title: NEDD8 Ultimate Buster 1 Long (NUB1L) Protein Suppresses Atypical Neddylation and Promotes the Proteasomal Degradation of Misfolded Proteins.
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, 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.
authors.affiliation: From the Vascular Biology Center and.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: From the Vascular Biology Center and.
authors.forename: Wenxia
authors.initials: W
authors.lastname: Ma
authors.affiliation: From the Vascular Biology Center and.
authors.forename: Huizhong
authors.initials: H
authors.lastname: Li
authors.affiliation: the Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York 14642, and.
authors.forename: Ning
authors.initials: N
authors.lastname: Hou
authors.affiliation: the Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, South Dakota 57069.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Wang
authors.affiliation: From the Vascular Biology Center and.
authors.forename: Il-man
authors.initials: IM
authors.lastname: Kim
authors.affiliation: the Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, New York 14642, and.
authors.forename: Faqian
authors.initials: F
authors.lastname: Li
authors.affiliation: From the Vascular Biology Center and Department of Pharmacology and Toxicology, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912, HSU@gru.edu.
authors.forename: Huabo
authors.initials: H
authors.lastname: Su
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D019943:Amino Acid Substitution; D000818:Animals; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D020125:Mutation, Missense; D000075687:NEDD8 Protein; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014452:Ubiquitins / Q000235:genetics / Q000378:metabolism*; D038203:alpha-Crystallin B Chain / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C059215:CRYAB protein, human; C525420:Cryab protein, mouse; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; C430242:NUB1 protein, human; C513172:Nedd8 protein, mouse; D014157:Transcription Factors; D014452:Ubiquitins; D038203:alpha-Crystallin B Chain; D046988:Proteasome Endopeptidase Complex
keywords: NEDD8; NUB1L; cardiomyopathy; posttranslational modification (PTM); proteasome; protein degradation; ubiquitin