Bence N F, Sampat R M, Kopito R R
Department of Biological Sciences, Stanford University, Stanford, CA 94305-5020, USA.
Science. 2001 May 25;292(5521):1552-5. doi: 10.1126/science.292.5521.1552.
Intracellular deposition of aggregated and ubiquitylated proteins is a prominent cytopathological feature of most neurodegenerative disorders. Whether protein aggregates themselves are pathogenic or are the consequence of an underlying molecular lesion is unclear. Here, we report that protein aggregation directly impaired the function of the ubiquitin-proteasome system. Transient expression of two unrelated aggregation-prone proteins, a huntingtin fragment containing a pathogenic polyglutamine repeat and a folding mutant of cystic fibrosis transmembrane conductance regulator, caused nearly complete inhibition of the ubiquitin-proteasome system. Because of the central role of ubiquitin-dependent proteolysis in regulating fundamental cellular events such as cell division and apoptosis, our data suggest a potential mechanism linking protein aggregation to cellular disregulation and cell death.
聚集且泛素化的蛋白质在细胞内沉积是大多数神经退行性疾病的一个显著细胞病理学特征。蛋白质聚集体本身是否具有致病性，或者是潜在分子损伤的结果尚不清楚。在此，我们报告蛋白质聚集直接损害了泛素-蛋白酶体系统的功能。两种不相关的易于聚集的蛋白质（一种含有致病性多聚谷氨酰胺重复序列的亨廷顿蛋白片段和囊性纤维化跨膜传导调节因子的折叠突变体）的瞬时表达几乎完全抑制了泛素-蛋白酶体系统。由于泛素依赖性蛋白水解在调节诸如细胞分裂和凋亡等基本细胞事件中起着核心作用，我们的数据提示了一种将蛋白质聚集与细胞调节紊乱和细胞死亡联系起来的潜在机制。
