SUMO modification of Huntingtin and Huntington's disease pathology
SUMO modification of Huntingtin and Huntington's disease pathology
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DOI：
10.1126/science.1092194
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发表时间：
2004-04-02
期刊：
影响因子：
56.9
通讯作者：
Marsh, JL
中科院分区：
文献类型：
--
作者：
Steffan, JS;Agrawal, N;Marsh, JL
亨廷顿病 (HD) 的特征是致病蛋白亨廷顿蛋白 (Htt) 的积累，该蛋白含有异常的多聚谷氨酰胺扩增。在这里，我们报道了 Htt (Httex1p) 的致病性片段可以通过小泛素样修饰剂 (SUMO)-1 或相同赖氨酸残基上的泛素进行修饰。在培养细胞中，SUMO 化可稳定 Httex1p，降低其形成聚集体的能力，并增强其抑制转录的能力。在 HD 果蝇模型中，Httex1p 的 SUMO 化会加剧神经变性，而 Httex1p 的泛素化会消除神经变性。阻止 Httex1p SUMO 化和泛素化的赖氨酸突变可减少 HD 病理，表明 SUMO 化对 HD 病理的贡献超出了阻止 Htt 泛素化和降解的范围。
Huntington's disease (HD) is characterized by the accumulation of a pathogenic protein, Huntingtin (Htt), that contains an abnormal polyglutamine expansion. Here, we report that a pathogenic fragment of Htt (Httex1p) can be modified either by small ubiquitin-like modifier (SUMO)-1 or by ubiquitin on identical lysine residues. In cultured cells, SUMOylation stabilizes Httex1p, reduces its ability to form aggregates, and promotes its capacity to repress transcription. In a Drosophila model of HD, SUMOylation of Httex1p exacerbates neurodegeneration, whereas ubiquitination of Httex1p abrogates neurodegeneration. Lysine mutations that prevent both SUMOylation and ubiquitination of Httex1p reduce HD pathology, indicating that the contribution of SUMOylation to HD pathology extends beyond preventing Htt ubiquitination and degradation.