Posttranslational Activation of Bone Morphogenetic Protein 2 Is Mediated by Proprotein Convertase 6 during Decidualization for Pregnancy Establishment
Posttranslational Activation of Bone Morphogenetic Protein 2 Is Mediated by Proprotein Convertase 6 during Decidualization for Pregnancy Establishment
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DOI：
10.1210/en.2010-0326
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发表时间：
2010-08-01
期刊：
影响因子：
4.8
通讯作者：
Nie, Guiying
中科院分区：
文献类型：
--
作者：
Heng, Sophea;Paule, Sarah;Nie, Guiying
骨形态发生蛋白（BMPs）需要主要的翻译后修饰才能具有生物活性。其中一个关键的修饰是对最初合成的非活性前体蛋白进行蛋白内水解裂解，以释放成熟的配体。在子宫间质去个体化的生理背景下，我们发现BMP2的分裂是由5/6蛋白转化酶（PC6）介导的。脱个体化是一种对胚胎着床至关重要的子宫重塑事件。BMP2或PC6的缺失或敲低均可抑制脱胎化，导致着床失败和女性不育。在这项研究中，我们提供了生化和生理证据，证明PC6蛋白水解激活BMP2。我们使用新分离的原代人子宫内膜基质细胞，并证明PC6是PC家族中唯一在去个体化过程中显著上调的成员。在脱个体化过程中，BMP2的前体形式减少，而其活性形式增加。抑制PC6活性可抑制去个体化，并伴有BMP2激活的完全阻断。重组活性BMP2的加入部分挽救了PC6抑制引起的去个体化阻滞。PC6在KREKR（282）向下箭头切割位点加工BMP2，该位点的突变阻止了该切割。因此，本研究首次证明了BMP2的蛋白水解激活和生物利用度是由PC6控制的。（中华医学会精神病学分会，2010）
Bone morphogenetic proteins (BMPs) require major posttranslational modifications to become biologically active. One such key modification is endoproteolytic cleavage of the initially synthesized nonactive precursor protein to release the mature ligand. Here we show in a physiological context of uterine stromal decidualization that BMP2 cleavage is mediated by proprotein convertase 5/6 (PC6). Decidualization is a uterine remodeling event critical for embryo implantation. Deletion or knockdown of either BMP2 or PC6 inhibits decidualization causing implantation failure and female infertility. In this study we provide biochemical and physiological evidence that PC6 proteolytically activates BMP2. We used freshly isolated primary human endometrial stromal cells and demonstrated that PC6 was the sole member of the PC family significantly up-regulated during decidualization. The precursor form of BMP2 was reduced, whereas its active form was increased during decidualization. Inhibition of PC6 activity inhibited decidualization, and this was accompanied by a total blockade of BMP2 activation. Addition of recombinant active BMP2 partially rescued the decidualization arrest caused by PC6 inhibition. PC6 processed BMP2 at the KREKR(282) down arrow cleavage site, and mutating this site prevented the cleavage. This study thus demonstrates for the first time that the proteolytic activation and thus bioavailability of BMP2 is controlled by PC6. (Endocrinology 151: 3909-3917, 2010)