Disturbance of proteasomal and autophagic protein degradation pathways by amyotrophic lateral sclerosis-linked mutations in ubiquilin 2
Disturbance of proteasomal and autophagic protein degradation pathways by amyotrophic lateral sclerosis-linked mutations in ubiquilin 2
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DOI：
10.1016/j.bbrc.2016.02.107
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发表时间：
2016-04-01
影响因子：
3.1
通讯作者：
Suzuki, Norihiro
中科院分区：
文献类型：
--
作者：
Osaka, Mayuko;Ito, Daisuke;Suzuki, Norihiro
泛素（Ubiquilin，UBQLN）是泛素样（ubiquitin-like，UBL）-泛素相关（ubiquitin-associated，乌巴）家族的成员，是细胞蛋白质降解系统中蛋白酶体和自噬分支的双重调节因子。编码泛素2的UBQLN 2基因突变导致X连锁肌萎缩侧索硬化症（ALS）/额颞叶痴呆（FTD），并且在具有UBQLN 2突变的ALS患者以及没有UBQLN 2突变的家族性和散发性ALS病例中已经鉴定出UBQLN 2阳性包涵体。令人信服的证据将UBQLN 2与神经元中蛋白质质量控制网络的干扰联系起来，但病理机制仍然不清楚。本研究旨在阐明UBQLN 2中ALS连锁突变如何影响蛋白质降解系统。UBQLN 2与ALS相关突变的过度表达导致神经元细胞中聚泛素化蛋白的积累，包括ALS相关蛋白TDP-43。这种作用依赖于乌巴结构域，但不依赖于包涵体的形成。IVm-UBQLN 2细胞分布的免疫细胞化学和蛋白分级分析表明，它从蛋白降解系统的蛋白酶体和自噬分支中螯合泛素化底物，导致聚泛素化底物的积累。这些发现为ALS/FTD相关蛋白质病的发展提供了分子基础，并为ALS建立了新的治疗靶点。(C)2016由Elsevier Inc.出版
Ubiquilin (UBQLN), a member of the ubiquitin-like (UBL)-ubiquitin-associated (UBA) family, is a dual regulator of both the proteasomal and autophagic branches of the cellular protein degradation system. Mutations in the UBQLN2 gene encoding ubiquilin 2 cause X-linked amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD), and UBQLN2-positive inclusions have been identified in ALS patients with UBQLN2 mutations as well as in cases of both familial and sporadic ALS without UBQLN2 mutations. Compelling evidence links UBQLN2 to disturbance of the protein quality control network in neurons, but the pathomechanisms remain obscure. This study aimed to clarify how ALS-linked mutations in UBQLN2 affect the protein degradation system. Overexpression of a UBQLN2 with ALS-associated mutations resulted in the accumulation of polyubiquitinated proteins in neuronal cells, including the ALS-associated protein TDP-43. This effect was dependent on the UBA domain but not on inclusion formation. Immunocytochemistry and protein fractionation analysis of IVm-UBQLN2 cellular distribution indicated that it sequesters ubiquitinated substrates from both the proteasomal and autophagic branches of the protein degradation system, resulting in accumulation of polyubiquitinated substrates. These findings provide a molecular basis for the development of ALS/FTD-associated proteinopathy and establish novel therapeutic targets for ALS. (C) 2016 Published by Elsevier Inc.