Mint3/X11gamma is an ADP-ribosylation factor-dependent adaptor that regulates the traffic of the Alzheimer's Precursor protein from the trans-Golgi network.
Mint3/X11gamma is an ADP-ribosylation factor-dependent adaptor that regulates the traffic of the Alzheimer's Precursor protein from the trans-Golgi network.
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发表时间：
2008
影响因子：
3.3
通讯作者：
P. Shrivastava-Ranjan;V. Faundez;G. Fang;H. Rees;J. Lah;A. Levey;R. Kahn
中科院分区：
文献类型：
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作者：
P. Shrivastava-Ranjan;V. Faundez;G. Fang;H. Rees;J. Lah;A. Levey;R. Kahn
β-淀粉样肽（Abeta）是阿尔茨海默病患者脑中斑块的主要成分，并且它们来源于β-淀粉样前体蛋白（APP）的蛋白水解加工。APP在细胞器之间的运动受到高度调节，并且与分泌酶的加工密切相关。我们先前提出，APP在细胞内的转运部分是通过将其分选到含有Mint/X11的载体中来介导的。为了验证我们的假设，我们从人神经母细胞瘤SH-SY 5 Y细胞中纯化了含APP的囊泡，我们发现Mint 2/3特异性富集，并且Mint 3和APP存在于相同的囊泡中。增加细胞APP水平增加APP和Mint 3在纯化的囊泡中的量。支持Mint 3在APP从trans-Golgi网络到质膜的运输中的专性作用的其他证据包括观察到通过小干扰RNA（siRNA）或APP的Mint结合结构域的突变消耗Mint 3改变APP从基底外侧到内体/溶酶体分选途径的输出途径。最后，我们发现Mint 3的表达增加减少，siRNA介导的敲除增加了神经毒性β-淀粉样肽Abeta（1-40）的分泌。总之，我们的数据暗示Mint 3活动是高尔基体后APP流量的关键决定因素。
Beta-amyloid peptides (Abeta) are the major component of plaques in brains of Alzheimer's patients, and are they derived from the proteolytic processing of the beta-amyloid precursor protein (APP). The movement of APP between organelles is highly regulated, and it is tightly connected to its processing by secretases. We proposed previously that transport of APP within the cell is mediated in part through its sorting into Mint/X11-containing carriers. To test our hypothesis, we purified APP-containing vesicles from human neuroblastoma SH-SY5Y cells, and we showed that Mint2/3 are specifically enriched and that Mint3 and APP are present in the same vesicles. Increasing cellular APP levels increased the amounts of both APP and Mint3 in purified vesicles. Additional evidence supporting an obligate role for Mint3 in traffic of APP from the trans-Golgi network to the plasma membrane include the observations that depletion of Mint3 by small interference RNA (siRNA) or mutation of the Mint binding domain of APP changes the export route of APP from the basolateral to the endosomal/lysosomal sorting route. Finally, we show that increased expression of Mint3 decreased and siRNA-mediated knockdowns increased the secretion of the neurotoxic beta-amyloid peptide, Abeta(1-40). Together, our data implicate Mint3 activity as a critical determinant of post-Golgi APP traffic.