Mammalian plasma fetuin-B is a selective inhibitor of ovastacin and meprin metalloproteinases
Mammalian plasma fetuin-B is a selective inhibitor of ovastacin and meprin metalloproteinases
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DOI：
10.1038/s41598-018-37024-5
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发表时间：
2019-01-24
影响因子：
4.6
通讯作者：
Stoecker, Walter
中科院分区：
文献类型：
--
作者：
Karmilin, Konstantin;Schmitz, Carlo;Stoecker, Walter
脊椎动物胎球蛋白是胱抑素超家族的多结构域血浆蛋白。人胎球蛋白-A也称为AHSG，α（2）-Heremans-Schmid-糖蛋白。小鼠基因敲除鉴定出胎球蛋白A对钙化基质代谢和骨矿化至关重要。另一方面，胎球蛋白-B缺陷小鼠由于未受精卵母细胞中的金属蛋白酶ovastacin引起的透明质酸“硬化”而雌性不育。在野生型小鼠中，胎球蛋白-B抑制ovastacin的活性，从而维持卵母细胞的可受精性。在这里，我们问，如果胎球蛋白影响进一步的蛋白酶可能是预期从他们的进化关系，单域半胱氨酸蛋白酶抑制剂，称为蛋白酶抑制剂。我们表明胎球蛋白-A不是任何测试的蛋白酶的抑制剂。与此形成鲜明对比的是，密切相关的胎球蛋白B选择性抑制虾红素金属蛋白酶，如meprins和ovastacin，但不抑制tolloid亚家族的虾红素，也不抑制任何其他蛋白酶。胎球蛋白-B在各种哺乳动物细胞类型，昆虫细胞中表达，并在细菌中表达的截短的鱼胎球蛋白的分析表明，胱抑素样结构域单独是必要的和足够的抑制。这份报告强调胎球蛋白B作为一个特定的拮抗剂的ovastacin和meprin金属蛋白酶。控制ovastacin被证明是女性生育力不可或缺的。另一方面，Meprin抑制使胎球蛋白-B成为控制血管生成、免疫防御、细胞外基质组装和一般细胞信号传导的蛋白水解网络中的潜在关键参与者，其对炎症、纤维化、神经退行性疾病和癌症具有影响。
Vertebrate fetuins are multi-domain plasma-proteins of the cystatin-superfamily. Human fetuin-A is also known as AHSG, alpha(2)-Heremans-Schmid-glycoprotein. Gene-knockout in mice identified fetuin-A as essential for calcified-matrix-metabolism and bone-mineralization. Fetuin-B deficient mice, on the other hand, are female infertile due to zona pellucida 'hardening' caused by the metalloproteinase ovastacin in unfertilized oocytes. In wildtype mice fetuin-B inhibits the activity of ovastacin thus maintaining oocytes fertilizable. Here we asked, if fetuins affect further proteases as might be expected from their evolutionary relation to single-domain-cystatins, known as proteinase-inhibitors. We show that fetuin-A is not an inhibitor of any tested protease. In stark contrast, the closely related fetuin-B selectively inhibits astacin-metalloproteinases such as meprins and ovastacin, but not astacins of the tolloid-subfamily, nor any other proteinase. The analysis of fetuin-B expressed in various mammalian cell types, insect cells, and truncated fish-fetuin expressed in bacteria, showed that the cystatin-like domains alone are necessary and sufficient for inhibition. This report highlights fetuin-B as a specific antagonist of ovastacin and meprin-metalloproteinases. Control of ovastacin was shown to be indispensable for female fertility. Meprin inhibition, on the other hand, renders fetuin-B a potential key-player in proteolytic networks controlling angiogenesis, immune-defense, extracellular-matrix-assembly and general cell-signaling, with implications for inflammation, fibrosis, neurodegenerative disorders and cancer.