A Mental Retardation-linked Nonsense Mutation in Cereblon Is Rescued by Proteasome Inhibition
Year: 2013
Type: article
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. Background: A nonsense mutation in cereblon, which results in the loss of the last 24 amino acids in the protein, causes mental retardation. Results: This mutant form of cereblon undergoes autoubiquitination by a CRL4 E3 ligase complex, leading to enhanced proteasomal degradation. Conclusion: The protein level of the mutant cereblon can be rescued by proteasome inhibition. Significance: These findings provide an approach for the treatment of mental retardation associated with this cereblon mutation.
Source: Journal of Biological Chemistry
Authors: Guoqiang Xu, Xiaogang Jiang, Samie R. Jaffrey
Institutions: Cornell University, Soochow University, Weill Cornell Medicine
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $3,430
OpenAlex ID: W2076088245