Neddylation is a posttranslational modification that controls diverse biological 
processes by covalently conjugating the ubiquitin-like protein NEDD8 to specific 
targets. Neddylation is commonly mediated by NEDD8-specific enzymes (typical 
neddylation) and, sometimes, by ubiquitin enzymes (atypical neddylation). 
Although typical neddylation is known to regulate protein function in many ways, 
the regulatory mechanisms and biological consequence of atypical neddylation 
remain largely unexplored. Here we report that NEDD8 conjugates were accumulated 
in the diseased hearts from mouse models and human patients. Proteotoxic 
stresses induced typical and atypical neddylation in cardiomyocytes. Loss of 
NUB1L exaggerated atypical neddylation, whereas NUB1L overexpression repressed 
atypical neddylation through promoting the degradation of NEDD8. Activation of 
atypical neddylation accumulated a surrogate misfolded protein, GFPu. In 
contrast, suppression of atypical neddylation by NUB1L overexpression enhanced 
GFPu degradation. Moreover, NUB1L depletion accumulated a cardiomyopathy-linked 
misfolded protein, CryAB(R120G), whereas NUB1L overexpression promoted its 
degradation through suppressing neddylation of ubiquitinated proteins in 
cardiomyocytes. Consequently, NUB1L protected cells from proteotoxic 
stress-induced cell injury. In summary, these data indicate that NUB1L 
suppresses atypical neddylation and promotes the degradation of misfolded 
proteins by the proteasome. Our findings also suggest that induction of NUB1L 
could potentially become a novel therapeutic strategy for diseases with 
increased proteotoxic stress.