葡萄糖通过 O-GlcNAcylation 介导的细胞骨架调节作用影响子宫内膜对胚胎植入的接受能力。

IF 5 2区 生物学 Q2 CELL BIOLOGY
Peter T Ruane, Isabel Paterson, Beth Reeves, Daman Adlam, Stéphane C Berneau, Lewis Renshall, Jan J Brosens, Susan J Kimber, Daniel R Brison, John D Aplin, Melissa Westwood
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引用次数: 0

摘要

子宫内膜上皮细胞的表型变化是妊娠开始时胚胎着床的接受性的基础,但高血糖对这些过程的影响仍鲜为人知。在这里,我们发现生理水平的葡萄糖(5mM)会降低子宫内膜上皮细胞系石川(Ishikawa)的接受能力。然而,由于葡萄糖通过己糖胺生物合成途径(HBP)和通过蛋白质 O-GlcNAcylation 调节细胞功能,17mM 葡萄糖支持胚胎附着。药物抑制 HBP 或蛋白 O-GlcNAcylation 可减少胚胎在 17mM 葡萄糖条件下的共培养中的附着。对石川细胞中的 O-GlcNAcylated 蛋白质组进行的质谱分析表明,肌球蛋白磷酸酶靶亚基 1 (MYPT1) 在 17mM 葡萄糖中的 O-GlcNAcyl 化程度更高,这与极化上皮细胞顶端细胞连接处其靶蛋白磷酸肌球蛋白轻链 2 的丢失有关。二维和三维形态学分析表明,较高的葡萄糖水平会通过 O-GlcNAcylation 减弱上皮的极性。抑制 RhoA 相关激酶(ROCK)或肌球蛋白 II 会导致在 5mM 葡萄糖中培养的细胞极性减弱、接受性增强,这与 MYPT1 在 ROCK 信号下游发挥作用的数据一致。这些数据表明,在子宫内膜接受性的获得过程中,子宫内膜上皮的极性是通过肌球蛋白收缩性上游的 RhoA 信号调节的。葡萄糖水平通过 MYPT1 的 O-GlcNAcylation 对这一途径产生影响,这可能会影响糖尿病妇女的子宫内膜对植入胚胎的接受能力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Glucose influences endometrial receptivity to embryo implantation through O-GlcNAcylation-mediated regulation of the cytoskeleton.

Phenotypic changes to endometrial epithelial cells underpin receptivity to embryo implantation at the onset of pregnancy but the effect of hyperglycemia on these processes remains poorly understood. Here, we show that physiological levels of glucose (5 mM) abolished receptivity in the endometrial epithelial cell line, Ishikawa. However, embryo attachment was supported by 17 mM glucose as a result of glucose flux through the hexosamine biosynthetic pathway (HBP) and modulation of cell function via protein O-GlcNAcylation. Pharmacological inhibition of HBP or protein O-GlcNAcylation reduced embryo attachment in cocultures at 17 mM glucose. Mass spectrometry analysis of the O-GlcNAcylated proteome in Ishikawa cells revealed that myosin phosphatase target subunit 1 (MYPT1) is more highly O-GlcNAcylated in 17 mM glucose, correlating with loss of its target protein, phospho-myosin light chain 2, from apical cell junctions of polarized epithelium. Two-dimensional (2-D) and three-dimensional (3-D) morphologic analysis demonstrated that the higher glucose level attenuates epithelial polarity through O-GlcNAcylation. Inhibition of Rho (ras homologous)A-associated kinase (ROCK) or myosin II led to reduced polarity and enhanced receptivity in cells cultured in 5 mM glucose, consistent with data showing that MYPT1 acts downstream of ROCK signaling. These data implicate regulation of endometrial epithelial polarity through RhoA signaling upstream of actomyosin contractility in the acquisition of endometrial receptivity. Glucose levels impinge on this pathway through O-GlcNAcylation of MYPT1, which may impact endometrial receptivity to an implanting embryo in women with diabetes.NEW & NOTEWORTHY Understanding how glucose regulates endometrial function will support preconception guidance and/or the development of targeted interventions for individuals living with diabetes wishing to embark on pregnancy. We found that glucose can influence endometrial epithelial cell receptivity to embryo implantation by regulating posttranslational modification of proteins involved in the maintenance of cell polarity. Impaired or inappropriate endometrial receptivity could contribute to fertility and/or early pregnancy complications caused by poor glucose control.

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来源期刊
CiteScore
9.10
自引率
1.80%
发文量
252
审稿时长
1 months
期刊介绍: The American Journal of Physiology-Cell Physiology is dedicated to innovative approaches to the study of cell and molecular physiology. Contributions that use cellular and molecular approaches to shed light on mechanisms of physiological control at higher levels of organization also appear regularly. Manuscripts dealing with the structure and function of cell membranes, contractile systems, cellular organelles, and membrane channels, transporters, and pumps are encouraged. Studies dealing with integrated regulation of cellular function, including mechanisms of signal transduction, development, gene expression, cell-to-cell interactions, and the cell physiology of pathophysiological states, are also eagerly sought. Interdisciplinary studies that apply the approaches of biochemistry, biophysics, molecular biology, morphology, and immunology to the determination of new principles in cell physiology are especially welcome.
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