Parkin-mediated ubiquitin signalling in aggresome formation and autophagy.
Parkin-mediated ubiquitin signalling in aggresome formation and autophagy.
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DOI：
10.1042/bst0380144
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发表时间：
2010-02
影响因子：
3.9
通讯作者：
Li L
中科院分区：
文献类型：
--
作者：
Chin LS;Olzmann JA;Li L
了解细胞如何处理和处置错误折叠的蛋白质是至关重要的，因为蛋白质错误折叠和聚集是许多神经退行性疾病的发病机制的基础，包括PD（帕金森病）和阿尔茨海默病。除了泛素-蛋白酶体系统之外，攻击体-自噬途径已经成为另一个重要的细胞防御系统，以对抗错误折叠蛋白质的毒性积累。与介导错误折叠蛋白质沿着与正常细胞蛋白质和细胞器的非选择性、大量清除的基础自噬相反，侵袭体-自噬途径越来越多地被认为是在蛋白毒性应激条件下介导错误折叠和聚集蛋白质的选择性清除的诱导自噬的专门类型。最近的证据表明PD连接的E3连接酶parkin是攻击性蛋白组-自噬途径的关键调节因子，并表明Lys 63连接的多聚泛素化在攻击性蛋白组形成和自噬的调节中具有信号传导作用。本文综述了攻击性自噬通路、帕金森蛋白介导的Lys 63-linked polyubiquitination对其的调控及其在神经退行性疾病中的功能障碍。
Understanding how cells handle and dispose of misfolded proteins is of paramount importance because protein misfolding and aggregation underlie the pathogenesis of many neurodegenerative disorders, including PD (Parkinson's disease) and Alzheimer's disease. In addition to the ubiquitin–proteasome system, the aggresome–autophagy pathway has emerged as another crucial cellular defence system against toxic build-up of misfolded proteins. In contrast with basal autophagy that mediates non-selective, bulk clearance of misfolded proteins along with normal cellular proteins and organelles, the aggresome–autophagy pathway is increasingly recognized as a specialized type of induced autophagy that mediates selective clearance of misfolded and aggregated proteins under the conditions of proteotoxic stress. Recent evidence implicates PD-linked E3 ligase parkin as a key regulator of the aggresome–autophagy pathway and indicates a signalling role for Lys63-linked polyubiquitination in the regulation of aggresome formation and autophagy. The present review summarizes the current knowledge of the aggresome–autophagy pathway, its regulation by parkin-mediated Lys63-linked polyubiquitination, and its dysfunction in neurodegenerative diseases.