Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, College of Basic Medical Science, Dalian Medical University, Dalian, 116044, China.
Department of Pathology, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, 116011, China.
Cell Death Dis. 2023 Oct 6;14(10):651. doi: 10.1038/s41419-023-06166-4.
Embryo implantation into the uterus is the gateway for successful pregnancy. Proper migration and invasion of embryonic trophoblast cells are the key for embryo implantation, and dysfunction causes pregnancy failure. Protein glycosylation plays crucial roles in reproduction. However, it remains unclear whether the glycosylation of trophoblasts is involved in trophoblast migration and invasion processes during embryo implantation failure. By Lectin array, we discovered the decreased α1,3-fucosylation, especially difucosylated Lewis Y (LeY) glycan, in the villus tissues of miscarriage patients when compared with normal pregnancy women. Downregulating LeY biosynthesis by silencing the key enzyme fucosyltransferase IV (FUT4) inhibited migration and invasion ability of trophoblast cells. Using proteomics and translatomics, the specific LeY scaffolding glycoprotein of mesoderm-specific transcript (MEST) with glycosylation site at Asn163 was identified, and its expression enhanced migration and invasion ability of trophoblast cells. The results also provided novel evidence showing that decreased LeY modification on MEST hampered the binding of MEST with translation factor eIF4E2, and inhibited implantation-related gene translation initiation, which caused pregnancy failure. The α1,3-fucosylation of MEST by FUT4 may serve as a new biomarker for evaluating the functional state of pregnancy, and a target for infertility treatment.
胚胎植入子宫是成功妊娠的关键。胚胎滋养细胞的正确迁移和侵袭是胚胎着床的关键，其功能障碍会导致妊娠失败。蛋白质糖基化在生殖中起着至关重要的作用。然而，滋养细胞的糖基化是否参与胚胎植入失败过程中的滋养细胞迁移和侵袭，目前尚不清楚。通过凝集素阵列，我们发现与正常妊娠妇女相比，流产患者绒毛组织中的α1,3-岩藻糖基化，尤其是双岩藻糖基化 Lewis Y（LeY）聚糖减少。通过沉默关键酶岩藻糖基转移酶 IV（FUT4）下调 LeY 生物合成，抑制滋养细胞的迁移和侵袭能力。通过蛋白质组学和转位组学，我们鉴定到具有糖基化位点天冬酰胺 163 的中胚层特异性转录物（MEST）的特异性 LeY 支架糖蛋白，其表达增强了滋养细胞的迁移和侵袭能力。结果还提供了新的证据表明，MEST 上的 LeY 修饰减少会阻碍 MEST 与翻译因子 eIF4E2 的结合，并抑制与植入相关的基因翻译起始，从而导致妊娠失败。FUT4 对 MEST 的α1,3-岩藻糖基化可能成为评估妊娠功能状态的新生物标志物，也可能成为治疗不孕的靶点。
