Protein neddylation: substrate landscape and target modulators

A review in the Journal of Translational Medicine maps protein neddylation, a reversible ubiquitin-like post-translational modification involved in protein degradation and other cellular regulatory processes. The article outlines the enzymes that install and remove the modification, summarizes an expanding set of non-Cullin substrates, and evaluates small-molecule inhibitors directed at several points along the pathway. The work is a synthesis of existing research rather than a new experimental or clinical study.

Neddylation proceeds through the sequential action of the NEDD8-activating enzyme NAE, the E2 conjugating enzymes UBE2M and UBE2F, and multiple E3 ligases, while deneddylases dynamically reverse the process. The best-established physiological substrates are members of the Cullin family, which form the core scaffolds of Cullin-RING ubiquitin ligases, the largest family of E3 ubiquitin ligases. Neddylation activates these complexes, which are estimated to mediate the ubiquitination of approximately 20% of proteins degraded through the ubiquitin-proteasome system.

Beyond Cullins, the review describes a growing list of non-Cullin substrates. Modification of these proteins predominantly affects their stability, enzymatic activity or subcellular localization, extending neddylation’s regulatory reach beyond proteolysis. Small-molecule drug development has targeted several components of the neddylation pathway, including NAE, DCN1 and CSN5.

According to the review, numerous inhibitors have been developed against these targets, and the NAE inhibitors MLN4924 and TAS4464 have advanced into clinical trials. Their movement into clinical investigation demonstrates that neddylation is being explored as a therapeutic target, but the review itself does not report a new clinical efficacy result. Instead, it critically evaluates the current inhibitor landscape and identifies opportunities for further drug development, while the supplied evidence does not provide comparative clinical-outcome data or establish the selectivity profile of the candidate drugs.

Subject of Research: Review of the molecular regulation, substrate landscape and pharmacological targeting of protein neddylation.

Article Title: Protein neddylation: substrate landscape and target modulators

Article References: Jing, Z., Wang, F., Li, H., Lu, B., Li, Z., Hu, W., Liang, S., Liang, W., Fu, X., & Wang, X. (2026). Protein neddylation: substrate landscape and target modulators. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-09076-z

Image Credits: AI Generated

DOI: 10.1186/s12967-026-09076-z

Keywords: protein neddylation, NEDD8, non-Cullin substrates, Cullin-RING ligases, ubiquitin-proteasome system, NAE inhibitors, MLN4924, TAS4464, deneddylation, cancer therapeutics, Protein, neddylation