The Accumulation of Heparan Sulfate S-Domains in Kidney Transthyretin Deposits Accelerates Fibril Formation and Promotes Cytotoxicity
The Accumulation of Heparan Sulfate S-Domains in Kidney Transthyretin Deposits Accelerates Fibril Formation and Promotes Cytotoxicity
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硫酸乙酰肝素 S 结构域在肾运甲状腺素蛋白沉积物中的积累加速原纤维形成并促进细胞毒性
DOI：
10.1016/j.ajpath.2018.09.015
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Nishitsuji K.
中科院分区：
文献类型：
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作者：
Kameyama H;Uchimura K;Yamashita T;Kuwabara K;Mizuguchi M;Hung SC;Okuhira K;Masuda T;Kosugi T;Ohgita T;Saito H;Ando Y;Nishitsuji K.
硫酸乙酰肝素 (HS) 的高度硫酸化结构域，别名 HS S 结构域，由重复的三硫酸化二糖单元 [艾杜糖醛酸 (2S)-葡萄糖胺 (NS, 6S)] 组成，并由细胞外内切葡萄糖胺 6-硫酸酯酶 (Sulfs) 选择性重塑。尽管 HS S 结构域对于多种生长因子的信号转导至关重要，但它们在淀粉样变性中的作用尚未完全了解。在此，我们在一名转甲状腺素蛋白淀粉样变性患者的肾脏中发现了 HS S 结构域。在使用稳定表达人 Sulfs 的细胞进行的体外测定中，肝素（HS S 结构域的结构类似物）以 HS S 结构域依赖性方式促进转甲状腺素蛋白的聚集。细胞与运甲状腺素蛋白原纤维的相互作用以及这些原纤维的细胞毒性也取决于细胞表面的 HS S 结构域。此外，由肾病综合征易感基因GPC5编码的磷脂酰肌醇蛋白聚糖5（glypican-5）被发现在转甲状腺素蛋白淀粉样变性肾脏中积累。因此，我们的研究为 HS S 结构域在淀粉样变性中的病理作用提供了新的见解，并且我们提出 Sulfs 对 HS 链的酶促重塑可能提供一种有效的方法来抑制淀粉样原纤维的形成和细胞毒性。
The highly sulfated domains of heparan sulfate (HS), alias HS S-domains, are made up of repeated trisulfated disaccharide units [iduronic acid (2S)-glucosamine (NS, 6S)] and are selectively remodeled by extracellular endoglucosamine 6-sulfatases (Sulfs). Although HS S-domains are critical for signal transduction of several growth factors, their roles in amyloidoses are not yet fully understood. Herein, we found HS S-domains in the kidney of a patient with transthyretin amyloidosis. Inin vitroassays with cells stably expressing human Sulfs, heparin, a structural analog of HS S-domains, promoted aggregation of transthyretin in an HS S-domain–dependent manner. Interactions of cells with transthyretin fibrils and cytotoxicity of these fibrils also depended on HS S-domains at the cell surface. Furthermore, glypican-5, encoded by the susceptibility gene for nephrotic syndromeGPC5, was found to be accumulated in the transthyretin amyloidosis kidney. Our study, thus, provides a novel insight into the pathologic roles of HS S-domains in amyloidoses, and we propose that enzymatic remodeling of HS chains by Sulfs may offer an effective approach to inhibiting formation and cytotoxicity of amyloid fibrils.