A Mental Retardation-linked Nonsense Mutation in Cereblon Is Rescued by Proteasome Inhibition
A Mental Retardation-linked Nonsense Mutation in Cereblon Is Rescued by Proteasome Inhibition
复制标题
蛋白酶体抑制可挽救大脑中与智力低下相关的无义突变
DOI：
10.1074/jbc.m113.472092
复制
发表时间：
2013-10-11
影响因子：
4.8
通讯作者：
Jaffrey, Samie R.
中科院分区：
文献类型：
--
作者：
Xu, Guoqiang;Jiang, Xiaogang;Jaffrey, Samie R.
cereblon（CRBN）的无义突变导致常染色体隐性遗传的非综合征性精神发育迟滞。Cereblon是Cullin-RING E3连接酶复合物的底物受体，并将泛素连接酶偶联至特异性泛素化靶标。CRBN无义突变（R419 X）导致蛋白质在其C末端缺少24个氨基酸。虽然这种突变与轻度精神发育迟滞有关，但这种突变影响CRBN功能的机制尚不清楚。在这里，我们使用生物化学和质谱方法来探索这种突变体的功能。我们发现，该蛋白保留其组装成Cullin-RING E3连接酶复合物的能力，并催化CRBN靶蛋白的泛素化。然而，我们发现，这种突变体表现出显着增加的autoubiquitination水平，更容易被蛋白酶体比野生型蛋白质降解。我们还表明，突变蛋白质的水平可以通过用临床上使用的蛋白酶体抑制剂治疗细胞来恢复，这表明该试剂可能用于治疗与CRBN R419 X突变相关的精神发育迟滞。这些数据表明，增强的autoubiquitination和降解的CRBN活性的缺陷，导致精神发育迟滞。
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.