NEDD8
NEDD8, also known as RUB1, is the ubiquitin-like modifier closest to ubiquitin in sequence and is conjugated by a dedicated cascade: the NAE1-UBA3 E1 heterodimer, the E2 enzymes UBE2M and UBE2F, and RING E3 ligases such as RBX1 and RBX2. Its best-characterized function is neddylation of the cullin scaffold subunit within CRL ubiquitin ligase complexes, a modification required for full ligase activity that ultimately controls the turnover of regulators such as p27, CDT1 and HIF-1alpha. DCN1 acts as a co-receptor that accelerates cullin neddylation. Because many oncogenic substrates depend on CRLs, the pathway is druggable: the NAE1 inhibitor pevonedistat has been evaluated in clinical trials for hematologic malignancies.
