title: A mental retardation-linked nonsense mutation in cereblon is rescued by proteasome inhibition.
abstract: A nonsense mutation in cereblon (CRBN) causes autosomal recessive nonsyndromic mental retardation. Cereblon is a substrate receptor for the Cullin-RING E3 ligase complex and couples the ubiquitin ligase to specific ubiquitination targets. The CRBN nonsense mutation (R419X) results in a protein lacking 24 amino acids at its C terminus. Although this mutation has been linked to mild mental retardation, the mechanism by which the mutation affects CRBN function is unknown. Here, we used biochemical and mass spectrometric approaches to explore the function of this mutant. We show that the protein retains its ability to assemble into a Cullin-RING E3 ligase complex and catalyzes the ubiquitination of CRBN-target proteins. However, we find that this mutant exhibits markedly increased levels of autoubiquitination and is more readily degraded by the proteasome than the wild type protein. We also show that the level of the mutant protein can be restored by a treatment of cells with a clinically utilized proteasome inhibitor, suggesting that this agent may be useful for the treatment of mental retardation associated with the CRBN R419X mutation. These data demonstrate that enhanced autoubiquitination and degradation account for the defect in CRBN activity that leads to mental retardation.
authors: From the Department of Pharmacology, College of Pharmaceutical Sciences, Jiangsu Key Laboratory of Translational Research for Neuro-Psycho-Diseases, Soochow University, Suzhou, Jiangsu 215123, China and.
authors: Guoqiang
authors: G
authors: Xu
authors: Xiaogang
authors: X
authors: Jiang
authors: Samie R
authors: SR
authors: Jaffrey
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D018389:Codon, Nonsense; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D008607:Intellectual Disability / Q000235:genetics*; D008239:Lysine / Q000235:genetics / Q000378:metabolism; D008856:Microscopy, Fluorescence; D050505:Mutant Proteins / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010447:Peptide Hydrolases / Q000235:genetics* / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology; D059748:Proteolysis / Q000187:drug effects; D011719:Pyrazines / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001897:Boronic Acids; C502543:CRBN protein, human; D018389:Codon, Nonsense; C429530:DTL protein, human; D050505:Mutant Proteins; D009687:Nuclear Proteins; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D044767:Ubiquitin-Protein Ligases; D010447:Peptide Hydrolases; D046988:Proteasome Endopeptidase Complex; D008239:Lysine
keywords: Cereblon; E3 Ubiquitin Ligase; Genetic Diseases; Mental Retardation; Mutant; Nonsense Mutation; Proteasome Inhibition; Protein Degradation; Ubiquitin; Ubiquitination
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