The Glycosyltransferase EOGT Regulates Adropin Expression in Decidualizing Human Endometrium
The Glycosyltransferase EOGT Regulates Adropin Expression in Decidualizing Human Endometrium
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DOI：
10.1210/en.2017-03064
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发表时间：
2018-02
期刊：
影响因子：
4.8
通讯作者：
J. Muter;M. Alam;P. Vrljicak;Flavio S. V. Barros;Peter T Ruane;L. Ewington;J. Aplin;M. Westwood;J. Brosens
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文献类型：
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作者：
J. Muter;M. Alam;P. Vrljicak;Flavio S. V. Barros;Peter T Ruane;L. Ewington;J. Aplin;M. Westwood;J. Brosens
在妊娠期间，子宫内膜蜕膜细胞对应激信号的抵抗力对于母胎界面的完整性以及妊娠的存活率至关重要。O-GlcN酰化是一种重要的翻译后修饰，它将葡萄糖感知与细胞的抗应激反应联系起来。出乎意料的是，原代子宫内膜间质细胞的蜕膜化与O-连接β-N-乙酰氨基葡萄糖(O-GlcNAc)修饰的蛋白质减少了60%相关，反映了将O-GlcNAc添加到底物上的酶(O-GlcNAc转移酶；OGT)的下调，而不是移除这种修饰的酶(O-GlcNAcase)。值得注意的是，表皮生长因子结构域特异的O-连接的GlcNAc转移酶(EOGT)是一种内质网特异的OGT，它改变了有限数量的分泌和膜蛋白，在分化EnSCs时被显著诱导。EOGT基因的敲除扰乱了参与多种细胞功能的蜕膜基因网络。在蜕皮化细胞中，抑制EOGT基因表达最多的基因是能量稳态相关基因(ENHO)，它编码阿德罗平，一种参与能量稳态以及葡萄糖和脂肪酸代谢的代谢激素。对黄体中期子宫内膜活检的分析显示，子宫内膜EOGT与ENHO表达和体重指数呈负相关。综上所述，我们的发现显示，肥胖损害了蜕膜细胞中的EOGT-肾上腺素轴，而蜕膜细胞轴反过来指向代谢紊乱和不良妊娠结局之间的机械联系。
In pregnancy, resistance of endometrial decidual cells to stress signals is critical for the integrity of the fetomaternal interface and, by extension, survival of the conceptus. O-GlcNAcylation is an essential posttranslational modification that links glucose sensing to cellular stress resistance. Unexpectedly, decidualization of primary endometrial stromal cells (EnSCs) was associated with a 60% reduction in O-linked β-N-acetylglucosamine (O-GlcNAc)‒modified proteins, reflecting downregulation of the enzyme that adds O-GlcNAc to substrates (O-GlcNAc transferase; OGT) but not the enzyme that removes the modification (O-GlcNAcase). Notably, epidermal growth factor domain-specific O-linked GlcNAc transferase (EOGT), an endoplasmic reticulum-specific OGT that modifies a limited number of secreted and membrane proteins, was markedly induced in differentiating EnSCs. Knockdown of EOGT perturbed a network of decidual genes involved in multiple cellular functions. The most downregulated gene upon EOGT knockdown in decidualizing cells was the energy homeostasis-associated gene (ENHO), which encodes adropin, a metabolic hormone involved in energy homeostasis and glucose and fatty acid metabolism. Analysis of midluteal endometrial biopsies revealed an inverse correlation between endometrial EOGT and ENHO expression and body mass index. Taken together, our findings revealed that obesity impairs the EOGT-adropin axis in decidual cells, which in turn points toward a mechanistic link between metabolic disorders and adverse pregnancy outcome.