NEDD8 Ultimate Buster 1 Long (NUB1L) protein suppresses atypical neddylation and promotes the proteasomal degradation of misfolded proteins

Jie Li, Wenxia Ma, Huizhong Li, Ning Hou, Xuejun Wang, Il Man Kim, Faqian Li, Huabo Su

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

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, 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.

Original languageEnglish (US)
Pages (from-to)23850-23862
Number of pages13
JournalJournal of Biological Chemistry
Volume290
Issue number39
DOIs
StatePublished - Sep 25 2015
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'NEDD8 Ultimate Buster 1 Long (NUB1L) protein suppresses atypical neddylation and promotes the proteasomal degradation of misfolded proteins'. Together they form a unique fingerprint.

  • Cite this