Cellular mechanism of fibril formation from serum amyloid A1 protein
Cellular mechanism of fibril formation from serum amyloid A1 protein
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DOI：
10.15252/embr.201643411
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发表时间：
2017-08-01
期刊：
影响因子：
7.7
通讯作者：
Faendrich, Marcus
中科院分区：
文献类型：
--
作者：
Claus, Stephanie;Meinhardt, Katrin;Faendrich, Marcus
血清淀粉样蛋白A1（SAA 1）是一种载脂蛋白，与血清中的高密度脂蛋白（HDL）结合，构成系统性AA淀粉样变性中的原纤维前体蛋白。我们在这里表明，HDL结合阻断原纤维形成可溶性SAA 1蛋白，而内化到单核吞噬细胞导致淀粉样蛋白的形成。细胞模型中的SAA 1聚集扰乱囊泡膜的完整性，并导致溶酶体渗漏和凋亡性死亡。形成的淀粉样蛋白沉积在细胞外，在那里它可以播种细胞外SAA 1的原纤化。我们的数据表明，细胞是短暂需要的淀粉样蛋白的级联反应，并促进初始成核的存款。这一机制使先前关于沉积物和淀粉样前体蛋白的细胞外定位的证据与观察结果相一致，即细胞对淀粉样蛋白的形成至关重要。
Serum amyloid A1 (SAA1) is an apolipoprotein that binds to the high-density lipoprotein (HDL) fraction of the serum and constitutes the fibril precursor protein in systemic AA amyloidosis. We here show that HDL binding blocks fibril formation from soluble SAA1 protein, whereas internalization into mononuclear phagocytes leads to the formation of amyloid. SAA1 aggregation in the cell model disturbs the integrity of vesicular membranes and leads to lysosomal leakage and apoptotic death. The formed amyloid becomes deposited outside the cell where it can seed the fibrillation of extracellular SAA1. Our data imply that cells are transiently required in the amyloidogenic cascade and promote the initial nucleation of the deposits. This mechanism reconciles previous evidence for the extracellular location of deposits and amyloid precursor protein with observations the cells are crucial for the formation of amyloid.