Differential ubiquitination and degradation of huntingtin fragments modulated by ubiquitin-protein ligase E3A
Differential ubiquitination and degradation of huntingtin fragments modulated by ubiquitin-protein ligase E3A
复制标题
DOI：
10.1073/pnas.1402215111
复制
发表时间：
2014-04-15
影响因子：
11.1
通讯作者：
Li, Xiao-Jiang
中科院分区：
文献类型：
--
作者：
Bhat, Kavita P.;Yan, Sen;Li, Xiao-Jiang
错误折叠蛋白的泛素化是许多神经退行性疾病的共同特征，它由泛素中不同的赖氨酸(K)残基介导，并改变有毒蛋白的水平。在亨廷顿病中，多聚谷氨酰胺的扩张导致亨廷顿蛋白(Htt)的N-末端错误折叠，导致神经退化。在这里，我们报告了较短的N末端Htt片段比较长的片段更稳定，并通过泛素的K63发现了差异泛素化。衰老减少了蛋白酶体介导的Htt降解，同时增加了K63介导的泛素化和随后在HD敲入小鼠中的Htt聚集。在衰老的小鼠脑中，Htt与K48特异的E3连接酶Ube3a的关联减少。在HD小鼠脑中过表达Ube3a可减少K63介导的泛素化和Htt聚集，通过K48泛素-蛋白酶体系统增强其降解。我们的发现表明，与年龄相关的Ube3a水平导致Htt片段的不同泛素化和降解，从而导致突变Htt的年龄相关神经毒性。
Ubiquitination of misfolded proteins, a common feature of many neurodegenerative diseases, is mediated by different lysine (K) residues in ubiquitin and alters the levels of toxic proteins. In Huntington disease, polyglutamine expansion causes N-terminal huntingtin (Htt) to misfold, inducing neurodegeneration. Here we report that shorter N-terminal Htt fragments are more stable than longer fragments and find differential ubiquitination via K63 of ubiquitin. Aging decreases proteasome-mediated Htt degradation, at the same time increasing K63-mediated ubiquitination and subsequent Htt aggregation in HD knock-in mice. The association of Htt with the K48-specific E3 ligase, Ube3a, is decreased in aged mouse brain. Overexpression of Ube3a in HD mouse brain reduces K63-mediated ubiquitination and Htt aggregation, enhancing its degradation via the K48 ubiquitin-proteasome system. Our findings suggest that aging-dependent Ube3a levels result in differential ubiquitination and degradation of Htt fragments, thereby contributing to the age-related neurotoxicity of mutant Htt.