Iowa Mutant Apolipoprotein A-I (ApoA-IIowa) Fibrils Target Lysosomes.
Iowa Mutant Apolipoprotein A-I (ApoA-IIowa) Fibrils Target Lysosomes.
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DOI：
10.1038/srep30391
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发表时间：
2016-07-28
影响因子：
4.6
通讯作者：
Sakashita N
中科院分区：
文献类型：
--
作者：
Kameyama H;Nakajima H;Nishitsuji K;Mikawa S;Uchimura K;Kobayashi N;Okuhira K;Saito H;Sakashita N
人类载脂蛋白 A-I (apoA-IIowa) 中的单氨基酸突变 G26R 是第一个与家族性 AApoA1 淀粉样变性相关的突变。含有该突变的apoA-I的N端片段（氨基酸残基1-83）以淀粉样原纤维的形式沉积在患者的组织和器官中，但细胞降解和细胞毒性的机制尚未阐明。在这项研究中，我们证明了人胚胎肾 293 细胞中 apoA-IIowa 原纤维通过自噬-溶酶体途径降解。 ApoA-IIowa 原纤维诱导溶酶体 pH 值升高和有毒溶酶体蛋白酶组织蛋白酶 B 的胞质释放。apoA-IIowa 原纤维引起的线粒体功能障碍依赖于组织蛋白酶 B，并通过增加 apoA-IIowa 原纤维的降解来改善。因此，虽然apoA-IIowa原纤维转运至溶酶体和溶酶体中的原纤维降解可能已经发生，但过量的apoA-IIowa原纤维的存在（超过溶酶体可以降解的数量）可能对细胞有害。因此，我们的结果提供了apoA-IIowa原纤维的靶标是溶酶体的证据，从而我们对AApoA1淀粉样变性的机制有了新的认识。
The single amino acid mutation G26R in human apolipoprotein A-I (apoA-IIowa) is the first mutation that was associated with familial AApoA1 amyloidosis. The N-terminal fragments (amino acid residues 1–83) of apoA-I containing this mutation deposit as amyloid fibrils in patients’ tissues and organs, but the mechanisms of cellular degradation and cytotoxicity have not yet been clarified. In this study, we demonstrated degradation of apoA-IIowa fibrils via the autophagy-lysosomal pathway in human embryonic kidney 293 cells. ApoA-IIowa fibrils induced an increase in lysosomal pH and the cytosolic release of the toxic lysosomal protease cathepsin B. The mitochondrial dysfunction caused by apoA-IIowa fibrils depended on cathepsin B and was ameliorated by increasing the degradation of apoA-IIowa fibrils. Thus, although apoA-IIowa fibril transport to lysosomes and fibril degradation in lysosomes may have occurred, the presence of an excess number of apoA-IIowa fibrils, more than the lysosomes could degrade, may be detrimental to cells. Our results thus provide evidence that the target of apoA-IIowa fibrils is lysosomes, and we thereby gained a novel insight into the mechanism of AApoA1 amyloidosis.