HIP14, a novel ankyrin domain-containing protein, links huntingtin to intracellular trafficking and endocytosis
HIP14, a novel ankyrin domain-containing protein, links huntingtin to intracellular trafficking and endocytosis
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DOI：
10.1093/hmg/11.23.2815
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发表时间：
2002-11-01
影响因子：
3.5
通讯作者：
Hayden, MR
中科院分区：
文献类型：
--
作者：
Singaraja, RR;Hadano, S;Hayden, MR
亨廷顿病（HD）是由蛋白质亨廷顿蛋白（htt）中的聚谷氨酰胺[poly(Q)]扩增引起的。虽然疾病进展的确切机制仍有待阐明，但突变htt与其蛋白伴侣的相互作用的改变可能有助于疾病的发生。利用酵母双杂交系统，我们分离到了一种新的htt相互作用蛋白HIP14。HIP14与htt的相互作用与htt中的poly(Q)长度呈负相关。HIP14基因转录了9和6 bp的mrna，其中6 kb的转录物主要在大脑中表达。HIP14蛋白在大脑中富集，在纹状体中与htt部分共定位，并在HD受影响的神经元亚群-中棘投射神经元中发现。HIP14定位于高尔基体和细胞质中的囊泡。HIP14蛋白序列与Akr1p相似，Akr1p是酿酒酵母内吞作用所必需的蛋白质。人类HIP14的表达可以挽救akr1Delta酵母细胞的温度敏感致死性，并进一步恢复其内吞作用的缺陷，证明HIP14在细胞内运输中的作用。我们的研究结果表明，htt和HIP14之间相互作用的减少可能通过扰乱神经元正常的细胞内运输途径而导致HD的神经元功能障碍。
Huntington disease (HD) is caused by polyglutamine [poly(Q)] expansion in the protein huntingtin (htt). Although the exact mechanism of disease progression remains to be elucidated, altered interactions of mutant htt with its protein partners could contribute to the disease. Using the yeast two-hybrid system, we have isolated a novel htt interacting protein, HIP14. HIP14's interaction with htt is inversely correlated to the poly(Q) length in htt. mRNAs of 9 and 6 bp are transcribed from the HIP14 gene, with the 6 kb transcript being predominantly expressed in the brain. HIP14 protein is enriched in the brain, shows partial co-localization with htt in the striatum, and is found in medium spiny projection neurons, the subset of neurons affected in HD. HIP14 localizes to the Golgi, and to vesicles in the cytoplasm. The HIP14 protein has sequence similarity to Akr1p, a protein essential for endocytosis in Saccharomyces cerevisiae. Expression of human HIP14 results in rescue of the temperature-sensitive lethality in akr1Delta yeast cells and, furthermore, restores their defect in endocytosis, demonstrating a role for HIP14 in intracellular trafficking. Our findings suggest that decreased interaction between htt and HIP14 could contribute to the neuronal dysfunction in HD by perturbing normal intracellular transport pathways in neurons.