Huntingtin proteolysis releases non-polyQ fragments that cause toxicity through dynamin 1 dysregulation
Huntingtin proteolysis releases non-polyQ fragments that cause toxicity through dynamin 1 dysregulation
复制标题
DOI：
10.15252/embj.201490808
复制
发表时间：
2015-09-02
期刊：
影响因子：
11.4
通讯作者：
Saudou, Frederic
中科院分区：
文献类型：
--
作者：
El-Daher, Marie-Therese;Hangen, Emilie;Saudou, Frederic
突变型亨廷顿蛋白（HTT）的切割是亨廷顿病（HD）的一个重要过程，HD是一种遗传性神经退行性疾病。裂解产生含有polyQ延伸段的N端片段，其核毒性已得到充分证实。然而，全长HTT的切割诱导的功能缺陷仍然难以捉摸。此外，非polyQ C-末端片段的贡献是未知的。使用全长HTT蛋白水解的时间和位点特异性控制，我们表明，需要特定的裂解破坏HTT内的分子内相互作用，并在细胞和苍蝇中引起毒性。令人惊讶的是，除了典型的致病性N-ter片段之外，产生的不含polyQ延伸的C-ter片段通过内质网（ER）的扩张和增加的ER应激诱导毒性。C-ter HTT与发动蛋白1结合，随后损害其在ER膜上的活性。我们的研究结果支持HTT对发动蛋白1功能和ER稳态的作用。蛋白水解诱导的这种功能的改变可能与疾病有关。
Cleavage of mutant huntingtin (HTT) is an essential process in Huntington's disease (HD), an inherited neurodegenerative disorder. Cleavage generates N-ter fragments that contain the polyQ stretch and whose nuclear toxicity is well established. However, the functional defects induced by cleavage of full-length HTT remain elusive. Moreover, the contribution of non-polyQ C-terminal fragments is unknown. Using time- and site-specific control of full-length HTT proteolysis, we show that specific cleavages are required to disrupt intramolecular interactions within HTT and to cause toxicity in cells and flies. Surprisingly, in addition to the canonical pathogenic N-ter fragments, the C-ter fragments generated, that do not contain the polyQ stretch, induced toxicity via dilation of the endoplasmic reticulum (ER) and increased ER stress. C-ter HTT bound to dynamin 1 and subsequently impaired its activity at ER membranes. Our findings support a role for HTT on dynamin 1 function and ER homoeostasis. Proteolysis-induced alteration of this function may be relevant to disease.