Co-chaperone CHIP associates with expanded polyglutamine protein and promotes their degradation by proteasomes
Co-chaperone CHIP associates with expanded polyglutamine protein and promotes their degradation by proteasomes
复制标题
DOI：
10.1074/jbc.m412042200
复制
发表时间：
2005-03-25
影响因子：
4.8
通讯作者：
Nukina, N
中科院分区：
文献类型：
--
作者：
Jana, NR;Dikshit, P;Nukina, N
多聚谷氨酰胺疾病的一个主要标志是疾病蛋白的神经元核内包涵体的形成，所述疾病蛋白是泛素化的并且通常与各种分子伴侣和蛋白酶体组分相关。但是，多聚谷氨酰胺蛋白如何被蛋白酶体泛素化和降解尚不清楚。在这里，我们证明了CHIP（热休克蛋白70相互作用蛋白的C末端）与多聚谷氨酰胺扩增的亨廷顿蛋白或共济失调蛋白-3共免疫沉淀，并与它们的聚集体相关联。CHIP的瞬时过表达增加了多聚谷氨酰胺扩展的亨廷顿蛋白或共济失调蛋白-3的泛素化和降解速率。最后，我们表明，过度表达的CHIP抑制聚集和细胞死亡介导的扩展的聚谷氨酰胺蛋白和抑制作用更突出时，CHIP与Hsc 70沿着过度表达。
A major hallmark of the polyglutamine diseases is the formation of neuronal intranuclear inclusions of the disease proteins that are ubiquitinated and often associated with various chaperones and proteasome components. But, how the polyglutamine proteins are ubiquitinated and degraded by the proteasomes are not known. Here, we demonstrate that CHIP (C terminus of Hsp70-interacting protein) co-immunoprecipitates with the polyglutamine-expanded huntingtin or ataxin-3 and associates with their aggregates. Transient overexpression of CHIP increases the ubiquitination and the rate of degradation of polyglutamine-expanded huntingtin or ataxin-3. Finally, we show that overexpression of CHIP suppresses the aggregation and cell death mediated by expanded polyglutamine proteins and the suppressive effect is more prominent when CHIP is overexpressed along with Hsc70.