Nedd8

NEDD8 (neural precursor cell expressed developmentally down-regulated 8) is a small ubiquitin-like modifier that covalently attaches to target proteins in a process called neddylation. The mature NEDD8 protein contains 81 amino acids and ends with a C-terminal glycine, which is essential for forming isopeptide bonds with lysine residues on substrates. NEDD8 is highly conserved across eukaryotes and is used to regulate a subset of cellular proteins through covalent modification.

The neddylation pathway uses a dedicated cascade of enzymes. Activation begins with the NEDD8-activating enzyme (NAE), a heterodimer composed of NAE1 (also known as APPBP1) and UBA3, which, in an ATP-dependent manner, activates NEDD8. The activated NEDD8 is transferred to an E2 conjugating enzyme, primarily UBE2M (also called UBC12) or, to a lesser extent, UBE2F. An E3 ligase, such as RBX1 or RBX2 in complex with other factors, facilitates transfer of NEDD8 to target substrates, most notably the Cullin family of proteins.

Neddylation most prominently modifies Cullin proteins (CUL1–CUL9), activating Cullin-RING ligases (CRLs). These E3 ubiquitin ligases ubiquitinate a wide range of substrates, marking them for proteasomal degradation. Neddylation thereby indirectly controls numerous cellular processes, including cell cycle progression, DNA replication, and genome stability. Deneddylation, the removal of NEDD8, is carried out by the COP9 signalosome and by NEDP1, allowing dynamic regulation of CRL activity.

Pharmacological inhibition of NEDD8 activation, such as with pevonedistat (MLN4924), disrupts CRL function and has been explored as an anti-cancer strategy. NEDD8 remains an essential, tightly regulated modifier with broad implications for cell biology and disease.