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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Removal of sialic acid involving Klotho causes cell-surface retention of TRPV5 channel via binding to galectin-1
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Removal of sialic acid involving Klotho causes cell-surface retention of TRPV5 channel via binding to galectin-1

机译：去除涉及Klotho的唾液酸会通过与半乳凝素1结合而导致TRPV5通道的细胞表面保留

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摘要

Klotho is a mammalian senescence-suppression protein that has homology with glycosidases. The extracellular domain of Klotho is secreted into urine and blood and may function as a humoral factor. Klotho-def icient mice have accelerated aging and imbalance of ion homeostasis. Klotho treatment increases cell-surface abundance of the renal epithelial Ca~(2+) channel TRPV5 by modifying its N-linked glycans. However, the precise sugar substrate and mechanism for regulation by Klotho is not known. Here, we report that the extracellular domain of Klotho activates plasma-membrane resident TRPV5 through removing terminal sialic acids from their glycan chains. Removal of sialic acids exposes underlying disac-charide galactose-N-acetylglucosamine, a ligand for a ubiquitous galactoside-binding lectin galectin-1. Binding to galectin-1 lattice at the extracellular surface leads to accumulation of functional TRPV5 on the plasma membrane. Knockdown of β-galactoside α2,6-sialyltransferase (ST6Gal-1) by RNA interference, but not other sialyltransferases, in a human cell line prevents the regulation by Klotho. Moreover, the regulation by Klotho is absent in a hamster cell line that lacks endogenous ST6Gal-1, but is restored by forced expression of recombinant ST6Gal-1. Thus, Klotho participates in specific removal of α2,6-linked sialic acids and regulates cell surface retention of TRPV5 through this activity. This action of Klotho represents a novel mechanism for regulation of the activity of cell-surface glycoproteins and likely contributes to maintenance of calcium balance by Klotho.
机译：Klotho是一种与糖苷酶具有同源性的哺乳动物衰老抑制蛋白。 Klotho的细胞外结构域分泌到尿液和血液中，并可能充当体液因子。缺乏Klotho缺陷的小鼠会加速衰老和离子稳态的失衡。 Klotho处理通过修饰N-连接的聚糖来增加肾上皮Ca〜（2+）通道TRPV5的细胞表面丰度。但是，尚不清楚精确的糖底物和由Klotho调节的机制。在这里，我们报道Klotho的胞外域通过从其聚糖链中除去末端唾液酸来激活血浆膜驻留TRPV5。唾液酸的去除暴露出潜在的二糖半乳糖-N-乙酰氨基葡糖，其为遍在的半乳糖苷结合的凝集素galectin-1的配体。在细胞外表面结合galectin-1晶格导致功能性TRPV5在质膜上积累。在人类细胞系中，通过RNA干扰敲除β-半乳糖苷α2,6-唾液酸转移酶（ST6Gal-1），但不会抑制其他唾液酸转移酶，从而阻止了Klotho的调控。此外，在缺乏内源性ST6Gal-1的仓鼠细胞系中不存在由Klotho进行的调节，但是通过强制表达重组ST6Gal-1而得以恢复。因此，Klotho参与了α2,6-连接的唾液酸的特异性清除，并通过该活性调节TRPV5的细胞表面保留。 Klotho的这种作用代表了一种调节细胞表面糖蛋白活性的新机制，并且可能有助于Klotho维持钙平衡。

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