Global impairment of the ubiquitin-proteasome system by nuclear or cytoplasmic protein aggregates precedes inclusion body formation
Global impairment of the ubiquitin-proteasome system by nuclear or cytoplasmic protein aggregates precedes inclusion body formation
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DOI：
10.1016/j.molcel.2004.12.021
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发表时间：
2005-02-04
期刊：
影响因子：
16
通讯作者：
Kopito, RR
中科院分区：
文献类型：
--
作者：
Bennett, EJ;Bence, NF;Kopito, RR
高度保守的泛素-蛋白酶体系统（UPS）控制着大多数细胞核和细胞质蛋白的稳定性，因此对细胞功能的几乎所有方面都是必不可少的。我们以前已经表明，UPS是受损的聚集蛋白的存在下，成为沉积到细胞质包涵体（IB）。在这里，我们报告说，生产的蛋白质聚集体专门针对细胞核或胞质溶胶导致全球的UPS功能在两个细胞隔室的损害，是独立的隔离到IB的聚集体。在缺乏可检测的聚集体或易聚集蛋白质的隔室中观察到严重的UPS损伤，以及在体外缺乏蛋白质聚集体对26 S蛋白酶体功能的干扰，表明UPS损伤不太可能是蛋白质聚集体直接窒息蛋白酶体的结果。这些数据表明，在神经退行性疾病的发病机制中，细胞核和细胞质蛋白聚集体具有共同的蛋白毒性机制。
The highly conserved ubiquitin-proteasome system (UPS) controls the stability of most nuclear and cytoplasmic proteins and is therefore essential for virtually all aspects of cellular function. We have previously shown that the UPS is impaired in the presence of aggregated proteins that become deposited into cytoplasmic inclusion bodies (IBs). Here, we report that production of protein aggregates specifically targeted to either the nucleus or cytosol leads to global impairment of UPS function in both cellular compartments and is independent of sequestration of aggregates into IBs. The observation of severe UPS impairment in compartments lacking detectable aggregates or aggregation-prone protein, together with the lack of interference of protein aggregates on 26S proteasome function in vitro, suggests that UPS impairment is unlikely to be a consequence of direct choking of proteasomes by protein aggregates. These data suggest a common proteotoxic mechanism for nuclear and cytoplasmic protein aggregates in the pathogenesis of neurodegenerative disease.