Protein neddylation: beyond cullin–RING ligases

Abstract

NEDD8 (neural precursor cell expressed developmentally downregulated protein 8) and ubiquitin have the highest sequence and structural similarity among all ubiquitin-like proteins. NEDD8-specific conjugation and de-conjugation pathways exist in all studied eukaryotes, which can discriminate between NEDD8 and other ubiquitin-like proteins through NEDD8-specific interaction domains. Nevertheless, a perturbed ratio of free NEDD8 and ubiquitin or cellular stress can result in the conjugation of NEDD8 through the ubiquitylation machinery onto ubiquitylation substrates. This can lead to mis-assignments of neddylation targets, and most published reports lack sufficient evidence to substantiate the discovery of genuine neddylation substrates. We propose a list of necessary criteria for bona fide neddylation substrates and re-evaluate published studies in the light of these criteria. Cullins are the best-studied and only neddylation targets to date that fulfill all of these criteria. We discuss potential examples of neddylation regulating non-cullin ubiquitin E3 ligases, transcription, ribosomal stress and various signalling pathways. Pharmacological inhibition of neddylation is a promising new direction for cancer therapy. We discuss the potential effects of inhibiting non-cullin, as well as cullin, neddylation.