A critical role of Hrd1 in the regulation of optineurin degradation and aggresome formation
A critical role of Hrd1 in the regulation of optineurin degradation and aggresome formation
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Hrd1 在调节 optineurin 降解和聚集体形成中的关键作用
DOI：
10.1093/hmg/ddx096
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发表时间：
2017-05-15
影响因子：
3.5
通讯作者：
Wang, Guanghui
中科院分区：
文献类型：
--
作者：
Mao, Jiahui;Xia, Qin;Wang, Guanghui
视神经磷酸酶（OPTN）的突变与几种人类疾病有关，包括肌萎缩侧索硬化症（ALS）和原发性开角型青光眼（POAG）。OPTN是一种多功能的自噬受体，在NF-κ B信号传导、囊泡运输、高尔基体的维持和自噬中起重要作用。鉴于神经元的损失和疾病蛋白质的异常聚集是神经退行性疾病的两个关键特征，蛋白质质量控制系统被认为与神经退行性疾病密切相关。在这项研究中，我们研究了泛素-蛋白酶体系统（UPS）和自噬-溶酶体途径，两个主要的细胞内蛋白质质量控制系统，在野生型（WT）OPTN，ALS连锁突变体E478 G OPTN和POAG连锁突变体E50 K OPTN的调节的参与。我们的数据表明，UPS，而不是自噬-溶酶体途径，是OPTN的降解和聚集的主要系统。此外，我们发现Hrd 1，一种E3泛素连接酶，可以在OPTN的蛋白质质量控制中发挥重要作用。我们的研究结果表明，Hrd 1的过表达增加了蛋白酶体降解和微管组织中心的OPTN的微管依赖性攻击体形成，而Hrd 1的敲低稳定OPTN和抑制OPTN的攻击体形成。
Mutations in optineurin (OPTN) are associated with several human disorders including amyotrophic lateral sclerosis (ALS) and primary open-angle glaucoma (POAG). OPTN is known to be a multifunctional autophagy receptor that plays important roles in NF-kappa B signaling, vesicle trafficking, maintenance of the Golgi apparatus and autophagy. Given that a loss of neurons and an abnormal aggregation of disease proteins are two key features of neurodegenerative diseases, protein quality control systems are considered to be tightly associated with neurodegeneration. In this study, we investigated the involvement of the ubiquitin-proteasome system (UPS) and the autophagy-lysosome pathway, two major intracellular protein quality control systems, in the regulation of wild-type (WT) OPTN, ALS-linked mutant E478G OPTN and POAG-linked mutant E50K OPTN. Our data revealed that the UPS, not the autophagy-lysosome pathway, is the major system for degradation and aggregation of OPTN. Moreover, we found that Hrd1, an E3 ubiquitin ligase, could play an important role in the protein quality control of OPTN. Our results demonstrated that overexpression of Hrd1 increased the proteasomal degradation and microtubule-dependent aggresome formation of OPTN in the microtubular organizing center, whereas knockdown of Hrd1 stabilized OPTN and inhibited aggresome formation of OPTN.