NEDD8 Ultimate Buster-1 Long (NUB1L) Protein Suppresses Atypical Neddylation and Promotes Proteasomal Degradation of Misfolded Proteins [Protein Synthesis and Degradation]

August 10th, 2015 by Li, J., Ma, W., Li, H., Hou, N., Wang, X., Kim, I.-M., Li, F., Su, H.

Neddylation is a post-translational 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, while 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 CryABR120G, 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.
  • Posted in Journal of Biological Chemistry, Publications
  • Comments Off on NEDD8 Ultimate Buster-1 Long (NUB1L) Protein Suppresses Atypical Neddylation and Promotes Proteasomal Degradation of Misfolded Proteins [Protein Synthesis and Degradation]