Nae1

NAE1, or NEDD8-activating enzyme E1 subunit 1, is a human gene that encodes a component of the NEDD8-activating enzyme (NAE). The functional NAE is a heterodimer composed of NAE1 and UBA3 and is responsible for the first step in the neddylation pathway, the covalent attachment of the ubiquitin-like modifier NEDD8 to substrate proteins.

In the neddylation cascade, the NAE1-UBA3 heterodimer activates NEDD8 in an ATP-dependent reaction, forming NEDD8-adenylate and subsequently transferring NEDD8 to a catalytic cysteine on the E1 enzyme to form a NEDD8 thioester. NEDD8 is then transferred to an E2 conjugating enzyme, such as UBE2M (UBC12) or UBE2F, and finally to substrate proteins, most notably the cullin family, thereby modulating the activity of Cullin-RING ubiquitin ligases (CRLs).

Neddylation regulates protein stability and activity and influences processes including cell cycle progression, DNA damage response, and signal transduction. Because CRLs control the degradation of numerous regulators, dysregulation of NAE1 or neddylation can impact cell growth and survival and has been linked to cancer and other diseases.

Therapeutic targeting of the NAE pathway has been pursued with inhibitors such as pevonedistat (MLN4924), which block NEDD8 activation and lead to accumulation of CRL substrates, replication stress, and tumor cell death in preclinical and clinical studies. These inhibitors are under evaluation in various cancers.

Related terms include NEDD8, neddylation, UBA3, and Cullin-RING ligases.