Adaptor complex AP2/PICALM, through interaction with LC3, targets Alzheimer's APP-CTF for terminal degradation via autophagy
Adaptor complex AP2/PICALM, through interaction with LC3, targets Alzheimer's APP-CTF for terminal degradation via autophagy
复制标题
DOI：
10.1073/pnas.1315110110
复制
发表时间：
2013-10-15
影响因子：
11.1
通讯作者：
Greengard, Paul
中科院分区：
文献类型：
--
作者：
Tian, Yuan;Chang, Jerry C.;Greengard, Paul
阿尔茨海默病（AD）的标志是淀粉样蛋白-β（A β）肽和tau蛋白的聚集体。自噬是导致去除聚集蛋白的主要细胞途径。我们最近报道，自噬是负责淀粉样前体蛋白裂解的C-末端片段（APP-CTF）降解和淀粉样β蛋白清除在Atg 5依赖的方式。本研究旨在阐明自噬介导APP-CTF降解和β淀粉样蛋白清除的分子机制。通过亲和纯化和质谱分析，我们鉴定了衔接蛋白（AP）2和磷脂酰肌醇网格蛋白组装淋巴-骨髓性白血病（PICALM）作为微管相关蛋白1轻链3（LC 3）的结合蛋白。进一步分析表明，AP 2调节APP-CTF的细胞水平。AP 2的敲低减少了自噬介导的APP-CTF降解。免疫沉淀和实时成像分析表明，AP 2和PICALM交联LC 3与APP-CTF。这些数据表明AP-2/PICALM复合物作为自噬货物受体起作用，用于识别APP-CTF并将其从内吞途径运送到LC 3标记的自噬降解途径。这种连接AP 2/PICALM和AD的分子机制与遗传证据一致，表明PICALM作为AD的危险因素。
The hallmarks of Alzheimer's disease (AD) are the aggregates of amyloid-beta (A beta) peptides and tau protein. Autophagy is a major cellular pathway leading to the removal of aggregated proteins. We have reported recently that autophagy was responsible for amyloid precursor protein cleaved C-terminal fragment (APP-CTF) degradation and amyloid beta clearance in an Atg5-dependent manner. Here we aimed to elucidate the molecular mechanism by which autophagy mediates the degradation of APP-CTF and the clearance of amyloid beta. Through affinity purification followed by mass spectrum analysis, we identified adaptor protein (AP) 2 together with phosphatidylinositol clathrin assembly lymphoid-myeloid leukemia (PICALM) as binding proteins of microtubule-associated protein 1 light chain 3 (LC3). Further analysis showed that AP2 regulated the cellular levels of APP-CTF. Knockdown of AP2 reduced autophagy-mediated APP-CTF degradation. Immunoprecipitation and live imaging analysis demonstrated that AP2 and PICALM cross-link LC3 with APP-CTF. These data suggest that the AP-2/PICALM complex functions as an autophagic cargo receptor for the recognition and shipment of APP-CTF from the endocytic pathway to the LC3-marked autophagic degradation pathway. This molecular mechanism linking AP2/PICALM and AD is consistent with genetic evidence indicating a role for PICALM as a risk factor for AD.