Conformation-dependent recognition of mutant HTT (huntingtin) proteins by selective autophagy
Conformation-dependent recognition of mutant HTT (huntingtin) proteins by selective autophagy
复制标题
通过选择性自噬对突变 HTT（亨廷顿蛋白）蛋白进行构象依赖性识别
DOI：
10.1080/15548627.2017.1382783
复制
发表时间：
2017-11
期刊：
影响因子：
13.3
通讯作者：
Boxun Lu
中科院分区：
文献类型：
--
作者：
Xiaoli Sun;Yuhua Fu;Yuyin Pan;Boxun Lu
摘要蛋白质错误折叠是包括亨廷顿病（HD）在内的神经退行性疾病的共同主题，其主要由突变HTT（亨廷顿）蛋白（mHTT）的细胞毒性引起。可溶性mHTT具有扩展的聚谷氨酰胺（polyQ）延伸段，其可以采用多种构象，其中由polyQ抗体3B 5 H10识别的构象由于未知机制而毒性最大。在最近的一项研究中，我们发现3B 5 H10识别的mHTT种类由于其对选择性巨自噬/自噬的抗性而具有较慢的降解速率。在HD小鼠脑组织以及HD患者成纤维细胞和死后脑组织中，3B 5 H10识别的mHTT种类缺乏Lys 63-聚泛素化和SQSTM 1/p62相互作用，这对于通过选择性自噬进行货物识别是必需的。总的来说，我们发现mHTT蛋白受到选择性自噬的构象依赖性识别，这比我们所认为的更具选择性：该过程可以在同一蛋白质的不同构象之间具有选择性，导致蛋白质降解和毒性的构象依赖性差异。
ABSTRACT Protein misfolding is the common theme for neurodegenerative disorders including Huntington disease (HD), which is mainly caused by cytotoxicity of the mutant HTT (huntingtin) protein (mHTT). The soluble mHTT has an expanded polyglutamine (polyQ) stretch that may adopt multiple conformations, among which the one recognized by the polyQ antibody 3B5H10 is the most toxic due to unknown mechanisms. In a recent study, we showed that the 3B5H10-recognized mHTT species has a slower degradation rate due to its resistance to selective macroautophagy/autophagy. In HD mouse brain tissues as well as HD patient fibroblasts and post-mortem brain tissues, the 3B5H10-recognized mHTT species lacks Lys63-polyubiquitination and SQSTM1/p62 interaction, which are essential for cargo recognition by selective autophagy. Collectively, we discovered that the mHTT protein is subject to conformation-dependent recognition by selective autophagy, which is more selective than what we perceived: the process can be selective among different conformations of the same protein, leading to conformation-dependent differences in protein degradation and toxicity.