Interplay between neddylation and the ubiquitin proteasome system

The ubiquitin proteasome system (UPS) is the eukaryotic cell's premier proteolytic machinery and is critical for maintaining cellular homeostasis. UPS dysfunction is now recognized as a major risk factor in many diseases ranging from cancers and cardiomyopathies to neurodegenerative disorders. Yet the regulatory mechanisms of the UPS remain incompletely understood. Among the ubiquitin superfamily of ~17 proteins, NEDD8 has the highest homology (~80%) with ubiquitin. NEDD8 modification of proteins, termed neddylation, is essential for several biological processes, including embryogenesis, adipogenesis, synapse formation, and tumorigenesis. Although neddylation does not directly signal modified substrates for degradation, it plays critical roles in maintaining protein homeostasis. Here we summarize recent advances in understanding the biology of both NEDD8 and ubiquitin and highlight the crosstalk between these two pathways. Knowledge of their crosstalk could lead to advances in the studies of diseases associated with defective protein quality control.