Department of Biochemistry and Molecular Biology, Dalian Medical University, Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, Dalian, China.
Biol Reprod. 2023 Aug 10;109(2):172-183. doi: 10.1093/biolre/ioad060.
Endometrial decidualization is critical to successful uterine receptivity and embryo implantation. Dysfunction of decidualization is associated with some pregnancy-related disorders, including miscarriage. Protein glycosylation is involved in many physiological and pathological processes. Protein O-fucosyltransferase 1 (poFUT1) is a key enzyme responsible for O-fucosylation biosynthesis on glycoproteins. Bone morphogenetic protein 1 (BMP1) is an essential glycoprotein in reproduction. However, the role and molecular mechanism of fucosylated BMP1 in endometrial stromal cell decidualization are still unknown. In the current study, we found that BMP1 contains a potential O-fucosylation site. Moreover, poFUT1 and BMP1 levels in the secretory phase are higher than those in the proliferative phase, and the highest level was observed in the human uterine tissues of early pregnancy, while a decrease of poFUT1 and BMP1 in the decidua was observed in miscarriage patients. Using human endometrial stromal cells (hESCs), we demonstrated that O-fucosylation of BMP1 was elevated after induced decidualization. Moreover, the increase of BMP1 O-fucosylation by poFUT1 promoted BMP1 secretion to the extracellular matrix, and more actively binds to CHRD. The binding of BMP1 and CHRD further released BMP4 originally bound to CHRD, and activated BMP/Smad signaling pathway, thereby accelerating the decidualization of human endometrial stromal cells. In summary, these results suggest that BMP1 O-fucosylation by poFUT1 could be a potential diagnostic and therapeutic target to predict miscarriage in early pregnancy examinations.
子宫内膜蜕膜化对于成功的子宫接受性和胚胎着床至关重要。蜕膜化功能障碍与一些与妊娠相关的疾病有关，包括流产。蛋白质糖基化参与许多生理和病理过程。蛋白 O-岩藻糖基转移酶 1（poFUT1）是负责糖蛋白 O-岩藻糖基合成的关键酶。骨形态发生蛋白 1（BMP1）是生殖中必不可少的糖蛋白。然而，糖基化 BMP1 在子宫内膜基质细胞蜕膜化中的作用和分子机制尚不清楚。在本研究中，我们发现 BMP1 含有一个潜在的 O-岩藻糖基化位点。此外，分泌期的 poFUT1 和 BMP1 水平高于增生期，在早孕的人子宫组织中观察到最高水平，而流产患者的蜕膜中 poFUT1 和 BMP1 水平下降。使用人子宫内膜基质细胞（hESC），我们证明了 BMP1 的 O-岩藻糖基化在诱导蜕膜化后增加。此外，poFUT1 增加 BMP1 的 O-岩藻糖基化促进了 BMP1 向细胞外基质的分泌，并更积极地与 CHRD 结合。BMP1 和 CHRD 的结合进一步释放了原本与 CHRD 结合的 BMP4，并激活了 BMP/Smad 信号通路，从而加速了人子宫内膜基质细胞的蜕膜化。总之，这些结果表明，poFUT1 对 BMP1 的 O-岩藻糖基化可能是预测早孕检查中流产的潜在诊断和治疗靶点。
