Hattula K, Peränen J
Institute of Biotechnology, Program in Cellular Biotechnology, P.O. Box 56 (Viikinkaari 9), FIN-00014, University of Helsinki, Finland.
Curr Biol. 2000;10(24):1603-6. doi: 10.1016/s0960-9822(00)00864-2.
Huntington's disease is characterised by the death of cortical and striatal neurons, and is the result of an expanded polyglutamine tract in the Huntingtin protein [1]. Huntingtin is present on both endocytic and secretory membrane organelles but its function is unclear [2,3]. Rab GTPases regulate both of these transport pathways [4]. We have previously shown that Rab8 controls polarised membrane transport by modulating cell morphogenesis [5]. To understand Rab8-mediated processes, we searched for Rab8-interacting proteins by the yeast two-hybrid system. Here, we report that Huntingtin is linked to the Rab8 protein through FIP-2, a tumour necrosis factor-alpha (TNF-alpha)-inducible coiled-coil protein related to the NEMO protein [6,7]. The activated form of Rab8 interacted with the amino-terminal region of FIP-2, whereas dominant-negative Rab8 did not. Huntingtin bound to the carboxy-terminal region of FIP-2. Coexpressed FIP-2 and Huntingtin enhanced the recruitment of Huntingtin to Rab8-positive vesicular structures, and FIP-2 promoted cell polarisation in a similar way to Rab8. We propose a model in which Huntingtin, together with FIP-2 and Rab8, are part of a protein network that regulates membrane trafficking and cellular morphogenesis.
亨廷顿舞蹈症的特征是皮质和纹状体神经元死亡，它是由亨廷顿蛋白中多聚谷氨酰胺序列的扩增导致的[1]。亨廷顿蛋白存在于内吞和分泌性膜细胞器上，但其功能尚不清楚[2,3]。Rab GTP酶调节这两种运输途径[4]。我们之前已经表明，Rab8通过调节细胞形态发生来控制极化膜运输[5]。为了了解Rab8介导的过程，我们通过酵母双杂交系统寻找与Rab8相互作用的蛋白。在此，我们报告亨廷顿蛋白通过FIP-2与Rab8蛋白相连，FIP-2是一种与NEMO蛋白相关的肿瘤坏死因子-α（TNF-α）诱导的卷曲螺旋蛋白[6,7]。活化形式的Rab8与FIP-2的氨基末端区域相互作用，而显性负性Rab8则不相互作用。亨廷顿蛋白与FIP-2的羧基末端区域结合。共表达的FIP-2和亨廷顿蛋白增强了亨廷顿蛋白向Rab8阳性囊泡结构的募集，并且FIP-2以与Rab8相似的方式促进细胞极化。我们提出了一个模型，其中亨廷顿蛋白与FIP-2和Rab8一起，是调节膜运输和细胞形态发生的蛋白质网络的一部分。
