State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Innovation Academy of Stem Cell and Regenerative Medicine, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 101408, China.
State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Innovation Academy of Stem Cell and Regenerative Medicine, Chinese Academy of Sciences, Beijing 100101, China; Beijing Academy of Stem Cell and Regenerative Medicine, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 101408, China.
Cell Chem Biol. 2021 Jun 17;28(6):788-801.e5. doi: 10.1016/j.chembiol.2021.01.024. Epub 2021 Feb 23.
Emerging evidence indicates the involvement of O-GlcNAc modification in placental development and pregnant health through mechanisms that are not well understood. Herein, by applying the quantitative O-GlcNAc proteomics, we established a database of O-GlcNAcylated proteins in human placental trophoblasts. Hundreds of proteins that were dynamically O-GlcNAcylated during trophoblast differentiation were identified, among which cystathionine γ-lyase (CSE) exhibited the most significant change. Site-specific analysis by mass spectrometry revealed Ser as the core O-GlcNAc site in CSE, and its O-GlcNAcylation promoted the enzymatic activity to produce HS, which in turn repressed trophoblast differentiation via inhibiting androgen receptor dimerization. Consistently, in preeclamptic placentas, remarkably enhanced CSE O-GlcNAcylation and HS production were associated with restricted trophoblast differentiation. The findings establish a resource of O-GlcNAc dynamics in human placenta, and provide a deeper insight into the biological significance of O-GlcNAcylation in placental development as well as potential therapeutic targets for the relevant pregnant complications.
新出现的证据表明，O-连接的 N-乙酰氨基葡萄糖（O-GlcNAc）修饰通过尚未完全了解的机制参与胎盘发育和孕妇健康。在此，通过应用定量 O-GlcNAc 蛋白质组学，我们建立了人胎盘滋养细胞中 O-GlcNAc 修饰蛋白的数据库。在滋养细胞分化过程中，数百种蛋白被动态 O-GlcNAc 修饰，其中半胱氨酸γ-裂解酶（CSE）的变化最为显著。通过质谱的特异性分析，发现 CSE 中的丝氨酸（Ser）是核心 O-GlcNAc 位点，其 O-GlcNAc 化促进了酶的活性以产生 HS，进而通过抑制雄激素受体二聚化来抑制滋养细胞分化。一致地，在子痫前期胎盘组织中，CSE 的 O-GlcNAc 化和 HS 产物显著增加，与滋养细胞分化受限有关。这些发现为人类胎盘 O-GlcNAc 动态变化提供了一个资源，并深入了解了 O-GlcNAc 修饰在胎盘发育中的生物学意义以及相关妊娠并发症的潜在治疗靶点。
