The enzymatic cascades for protein neddylation and deneddylation. Schematic representation of each step of the NEDD8 conjugation pathway, including NEDD8 precursor processing, NEDD8 activation by NAE, E2 loading, conjugation to a substrate by an E3 and recycling of NEDD8 by a NEDD8 isopeptidase. The involving enzymes in each step are listed. NAE, NEDD8-activating enzyme. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars