Identification of NUB1 as a suppressor of mutant Huntingtin toxicity via enhanced protein clearance
Identification of NUB1 as a suppressor of mutant Huntingtin toxicity via enhanced protein clearance
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DOI：
10.1038/nn.3367
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发表时间：
2013-05-01
影响因子：
25
通讯作者：
Palacino, James
中科院分区：
文献类型：
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作者：
Lu, Boxun;Al-Ramahi, Ismael;Palacino, James
亨廷顿病是由HTT中CAG重复序列扩增引起的，其赋予突变HTT（mHTT）蛋白毒性功能增益。减少mHTT量被假定为治疗干预的策略。我们对修饰mHTT丰度的基因进行了全基因组RNA干扰筛选，并确定了13个命中。我们在黑腹果蝇亨廷顿病模型中体内测试了10个，并且6个表现出与体外筛选结果一致的活性。其中，泛素样蛋白1（NUB 1）过表达的负调节因子降低了神经元模型中的mHTT，并挽救了mHTT诱导的死亡。NUB 1通过增强mHTT蛋白的多聚泛素化和蛋白酶体降解来减少mHTT的量。该过程需要CUL 3和CUL 3活化所必需的泛素样蛋白NEDD 8。作为调节NUB 1进行治疗的潜在方法，干扰素-β降低了mHTT并通过诱导NUB 1来挽救神经元毒性。因此，我们已经使用高通量筛选鉴定了修饰内源性mHTT的基因，并证明NUB 1是亨廷顿病治疗干预的示例性切入点。
Huntington's disease is caused by expanded CAG repeats in HTT, conferring toxic gain of function on mutant HTT (mHTT) protein. Reducing mHTT amounts is postulated as a strategy for therapeutic intervention. We conducted genome-wide RNA interference screens for genes modifying mHTT abundance and identified 13 hits. We tested 10 in vivo in a Drosophila melanogaster Huntington's disease model, and 6 exhibited activity consistent with the in vitro screening results. Among these, negative regulator of ubiquitin-like protein 1 (NUB1) overexpression lowered mHTT in neuronal models and rescued mHTT-induced death. NUB1 reduces mHTT amounts by enhancing polyubiquitination and proteasomal degradation of mHTT protein. The process requires CUL3 and the ubiquitin-like protein NEDD8 necessary for CUL3 activation. As a potential approach to modulating NUB1 for treatment, interferon-beta lowered mHTT and rescued neuronal toxicity through induction of NUB1. Thus, we have identified genes modifying endogenous mHTT using high-throughput screening and demonstrate NUB1 as an exemplar entry point for therapeutic intervention of Huntington's disease.