Co-chaperone CHIP promotes aggregation of ataxin-1
Co-chaperone CHIP promotes aggregation of ataxin-1
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DOI：
10.1016/j.mcn.2006.10.002
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发表时间：
2007-01-01
影响因子：
3.5
通讯作者：
Lee, Do Hee
中科院分区：
文献类型：
--
作者：
Choi, Jung Young;Ryu, Jeong Hee;Lee, Do Hee
最近的研究表明，共伴侣/E3 连接酶 CHIP（hsp70 相互作用蛋白的 C 末端）介导泛素化并抑制聚谷氨酰胺 (polyQ) 蛋白（如亨廷顿蛋白或 ataxin-3）的聚集。在本研究中，我们研究了 CHIP 对另一种 polyQ 蛋白 ataxin-1 降解的影响。有趣的是，CHIP 不仅与 polyQ 扩增的 ataxin-1 相关，而且与正常的 ataxin-1 相关。此外，通过增强ataxin-1泛素化，CHIP过表达导致ataxin-1溶解度降低，从而增加聚集体形成，尤其是polyQ扩展的ataxin-1。域分析表明，TPR 域是促进聚集所必需的。相比之下，其他共伴侣或 E3 连接酶，例如 BAG-1 或 Parkin，对 ataxin-1 的聚集没有表现出类似的影响。重要的是，CHIP 的效果会因 ataxin-1 Ser776 的突变而受到损害，该突变的磷酸化对于 ataxin-1 的聚集至关重要。我们的研究结果表明，CHIP 在 PolyQ 蛋白聚集中的作用根据全长 PolyQ 蛋白的背景而有很大差异。 (c) 2006 Elsevier Inc. 保留所有权利。
Recent studies demonstrated that co-chaperone/E3 ligase CHIP (C-terminus of hsp70-interacting protein) mediates the ubiquitylation and suppresses the aggregation of polyglutamine (polyQ) proteins, such as huntingtin or ataxin-3. In this study, we investigated the effects of CHIP on the degradation of another polyQ protein ataxin-1. Interestingly CHIP associates not only with the polyQ-expanded ataxin-1 but also with the normal ataxin-1. Moreover, by enhancing ataxin-1 ubiquitylation, CHIP over-expression leads to a reduction in the solubility of ataxin-1 and thus increases the aggregate formation, especially that of polyQ-expanded ataxin-1. Domain analysis revealed that the TPR domain is required for the promotion of aggregation. By contrast, other co-chaperones or E3 ligases, such as BAG-1 or parkin, did not show similar effects on the aggregation of ataxin-1. Importantly, the effect of CHIP is impaired by the mutation of Ser776 of ataxin-1 whose phosphorylation is crucial for ataxin-1 aggregation. Our findings suggest that the role of CHIP in aggregation of polyQ proteins greatly varies depending on the context of full-length polyQ proteins. (c) 2006 Elsevier Inc. All rights reserved.