Cytoplasmic Ubiquitin-Specific Protease 19 (USP19) Modulates Aggregation of Polyglutamine-Expanded Ataxin-3 and Huntingtin through the HSP90 Chaperone.
Cytoplasmic Ubiquitin-Specific Protease 19 (USP19) Modulates Aggregation of Polyglutamine-Expanded Ataxin-3 and Huntingtin through the HSP90 Chaperone.
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细胞质泛素特异性蛋白酶 19 (USP19) 通过 HSP90 伴侣调节聚谷氨酰胺扩增的 Ataxin-3 和亨廷顿蛋白的聚集
DOI：
10.1371/journal.pone.0147515
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Hu HY
中科院分区：
文献类型：
--
作者：
He WT;Zheng XM;Zhang YH;Gao YG;Song AX;van der Goot FG;Hu HY
泛素特异性蛋白酶19（USP 19）是一种去泛素化酶（DUBs），参与调节底物蛋白的泛素化状态。USP 19有两种主要亚型，具有不同的C-末端; USP 19_a亚型具有锚定内质网的跨膜结构域，而USP 19_b含有EEVD基序。在这里，我们报告了细胞质亚型USP19_b上调了含聚谷氨酰胺（polyQ）的蛋白质、共济失调蛋白-3（Atx3）和亨廷顿蛋白（Htt）的蛋白质水平，从而促进了细胞模型中polyQ扩增物质的聚集。我们的数据表明，USP19_b可能通过热休克蛋白90（HSP 90）伴侣系统协调polyQ扩增蛋白的稳定性、聚集和降解。USP19_b通过其N-末端CS（CHORD和SGT1）/P23结构域与HSP90直接相互作用。与HSP 90一起，细胞质USP 19可能在疾病相关polyQ扩增底物的分类决策中发挥关键作用，表明USP 19通过调节其蛋白水平在错误折叠蛋白质的质量控制中发挥作用。
Ubiquitin-specific protease 19 (USP19) is one of the deubiquitinating enzymes (DUBs) involved in regulating the ubiquitination status of substrate proteins. There are two major isoforms of USP19 with distinct C-termini; the USP19_a isoform has a transmembrane domain for anchoring to the endoplasmic reticulum, while USP19_b contains an EEVD motif. Here, we report that the cytoplasmic isoform USP19_b up-regulates the protein levels of the polyglutamine (polyQ)-containing proteins, ataxin-3 (Atx3) and huntingtin (Htt), and thus promotes aggregation of their polyQ-expanded species in cell models. Our data demonstrate that USP19_b may orchestrate the stability, aggregation and degradation of the polyQ-expanded proteins through the heat shock protein 90 (HSP90) chaperone system. USP19_b directly interacts with HSP90 through its N-terminal CS (CHORD and SGT1)/P23 domains. In conjunction with HSP90, the cytoplasmic USP19 may play a key role in triage decision for the disease-related polyQ-expanded substrates, suggesting a function of USP19 in quality control of misfolded proteins by regulating their protein levels.