Regulation of intracellular trafficking of huntingtin-associated protein-1 is critical for TrkA protein levels and neurite outgrowth
Regulation of intracellular trafficking of huntingtin-associated protein-1 is critical for TrkA protein levels and neurite outgrowth
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DOI：
10.1523/jneurosci.1251-06.2006
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发表时间：
2006-05-31
影响因子：
5.3
通讯作者：
Li, Xiao-Jiang
中科院分区：
文献类型：
--
作者：
Rong, Juan;McGuire, John R.;Li, Xiao-Jiang
突变亨廷顿蛋白可以通过其异常的蛋白质相互作用影响囊泡和受体运输，这表明细胞内运输的损伤可能有助于亨廷顿病。越来越多的证据表明，亨廷顿蛋白相关蛋白-1（HAP 1）也与微管依赖性转运蛋白相互作用，并参与细胞内运输。然而，目前尚不清楚HAP 1的运输是如何调节的，并有助于神经元功能。在这里，我们报告，磷酸化的HAP 1减少其与微管依赖性转运蛋白dynactin p150和驱动蛋白轻链的关联，并减少其在轴突尖端的定位。通过RNA干扰抑制HAP 1表达可减少神经突生长和原肌球蛋白相关激酶A受体酪氨酸激酶（TrkA）的水平，TrkA是一种神经生长因子受体，其内化和运输是神经突生长所必需的。HAP 1通过阻止内化TrkA的降解来维持膜TrkA的正常水平。突变亨廷顿蛋白还减少了HAP 1与动力蛋白p150和驱动蛋白轻链的结合，从而降低了TrkA的细胞内水平。这些发现表明，HAP 1的运输是至关重要的稳定性的TrkA和神经突的功能，这两者都可以减弱突变亨廷顿。
Mutant huntingtin can affect vesicular and receptor trafficking via its abnormal protein interactions, suggesting that impairment of intracellular trafficking may contribute to Huntington's disease. There is growing evidence that huntingtin-associated protein-1 ( HAP1) also interacts with microtubule-dependent transporters and is involved in intracellular trafficking. However, it remains unclear how the trafficking of HAP1 is regulated and contributes to neuronal function. Here we report that phosphorylation of HAP1 decreases its association with microtubule-dependent transport proteins dynactin p150 and kinesin light chain and reduces its localization in neurite tips. Suppressing HAP1 expression by RNA interference reduces neurite outgrowth and the level of tropomyosin-related kinase A receptor tyrosine kinase ( TrkA), a nerve growth factor receptor whose internalization and trafficking are required for neurite outgrowth. HAP1 maintains the normal level of membrane TrkA by preventing the degradation of internalized TrkA. Mutant huntingtin also reduces the association of HAP1 with dynactin p150 and kinesin light chain and thereby decreases the intracellular level of TrkA. These findings suggest that HAP1 trafficking is critical for the stability of TrkA and neurite function, both of which can be attenuated by mutant huntingtin.