The Machado-Joseph Disease Deubiquitinase Ataxin-3 Regulates the Stability and Apoptotic Function of p53.
The Machado-Joseph Disease Deubiquitinase Ataxin-3 Regulates the Stability and Apoptotic Function of p53.
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Machado-Joseph 病去泛素酶 Ataxin-3 调节 p53 的稳定性和凋亡功能。
DOI：
10.1371/journal.pbio.2000733
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发表时间：
2016-11
期刊：
影响因子：
9.8
通讯作者：
Tang TS
中科院分区：
文献类型：
--
作者：
Liu H;Li X;Ning G;Zhu S;Ma X;Liu X;Liu C;Huang M;Schmitt I;Wüllner U;Niu Y;Guo C;Wang Q;Tang TS
作为一种去泛素化酶（DUB）， ataxin-3 （ATX-3）的生理底物尚不明确，这限制了我们对其正常细胞功能和脊髓小脑性失调性3型（SCA3）发病机制的认识。在这里，我们发现p53是ATX-3的一个新的底物。ATX-3结合天然和多泛素化p53和去泛素化p53，并通过泛素(Ub)-蛋白酶体途径抑制其降解来稳定p53。ATX-3缺失会破坏p53的稳定性，导致p53活性和功能的缺乏，而ATX-3的异位表达会诱导p53靶基因的选择性转录/表达，并促进哺乳动物细胞和斑马鱼中枢神经系统中p53依赖性的凋亡。此外，聚谷氨酰胺（polyQ）扩展的ATX-3保留了对p53的增强相互作用和去泛素化催化活性，并在斑马鱼大脑和转基因SCA3小鼠模型的黑质致密部（SNpc）或纹状体中引起更严重的p53依赖性神经变性。我们的研究发现了ATX-3与p53介导的细胞死亡之间的一种新的分子联系，并为p53直接参与SCA3疾病的发病机制提供了解释。Ataxin-3 （ATX-3）是一种普遍表达的蛋白，在脊髓小脑共济失调3型（SCA3）神经退行性疾病中发生突变。它在其c端附近含有一个聚谷氨酰胺（polyQ）束，已知其扩张是SCA3的致病因素。很早以前人们就知道ATX-3是一种去泛素化酶（DUB）。然而，ATX-3在生理背景下靶向的底物仍然是未知的，这在很大程度上限制了我们对其细胞功能和SCA3致病机制的理解。本研究发现p53是ATX-3的新型底物，其功能受到ATX-3的严格调控。PolyQ扩增增强了ATX-3在p53调控中的细胞功能。在斑马鱼和小鼠模型中，polyq扩增的ATX-3由于与p53的相互作用增强和p53的上调，导致p53依赖性神经元细胞死亡增加，从而为p53直接参与SCA3病理提供了明确的体内证据。本研究不仅确立了ATX-3的基本功能，还解释了ATX-3与p53之间的相互作用如何促进SCA3的发病机制；因此，这是对这种目前无法治疗的神经退行性疾病治疗方法的未来发展的重要贡献。
As a deubiquitinating enzyme (DUB), the physiological substrates of ataxin-3 (ATX-3) remain elusive, which limits our understanding of its normal cellular function and that of pathogenic mechanism of spinocerebellar ataxia type 3 (SCA3). Here, we identify p53 to be a novel substrate of ATX-3. ATX-3 binds to native and polyubiquitinated p53 and deubiquitinates and stabilizes p53 by repressing its degradation through the ubiquitin (Ub)-proteasome pathway. ATX-3 deletion destabilizes p53, resulting in deficiency of p53 activity and functions, whereas ectopic expression of ATX-3 induces selective transcription/expression of p53 target genes and promotes p53-dependent apoptosis in both mammalian cells and the central nervous system of zebrafish. Furthermore, the polyglutamine (polyQ)-expanded ATX-3 retains enhanced interaction and deubiquitination catalytic activity to p53 and causes more severe p53-dependent neurodegeneration in zebrafish brains and in the substantia nigra pars compacta (SNpc) or striatum of a transgenic SCA3 mouse model. Our findings identify a novel molecular link between ATX-3 and p53-mediated cell death and provide an explanation for the direct involvement of p53 in SCA3 disease pathogenesis. Ataxin-3 (ATX-3) is a ubiquitously expressed protein that mutated in a neurodegenerative disease called spinocerebellar ataxia type 3 (SCA3). It contains a polyglutamine (polyQ) tract near its C-terminus, the expansion of which is known to be the causative factor for SCA3. It has been known for a long time that ATX-3 is a deubiquitinating enzyme (DUB). However, the substrates targeted by ATX-3 in the physiological context remain elusive, thus largely limiting our understanding of its cellular function and that of the pathogenic mechanism of SCA3. This study has identified p53 to be a novel substrate of ATX-3, and its function is tightly regulated by ATX-3. PolyQ expansion augments ATX-3’s cellular function in p53 regulation. Due to enhanced interaction to p53 and up-regulation of p53, polyQ-expanded ATX-3 led to an increased p53-dependent neuronal cell death in zebrafish and mouse models, thus providing clear in vivo evidences for the direct involvement of p53 in SCA3 pathology. This study not only establishes a basic function of ATX-3 but also provides an explanation of how the interplays between ATX-3 and p53 contribute to the SCA3 pathogenesis; thus, it is an important contribution for the future development of therapeutic approaches for this currently untreatable neurodegenerative disease.
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DOI：
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发表时间：
2006-03-28
影响因子：
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作者：
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