O-GlcNAcylation通过重新连接有氧糖酵解介导Wnt刺激的骨形成。

IF 6.5 1区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY EMBO Reports Pub Date : 2024-09-10 DOI:10.1038/s44319-024-00237-z
Chengjia You,Fangyuan Shen,Puying Yang,Jingyao Cui,Qiaoyue Ren,Moyu Liu,Yujie Hu,Boer Li,Ling Ye,Yu Shi
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引用次数: 0

摘要

Wnt 信号是骨质疏松症同化疗法的一个重要靶点。在动物模型和临床研究中,一种能阻断 Wnt 信号抑制剂(硬骨素)的硬骨素中和抗体(Scl-Ab)已被证明能促进骨量。然而,Wnt 信号促进成骨的细胞机制仍有待进一步研究。O-GlcNA酰化是蛋白质的一种动态翻译后修饰,它控制着多种关键的生物过程,包括转录、翻译和细胞命运决定。在此,我们报告了 Wnt3a 通过 Ca2+-PKA-Gfat1 轴快速诱导 O-GlcNAcylation 或在长时间刺激后以 Wnt-β-catenin 依赖性方式增加 O-GlcNAcylation 的情况。重要的是,我们发现 O-GlcNAcylation 对体内和体外成骨细胞的形成都是不可或缺的。遗传性消减成骨细胞系中的 O-GlcNAcylation 会减少骨形成并延迟体内 Wnt 刺激下的骨折愈合。从机理上讲,Wnt3a诱导PDK1丝氨酸174处的O-GlcNAcylation以稳定该蛋白,从而导致糖酵解和骨生成增加。这些发现强调了O-GlcNAcylation是调节Wnt诱导的糖代谢和骨合成代谢的重要机制。
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O-GlcNAcylation mediates Wnt-stimulated bone formation by rewiring aerobic glycolysis.
Wnt signaling is an important target for anabolic therapies in osteoporosis. A sclerostin-neutralizing antibody (Scl-Ab), that blocks the Wnt signaling inhibitor (sclerostin), has been shown to promote bone mass in animal models and clinical studies. However, the cellular mechanisms by which Wnt signaling promotes osteogenesis remain to be further investigated. O-GlcNAcylation, a dynamic post-translational modification of proteins, controls multiple critical biological processes including transcription, translation, and cell fate determination. Here, we report that Wnt3a either induces O-GlcNAcylation rapidly via the Ca2+-PKA-Gfat1 axis, or increases it in a Wnt-β-catenin-dependent manner following prolonged stimulation. Importantly, we find O-GlcNAcylation indispensable for osteoblastogenesis both in vivo and in vitro. Genetic ablation of O-GlcNAcylation in the osteoblast-lineage diminishes bone formation and delays bone fracture healing in response to Wnt stimulation in vivo. Mechanistically, Wnt3a induces O-GlcNAcylation at Serine 174 of PDK1 to stabilize the protein, resulting in increased glycolysis and osteogenesis. These findings highlight O-GlcNAcylation as an important mechanism regulating Wnt-induced glucose metabolism and bone anabolism.
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来源期刊
EMBO Reports
EMBO Reports 生物-生化与分子生物学
CiteScore
11.20
自引率
1.30%
发文量
267
审稿时长
1 months
期刊介绍: EMBO Reports is a scientific journal that specializes in publishing research articles in the fields of molecular biology, cell biology, and developmental biology. The journal is known for its commitment to publishing high-quality, impactful research that provides novel physiological and functional insights. These insights are expected to be supported by robust evidence, with independent lines of inquiry validating the findings. The journal's scope includes both long and short-format papers, catering to different types of research contributions. It values studies that: Communicate major findings: Articles that report significant discoveries or advancements in the understanding of biological processes at the molecular, cellular, and developmental levels. Confirm important findings: Research that validates or supports existing knowledge in the field, reinforcing the reliability of previous studies. Refute prominent claims: Studies that challenge or disprove widely accepted ideas or hypotheses in the biosciences, contributing to the correction and evolution of scientific understanding. Present null data: Papers that report negative results or findings that do not support a particular hypothesis, which are crucial for the scientific process as they help to refine or redirect research efforts. EMBO Reports is dedicated to maintaining high standards of scientific rigor and integrity, ensuring that the research it publishes contributes meaningfully to the advancement of knowledge in the life sciences. By covering a broad spectrum of topics and encouraging the publication of both positive and negative results, the journal plays a vital role in promoting a comprehensive and balanced view of scientific inquiry. 
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