Retrograde trafficking of VMAT2 and its role in protein stability in non-neuronal cells.
Retrograde trafficking of VMAT2 and its role in protein stability in non-neuronal cells.
复制标题
VMAT2 的逆行运输及其在非神经元细胞中蛋白质稳定性中的作用
DOI：
10.7555/jbr.30.20160061
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发表时间：
2016-11
影响因子：
2.3
通讯作者：
Liu Y
中科院分区：
文献类型：
--
作者：
Wu Q;Xu H;Wang W;Chang F;Jiang Y;Liu Y
越来越多的证据表明，囊泡单胺转运体2（VMAT 2）的神经保护功能受损与帕金森病的发病机制有关。最近对家族性帕金森病的基因组研究强烈表明，这与异常的亚细胞逆行运输有关。然而，VMAT 2功能是否受逆行运输的调控尚不清楚。通过使用生物化学和细胞生物学方法，我们已经表明，VMAT 2严格定位于trans-Golgi网络，并在非神经元细胞中进行逆行运输。该转运蛋白还与逆转录酶的关键成分Vps 35进行生物化学和亚细胞相互作用。使用特异性siRNA，我们进一步表明Vps 35缺失改变了VMAT 2的亚细胞定位。此外，siRNA介导的Vps 35敲低也降低了VMAT 2的稳定性，如通过减少的半衰期所证明的。因此，我们的工作表明，改变VMAT 2的囊泡运输可能在转运蛋白的神经保护以及帕金森病的发病机制中发挥重要作用。
Abstract Increasing evidence suggests that the impaired neuroprotection of vesicular monoamine transporter 2 (VMAT2) contributes to the pathogenesis of Parkinson's disease. That has been linked to aberrant subcellular retrograde trafficking as strongly indicated by recent genomic studies on familial Parkinson's diseases. However, whether VMAT2 function is regulated by retrograde trafficking is unknown. By using biochemistry and cell biology approaches, we have shown that VMAT2 was stringently localized to the trans-Golgi network and underwent retrograde trafficking in non-neuronal cells. The transporter also interacted with the key component of retromer, Vps35, biochemically and subcellularly. Using specific siRNA, we further showed that Vps35 depletion altered subcellular localization of VMAT2. Moreover, siRNA-mediated Vps35 knockdown also decreased the stability of VMAT2 as demonstrated by the reduced half-life. Thus, our work suggested that altered vesicular trafficking of VMAT2 may play a vital role in neuroprotection of the transporter as well as in the pathogenesis of Parkinson's disease.