Isoform-dependent lysosomal degradation and internalization of apolipoprotein E requires autophagy proteins.
Isoform-dependent lysosomal degradation and internalization of apolipoprotein E requires autophagy proteins.
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DOI：
10.1242/jcs.258687
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发表时间：
2022-01-15
影响因子：
4
通讯作者：
Steffan JS
中科院分区：
文献类型：
--
作者：
Fote GM;Geller NR;Efstathiou NE;Hendricks N;Vavvas DG;Reidling JC;Thompson LM;Steffan JS
人类载脂蛋白E4亚型(APOE4)是晚发性阿尔茨海默病(AD)最强的遗传危险因素，溶酶体功能障碍与AD的发病机制有关。通过检测稳定表达各种APOE异构体的细胞，我们发现APOE4增加了溶酶体的转运，聚集在扩大的溶酶体和晚期的内吞体内，改变了自噬通量和自噬蛋白和脂滴的丰度，并改变了内化后溶酶体的蛋白质组内容。我们进一步研究了细胞培养中与APOE相关的溶酶体运输，发现来自高尔基体后隔室的APOE通过自噬被降解。我们发现，这种自噬过程需要在永生化的神经元样细胞和肝细胞以及小鼠脑组织中使用溶酶体膜蛋白LAMP2。在肝细胞中，APOE的自噬降解和内化也需要几个与自噬相关的蛋白。我们观察到的APOE4自噬通量和溶酶体转运的失调提示了一种可能参与AD发病的新机制。摘要：阿尔茨海默病相关的APOE4亚型聚集在溶酶体中，调节自噬通量。APOE可以通过自噬进入溶酶体，需要LAMP2A，它是伴侣介导的自噬的受体。
The human apolipoprotein E4 isoform (APOE4) is the strongest genetic risk factor for late-onset Alzheimer's disease (AD), and lysosomal dysfunction has been implicated in AD pathogenesis. We found, by examining cells stably expressing each APOE isoform, that APOE4 increases lysosomal trafficking, accumulates in enlarged lysosomes and late endosomes, alters autophagic flux and the abundance of autophagy proteins and lipid droplets, and alters the proteomic contents of lysosomes following internalization. We investigated APOE-related lysosomal trafficking further in cell culture, and found that APOE from the post-Golgi compartment is degraded through autophagy. We found that this autophagic process requires the lysosomal membrane protein LAMP2 in immortalized neuron-like and hepatic cells, and in mouse brain tissue. Several macroautophagy-associated proteins were also required for autophagic degradation and internalization of APOE in hepatic cells. The dysregulated autophagic flux and lysosomal trafficking of APOE4 that we observed suggest a possible novel mechanism that might contribute to AD pathogenesis. Summary: Alzheimer's disease-associated isoform APOE4 accumulates in lysosomes and dysregulates autophagic flux. APOE can enter the lysosome through autophagy requiring LAMP2A, a receptor for chaperone-mediated autophagy.
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