Department of Molecular Neuroscience on Neurodegeneration, University of Tokyo, Tokyo, Japan.
J Biol Chem. 2011 Aug 26;286(34):29594-600. doi: 10.1074/jbc.M111.261032. Epub 2011 Jul 8.
Expansion of polyglutamine (pQ) chain by expanded CAG repeat causes dominantly inherited neurodegeneration such as Huntington disease, dentatorubral-pallidoluysian atrophy (DRPLA), and numbers of other spinocerebellar ataxias. Expanded pQ disrupts the stability of the pQ-harboring protein and increases its susceptibility to aggregation. Aggregated pQ protein is recognized by the ubiquitin proteasome system, and the enzyme ubiquitin ligase covalently attaches ubiquitin, which serves as a degradation signal by the proteasome. However, accumulation of the aggregated proteins in the diseased brain suggests insufficient degradation machinery. Ubiquitin has several functionally related proteins that are similarly attached to target proteins through its C terminus glycine residue. They are called ubiquitin-like molecules, and some of them are similarly related to the protein degradation pathway. One of the ubiquitin-like molecules, FAT10, is known to accelerate protein degradation through a ubiquitin-independent manner, but its role in pQ aggregate degradation is completely unknown. Thus we investigated its role in a Huntington disease cellular model and found that FAT10 molecules were covalently attached to huntingtin through their C terminus glycine. FAT10 binds preferably to huntingtin with a short pQ chain and completely aggregated huntingtin was FAT10-negative. In addition, ataxin-1,3 and DRPLA proteins were both positive for FAT10, and aggregation enhancement was observed upon FAT10 knockdown. These findings were similar to those for huntingtin. Our new finding will provide a new role for FAT10 in the pathogenesis of polyglutamine diseases.
聚谷氨酰胺（pQ）链的扩展由扩展的 CAG 重复引起显性遗传性神经退行性疾病，如亨廷顿病、齿状核红核苍白球路易体萎缩症（DRPLA）和许多其他脊髓小脑共济失调。扩展的 pQ 破坏了携带 pQ 的蛋白质的稳定性，并增加了其聚集的易感性。聚集的 pQ 蛋白被泛素蛋白酶体系统识别，酶泛素连接酶通过其 C 末端甘氨酸残基共价连接泛素，泛素作为蛋白酶体的降解信号。然而，患病大脑中聚集蛋白的积累表明降解机制不足。泛素有几个功能相关的蛋白质，它们通过其 C 末端甘氨酸残基类似地连接到靶蛋白上。它们被称为泛素样分子，其中一些与蛋白质降解途径类似。泛素样分子之一 FAT10 已知通过非泛素依赖的方式加速蛋白质降解，但它在 pQ 聚集体降解中的作用完全未知。因此，我们在亨廷顿病细胞模型中研究了它的作用，发现 FAT10 分子通过其 C 末端甘氨酸共价连接到亨廷顿蛋白上。FAT10 更喜欢与短 pQ 链的亨廷顿蛋白结合，完全聚集的亨廷顿蛋白是 FAT10 阴性的。此外，ataxin-1、3 和 DRPLA 蛋白都对 FAT10 呈阳性，并且在 FAT10 敲低时观察到聚集增强。这些发现与亨廷顿蛋白的发现相似。我们的新发现将为 FAT10 在聚谷氨酰胺疾病发病机制中的新作用提供依据。
