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.
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DOI：
10.1172/jci.insight.150551
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发表时间：
2021-10-08
期刊：
影响因子：
8
通讯作者：
Jin J
中科院分区：
文献类型：
--
作者：
Xie X;Gao L;Liu P;Lv J;Lu WH;Zhang H;Jin J
伊加肾病是由循环IgA 1在肾脏中沉积引起的。低半乳糖基化的IgA 1具有形成易于沉积的多聚IgA聚集体的倾向。在此，我们纯化的多聚IgA从伊加肾病患者的血浆中，并表明，该复合物是容易还原的条件下，这表明伊加单位之间的分子间二硫键连接。我们试图找到形成分子间二硫键的半胱氨酸残基。天然组装的二聚体伊加，也称为分泌型伊加，涉及通过伊加重链的“尾片段”区段上的倒数第二个半胱氨酸-471残基与2个IgA 1分子连接的J链亚基。这是合理的，与J链的情况下，mono-IgA 1的半胱氨酸残基可能会异常地形成二硫键的poly-IgA的形成。诱变证实半胱氨酸-471能够促进伊加聚集。这些发现促使我们测试基于巯基的药物来稳定半胱氨酸。具体地，用于治疗胱氨酸病的胱氨酸还原药物半胱胺在防止伊加的自聚集方面显示出显著的效力。当给予伊加肾病的大鼠和小鼠模型时，半胱胺显著减少肾小球伊加沉积。总的来说，我们的研究结果揭示了一种潜在的新的异常形成伊加聚集体的分子机制，其中重新利用胱氨酸病药物半胱胺有效地防止肾脏伊加沉积。
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.