NEDD8ubiquitin

NEDD8ubiquitin refers to the covalent attachment of NEDD8 (Neural precursor cell expressed, developmentally downregulated gene 8) to a target protein, often through a similar cascade as ubiquitin conjugation. While ubiquitin is a well-known protein modifier involved in protein degradation and signaling, NEDD8 is a related ubiquitin-like modifier (UBL) that plays distinct roles. The NEDD8 conjugation pathway, termed neddylation, primarily targets proteins within the Cullin-RING ligase (CRL) family of E3 ubiquitin ligases.

The process of neddylation involves a cascade of activating enzymes (E1, E2, and E3), analogous to ubiquitination. A specific NEDD8 E1 enzyme activates NEDD8, which is then transferred to a NEDD8 E2 conjugating enzyme. Finally, a NEDD8 E3 ligase facilitates the transfer of NEDD8 to the substrate. For CRLs, the conjugation of NEDD8 to the cullin subunit is a critical regulatory step.

Neddylation of CRLs enhances their E3 ligase activity, thereby promoting the ubiquitination and subsequent degradation of various substrate proteins. This regulation is crucial for diverse cellular processes including cell cycle progression, DNA repair, and signal transduction. Proteins involved in the deconjugation of NEDD8 from substrates, known as NEDD8-specific proteases (deneddylases), also play a role in fine-tuning neddylation activity. Dysregulation of the NEDD8 pathway has been implicated in various diseases, including cancer, making it a target of therapeutic interest.