Propensity of IgA to self-aggregate via tailpiece cysteine-471 and treatment of IgA nephropathy using cysteamine
Propensity of IgA to self-aggregate via tailpiece cysteine-471 and treatment of IgA nephropathy using cysteamine
复制标题
IgA 通过尾部半胱氨酸 471 自我聚集的倾向以及使用半胱胺治疗 IgA 肾病
DOI：
10.1172/jci.insight.150551
复制
发表时间：
2021-10-08
期刊：
影响因子：
8
通讯作者：
Jin, Jing
中科院分区：
文献类型：
--
作者：
Xie, Xinfang;Gao, Li;Jin, Jing
IgA 肾病是由循环 IgA1 在肾脏沉积引起的。低半乳糖基化 IgA1 具有形成易于沉积的多聚 IgA 聚集体的倾向。在此，我们从 IgA 肾病患者的血浆中纯化了聚 IgA，并表明该复合物对还原条件敏感，表明 IgA 单元之间存在分子间二硫键连接。我们试图找到形成分子间二硫键的半胱氨酸残基。自然组装的二聚体 IgA，也称为分泌型 IgA，涉及一个 J 链亚基，通过 IgA 重链“尾片”片段上的倒数第二个半胱氨酸 471 残基与 2 个 IgA1 分子连接。可能的是，由于缺乏 J 链，单 IgA1 的半胱氨酸残基可能在多聚 IgA 形成过程中异常形成二硫键。诱变证实 Cysteine-471 能够促进 IgA 聚集。这些发现促使我们测试基于硫醇的药物来稳定半胱氨酸。具体来说，用于治疗胱氨酸病的胱氨酸还原药物半胱胺在防止 IgA 自身聚集方面显示出显着的功效。当给予 IgA 肾病大鼠和小鼠模型时，半胱胺显着减少肾小球 IgA 沉积。总的来说，我们的结果揭示了 IgA 聚集体异常形成的潜在新分子机制，其中重新利用的胱氨酸病药物半胱胺可有效预防肾脏 IgA 沉积。
IgA nephropathy is caused by deposition of circulatory IgA1 in the kidney. Hypogalactosylated IgA1 has the propensity to form poly-IgA aggregates that are prone to deposition. Herein, we purified poly-IgA from the plasma of patients with IgA nephropathy and showed that the complex is susceptible to reducing conditions, suggesting intermolecular disulfide connections between IgA units. We sought to find the cysteine residue(s) that form intermolecular disulfide. Naturally assembled dimeric IgA, also known as secretory IgA, involves a J chain subunit connected with 2 IgA1 molecules via their penultimate cysteine-471 residue on a “tailpiece” segment of IgA heavy chain. It is plausible that, with the absence of J chain, the cysteine residue of mono-IgA1 might aberrantly form a disulfide bond in poly-IgA formation. Mutagenesis confirmed that cysteine-471 is capable of promoting IgA aggregation. These discoveries prompted us to test thiol-based drugs for stabilizing cysteine. Specifically, the cystine-reducing drug cysteamine used for treatment of cystinosis showed a remarkable potency in preventing self-aggregation of IgA. When administrated to rat and mouse models of IgA nephropathy, cysteamine significantly reduced glomerular IgA deposition. Collectively, our results reveal a potentially novel molecular mechanism for aberrant formation of IgA aggregates, to which the repurposed cystinosis drug cysteamine was efficacious in preventing renal IgA deposition.