Polyglutamine expansion of huntingtin impairs its nuclear export
Polyglutamine expansion of huntingtin impairs its nuclear export
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DOI：
10.1038/ng1503
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发表时间：
2005-02-01
期刊：
影响因子：
30.8
通讯作者：
Li, XJ
中科院分区：
文献类型：
--
作者：
Cornett, J;Cao, FK;Li, XJ
具有多聚谷氨酰胺 (polyQ) 扩展的蛋白质在细胞核中积累并影响基因表达(1,2)。突变型亨廷顿蛋白 (htt) 在核内积累的机制尚不清楚；野生型 htt 是一种功能未知的 350 kDa 蛋白质，通常存在于细胞质中 (3-5)。突变 htt 的 N 末端片段包含 PolyQ 扩展（> 37 个谷氨酰胺），没有保守的核定位序列或核输出序列，但可以在细胞核中积累并导致转基因小鼠出现神经系统问题 (6,7)。在这里，我们报道 N 端 htt 以不依赖 Ran GTP 酶的方式在细胞质和细胞核之间穿梭。小的 N 端 htt 片段与核孔蛋白易位启动子区 (Tpr) 相互作用，该区域参与核输出。 PolyQ 扩展和聚集减少了这种相互作用并增加了 htt 的核积累。通过RNA干扰或缺失htt N端10个氨基酸来减少Tpr的表达，这对于htt与Tpr相互作用至关重要，从而增加了htt的核积累。这些结果表明，Tpr 在 N 端 htt 的核输出中发挥作用，并且 polyQ 扩展会减少这种核输出，从而导致 htt 的核积累。
Proteins with polyglutamine (polyQ) expansions accumulate in the nucleus and affect gene expression(1,2). The mechanism by which mutant huntingtin (htt) accumulates intranuclearly is not known; wild-type htt, a 350-kDa protein of unknown function, is normally found in the cytoplasm(3-5).N-terminal fragments of mutant htt, which contain a polyQ expansion (>37 glutamines), have no conserved nuclear localization sequences or nuclear export sequences but can accumulate in the nucleus and cause neurological problems in transgenic mice(6,7). Here we report that N-terminal htt shuttles between the cytoplasm and nucleus in a Ran GTPase-independent manner. Small N-terminal htt fragments interact with the nuclear pore protein translocated promoter region(Tpr), which is involved in nuclear export. PolyQ expansion and aggregation decrease this interaction and increase the nuclear accumulation of htt. Reducing the expression of Tpr by RNA interference or deletion of ten amino acids of N-terminal htt, which are essential for the interaction of htt with Tpr, increased the nuclear accumulation of htt. These results suggest that Tpr has a role in the nuclear export of N-terminal htt and that polyQ expansion reduces this nuclear export to cause the nuclear accumulation of htt.