Jana Nihar Ranjan, Dikshit Priyanka, Goswami Anand, Kotliarova Svetlana, Murata Shigeo, Tanaka Keiji, Nukina Nobuyuki
Cellular and Molecular Neuroscience Laboratory, National Brain Research Centre, Manesar, Gurgaon 122-050, India.
J Biol Chem. 2005 Mar 25;280(12):11635-40. doi: 10.1074/jbc.M412042200. Epub 2005 Jan 21.
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.
多聚谷氨酰胺疾病的一个主要标志是疾病蛋白在神经元核内形成包涵体，这些包涵体被泛素化，并且常常与各种伴侣蛋白和蛋白酶体成分相关联。但是，多聚谷氨酰胺蛋白如何被泛素化以及如何被蛋白酶体降解尚不清楚。在此，我们证明CHIP（Hsp70相互作用蛋白的C末端）与多聚谷氨酰胺扩展的亨廷顿蛋白或ataxin-3共免疫沉淀，并与其聚集体相关联。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ataxin-3的泛素化和降解速率。最后，我们表明CHIP的过表达抑制了由扩展的多聚谷氨酰胺蛋白介导的聚集和细胞死亡，并且当CHIP与Hsc70一起过表达时，抑制作用更为显著。
