Hypertonia-associated protein Trak1 is a novel regulator of endosome-to-lysosome trafficking.
Hypertonia-associated protein Trak1 is a novel regulator of endosome-to-lysosome trafficking.
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张力亢进相关蛋白 Trak1 是内体到溶酶体运输的新型调节因子。
DOI：
10.1016/j.jmb.2008.07.045
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发表时间：
2008
影响因子：
5.6
通讯作者：
Chin,Lih-Shen
中科院分区：
文献类型：
--
作者：
Webber,Elizabeth;Li,Lian;Chin,Lih-Shen
以僵硬步态、异常姿势、急动和震颤为特征的张力亢进与许多神经系统疾病相关，包括脑瘫、肌张力障碍、帕金森病、中风和脊髓损伤。最近，在编码运输蛋白，驱动蛋白结合1（Trak 1）的基因中的自发突变被确定为导致小鼠肌张力过高的遗传缺陷。Trak 1的亚细胞定位和生物学功能尚不清楚。在这里，我们报告Trak 1与肝细胞生长因子调节的酪氨酸激酶底物（Hrs）相互作用，这是内体分选和运输机制的重要组成部分。双标记免疫荧光共聚焦研究表明，内源性Trak 1蛋白与早期内体上的Hrs部分共定位。像Hrs一样，Trak 1的过表达和小干扰RNA介导的敲低都通过阻断内体到溶酶体的运输来抑制内化的表皮生长因子受体的降解。我们的研究结果支持Trak 1在调节Hrs介导的内体分选中的作用，并对理解与神经系统疾病相关的张力过高具有重要意义。
Hypertonia, which is characterized by stiff gait, abnormal posture, jerky movements, and tremor, is associated with a number of neurological disorders, including cerebral palsy, dystonia, Parkinson's disease, stroke, and spinal cord injury. Recently, a spontaneous mutation in the gene encoding trafficking protein, kinesin-binding 1 (Trak1), was identified as the genetic defect that causes hypertonia in mice. The subcellular localization and biological function of Trak1 remain unclear. Here we report that Trak1 interacts with hepatocyte-growth-factor-regulated tyrosine kinase substrate (Hrs), an essential component of the endosomal sorting and trafficking machinery. Double-label immunofluorescence confocal studies show that the endogenous Trak1 protein partially colocalizes with Hrs on early endosomes. Like Hrs, both overexpression and small-interfering-RNA-mediated knockdown of Trak1 inhibit degradation of internalized epidermal growth factor receptors through a block in endosome-to-lysosome trafficking. Our findings support a role for Trak1 in the regulation of Hrs-mediated endosomal sorting and have important implications for understanding hypertonia associated with neurological disorders.