Intranuclear Degradation of Polyglutamine Aggregates by the Ubiquitin-Proteasome System
Intranuclear Degradation of Polyglutamine Aggregates by the Ubiquitin-Proteasome System
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DOI：
10.1074/jbc.m809739200
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发表时间：
2009-04-10
影响因子：
4.8
通讯作者：
Tsuji, Shoji
中科院分区：
文献类型：
--
作者：
Iwata, Atsushi;Nagashima, Yu;Tsuji, Shoji
亨廷顿病及其相关的常染色体显性多聚谷氨酰胺（pQ）神经退行性疾病的特征是蛋白质聚集体的神经元内积聚。对蛋白质聚集体的研究揭示了泛素-蛋白酶体系统作为针对异常蛋白质的蛋白质质量控制（PQC）机制的前线的重要性。最近，我们发现自噬-溶酶体系统也参与了细胞质聚集体的降解，但细胞核缺乏这种活性。因此，细胞核完全依赖于泛素-蛋白酶体系统进行PQC。根据先前的研究，核聚集体具有比它们的细胞质对应物更高的细胞毒性，然而核聚集体的降解动力学知之甚少。在这里，我们表明，核泛素连接酶San 1 p和UHRF-2各自增强核pQ聚集体降解和拯救pQ诱导的细胞毒性培养细胞和原代神经元。此外，在体外和体内，UHRF-2与核包涵体相关。我们的数据表明，UHRF-2是一个必不可少的分子核pQ降解作为一个组成部分的核PQC机制在哺乳动物细胞。
Huntington disease and its related autosomal-dominant polyglutamine (pQ) neurodegenerative diseases are characterized by intraneuronal accumulation of protein aggregates. Studies on protein aggregates have revealed the importance of the ubiquitin-proteasome system as the front line of protein quality control (PQC) machinery against aberrant proteins. Recently, we have shown that the autophagy-lysosomal system is also involved in cytoplasmic aggregate degradation, but the nucleus lacked this activity. Consequently, the nucleus relies entirely on the ubiquitin-proteasome system for PQC. According to previous studies, nuclear aggregates possess a higher cellular toxicity than do their cytoplasmic counterparts, however degradation kinetics of nuclear aggregates have been poorly understood. Here we show that nuclear ubiquitin ligases San1p and UHRF-2 each enhance nuclear pQ aggregate degradation and rescued pQ-induced cytotoxicity in cultured cells and primary neurons. Moreover, UHRF-2 is associated with nuclear inclusion bodies in vitro and in vivo. Our data suggest that UHRF-2 is an essential molecule for nuclear pQ degradation as a component of nuclear PQC machinery in mammalian cells.