A stress sensitive ER membrane-association domain in Huntingtin protein defines a potential role for Huntingtin in the regulation of autophagy
A stress sensitive ER membrane-association domain in Huntingtin protein defines a potential role for Huntingtin in the regulation of autophagy
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DOI：
10.4161/auto.5201
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发表时间：
2008-01-01
期刊：
影响因子：
13.3
通讯作者：
Truant, Ray
中科院分区：
文献类型：
--
作者：
Atwal, Randy Singh;Truant, Ray
我们最近发表了亨廷顿蛋白氨基末端膜结合结构域的精确定义，能够靶向内质网和晚期内体以及自噬小泡。在几种途径诱导的内质网应激中，亨廷顿蛋白从细胞膜上释放出来，并迅速移位到细胞核中。因此，在没有压力的情况下，亨廷顿蛋白能够进行核输出并与内质网重新结合。当亨廷顿蛋白含有亨廷顿病中出现的多谷氨酰胺扩张时，这种释放被抑制。因此，表达亨廷顿蛋白的突变细胞有一个扰动的内质网，并增加了自噬小泡。在这里，我们讨论了亨廷顿蛋白作为内质网哨兵的潜在功能，潜在地调节自噬反应内质网应激。我们将这些最近的发现与雷帕霉素的哺乳动物靶标mTOR进行了比较，mTOR是一种十多年前被描述为通过富含亮氨酸的重复加热序列在结构上与Hunting tin相关的蛋白质。从那时起，亨廷顿蛋白和mTOR之间的功能相似性是惊人的，这一关于亨廷顿蛋白与自噬小泡直接关联的新信息表明，这种结构相似性可能延伸到对内质网功能和自噬产生影响的功能相似性。
We have recently published the precise definition of an amino-terminal membrane association domain in huntingtin, capable of targeting to the endoplasmic reticulum and late endosomes as well as autophagic vesicles. In response to ER stress induced by several pathways, huntingtin releases from membranes and rapidly translocates into the nucleus. Huntingtin is then capable of nuclear export and re-association with the ER in the absence of stress. This release is inhibited when huntingtin contains the polyglutamine expansion seen in Huntington's disease. As a result, mutant huntingtin expressing cells have a perturbed ER and an increase in autophagic vesicles. Here, we discuss the potential function of the huntingtin protein as an ER sentinel, potentially regulating autophagy in response to ER stress. We compare these recent findings to the well characterized mammalian target of rapamycin, mTor, a protein described over a decade ago as related to huntingtin structurally by leucine-rich, repetitive HEAT sequences. Since then, the described functional similarities between Huntingtin and mTor are striking, and this new information about huntingtin's direct association with autophagic vesicles indicates that this structural similarity may extend to functional similarities having an impact upon ER functionality and autophagy.