachment of the ubiquitin-like activator NEDD8 to the cullin moiety and its proteolytic removal leading to deactivation and disassembly[22,23,24] (Fig. 1a)
CRL neddylation is catalysed by the NEDD8-activating enzyme[25] (NAE1) and induces a conformational rearrangement that enables the transfer of ubiquitin from the E2 enzyme to the ubiquitin-receiving substrate, which is recruited by the substrate receptor module (SRM) of the respective CRL
Summary
The COP9 signalosome (CSN) is a central component of the activation and remodelling cycle of cullin-RING E3 ubiquitin ligases (CRLs), the largest enzyme family of the ubiquitin–proteasome system in humans. Remodelling of CRLs is initiated by CSN-catalysed cleavage of the ubiquitin-like activator NEDD8 from CRLs. Here we describe CSN5i-3, a potent, selective and orally available inhibitor of CSN5, the proteolytic subunit of CSN. E3 ubiquitin ligases define the substrate specificity of the UPS and comprise the largest enzyme family of the system with more than 600 putative members encoded by the human genome[15] Within this family, cullin-RING E3 ubiquitin ligases (CRLs) are the largest subfamily, responsible for B20% of total cellular protein turnover[4,16,17]. We show how pharmacologic inhibition of CSN modulates CRLs in vitro and demonstrate the potential therapeutic value of an orally available CSN5 inhibitor in a human xenograft model
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