A large scale Huntingtin protein interaction network implicates Rho GTPase signaling pathways in Huntington disease.
A large scale Huntingtin protein interaction network implicates Rho GTPase signaling pathways in Huntington disease.
复制标题
大规模亨廷顿蛋白相互作用网络暗示亨廷顿病中的 Rho GTPase 信号通路。
DOI：
10.1074/jbc.m113.523696
复制
发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Hughes,RobertE
中科院分区：
文献类型：
--
作者：
Tourette,Cendrine;Li,Biao;Bell,Russell;O'Hare,Shannon;Kaltenbach,LindaS;Mooney,SeanD;Hughes,RobertE
亨廷顿病（Huntington disease，HD）是一种遗传性神经退行性疾病，由HT基因CAG扩增引起。使用酵母双杂交方法，我们确定了一个大的一组与亨廷顿蛋白（HTT）相互作用的蛋白质。该网络由HTT相互作用蛋白（HIP）和与这些主要节点相互作用的蛋白质组成，包含2141个高度互连的蛋白质之间的3235个相互作用。这些蛋白质的功能注释的分析表明，初级和次级HIP富集在涉及HD的途径中，包括哺乳动物雷帕霉素靶点、Rho GT3信号传导和氧化应激反应。为了验证HIP在突变HTT毒性中的作用，我们表明Rho GT3信号传导组分BAIAP2、EZR、PIK3R1、PAK2和RAC 1是突变HTT毒性的修饰剂。我们还表明，HTT共定位与BAIAP2在丝状伪足和突变HTT干扰丝状伪足动力学。这些数据表明，HTT直接参与膜动力学，细胞附着和运动。此外，他们暗示这些途径的失调是HD的病理机制。
Huntington disease (HD) is an inherited neurodegenerative disease caused by a CAG expansion in theHTTgene. Using yeast two-hybrid methods, we identified a large set of proteins that interact with huntingtin (HTT)-interacting proteins. This network, composed of HTT-interacting proteins (HIPs) and proteins interacting with these primary nodes, contains 3235 interactions among 2141 highly interconnected proteins. Analysis of functional annotations of these proteins indicates that primary and secondary HIPs are enriched in pathways implicated in HD, including mammalian target of rapamycin, Rho GTPase signaling, and oxidative stress response. To validate roles for HIPs in mutant HTT toxicity, we show that the Rho GTPase signaling components, BAIAP2, EZR, PIK3R1, PAK2, and RAC1, are modifiers of mutant HTT toxicity. We also demonstrate that Htt co-localizes with BAIAP2 in filopodia and that mutant HTT interferes with filopodial dynamics. These data indicate that HTT is involved directly in membrane dynamics, cell attachment, and motility. Furthermore, they implicate dysregulation in these pathways as pathological mechanisms in HD.