Fig. 10.

Model for the role of NEDDylation in nuclear proteotoxic stress response. Upon proteotoxic stress the load of misfolded ubiquitinated proteins is increased compromising the function of UPS. The activation of NEDD8 by the ubiquitin E1 enzyme UBA1 and its conjugation by E3-ligases such as HUWE1 results in the modification of substrates with NEDD8 and ubiquitin possibly with hybrid NEDD8/ubiquitin chains. This provides a regulatory pathway to prevent substrate targeting to the proteasome, promoting the transient aggregation of a group of proteins. This protects the UPS from the stress-induced toxicity