SorLA/LR11 regulates processing of amyloid precursor protein via interaction with adaptors GGA and PACS-1
SorLA/LR11 regulates processing of amyloid precursor protein via interaction with adaptors GGA and PACS-1
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DOI：
10.1074/jbc.m705073200
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发表时间：
2007-11-09
影响因子：
4.8
通讯作者：
Willnow, Thomas E.
中科院分区：
文献类型：
--
作者：
Schmidt, Vanessa;Sporbert, Anje;Willnow, Thomas E.
SorLA已被认为是一种新型的分选受体，其调节淀粉样前体蛋白（APP）的运输和加工，并且是散发性阿尔茨海默病的重要危险因素。在这里，我们研究了控制胞内运输的sorLA及其相关的APP处理的细胞机制。我们证明，sorLA作为APP的保留因子在trans-Golgi隔室/trans-Golgi网络，防止释放的前体进入正常的加工途径。sorLA的正确定位和活性依赖于与GGA和PACS-1的功能相互作用，GGA和PACS-1是参与蛋白质运输到高尔基体网络和从高尔基体网络运输的衔接蛋白。sorLA异常靶向再循环区室或质膜导致错误的APP运输和非淀粉样蛋白和淀粉样蛋白加工命运的不平衡。因此，我们的研究结果确定改变路由sorLA作为一个主要的细胞机制，有助于异常APP加工和增强淀粉样α-肽的形成。
SorLA has been recognized as a novel sorting receptor that regulates trafficking and processing of the amyloid precursor protein (APP) and that represents a significant risk factor for sporadic Alzheimer disease. Here, we investigated the cellular mechanisms that control intracellular trafficking of sorLA and their relevance for APP processing. We demonstrate that sorLA acts as a retention factor for APP in trans-Golgi compartments/trans-Golgi network, preventing release of the precursor into regular processing pathways. Proper localization and activity of sorLA are dependent on functional interaction with GGA and PACS-1, adaptor proteins involved in protein transport to and from the trans-Golgi network. Aberrant targeting of sorLA to the recycling compartment or the plasma membrane causes faulty APP trafficking and imbalance in non-amyloidogenic and amyloidogenic processing fates. Thus, our findings identified altered routing of sorLA as a major cellular mechanism contributing to abnormal APP processing and enhanced amyloid alpha-peptide formation.