与Hippo信号结合的蛋白质O-GlcNAcylation驱动糖尿病视网膜病变中的血管功能障碍
Yi Lei1,2, Qiangyun Liu1, Binggui Chen2
1Department of Ophthalmology, Laboratory of Molecular Ophthalmology and Tianjin Key Laboratory of Ocular Trauma, Ministry of Education International Joint Laboratory of Ocular Diseases, Tianjin Medical University General Hospital, Tianjin, China.
Nature communications
|October 30, 2024
概括
糖尿病视网膜病变涉及视网膜细胞中营养传感器O-GlcNAcylation的升高. 抑制O-GlcNAc转移酶通过向O-GlcNAc-Hippo轴来改善血管功能.
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 血管生物学 血管生物学
背景情况:
- 代谢障碍,特别是糖尿病,是糖尿病视网膜病变的主要原因,是导致失明的主要原因.
- 在糖尿病视网膜病变中,将代谢失调与血管功能障碍联系起来的分子机制尚未完全理解.
- O-GlcNAcylation是一种对葡萄糖水平敏感的翻译后修饰,涉及营养感应.
研究的目的:
- 研究O-GlcNAcylation在糖尿病视网膜病变的发病过程中的作用.
- 阐明O-GlcNAcylation有助于糖尿病视网膜病变中的血管功能障碍的分子机制.
- 为了确定糖尿病视网膜病变的潜在治疗点.
主要方法:
- 从糖尿病视网膜病变患者和小鼠模型的视网膜内皮细胞中量化O-GlcNAc水平.
- 内皮特异性衰竭和O-GlcNAc转移酶 (OGT) 的药理抑制.
- 对Hippo通路效应者的分析 是相关蛋白 (YAP) 和具有PDZ结合动机 (TAZ) 的转录协活性剂 O-GlcNAcylation和酸化.
- 在YAP上识别O-GlcNAc站点及其功能后果.
主要成果:
- 在糖尿病视网膜病变患者和小鼠模型的视网膜内皮细胞中观察到O-GlcNAc水平升高.
- 内皮特异性OGT耗尽或抑制显著减轻了血管功能障碍.
- 在糖尿病视网膜病变中,Key Hippo路径组件YAP和TAZ被发现是O-GlcNAcylated.
- 在YAP上,threonine 383被确定为O-GlcNAc位点,抑制其酸化并导致稳定和激活.
- 激活的YAP/TAZ促进了亲血管和葡萄糖代谢转录程序,导致血管功能障碍.
结论:
- O-GlcNAc-Hippo轴在糖尿病视网膜病变的发病过程中发挥着至关重要的作用.
- 异常O-GlcNAcylation的YAP/TAZ通过促进亲血管和代谢变化,有助于血管功能障碍.
- 准O-GlcNAc-Hippo轴为糖尿病视网膜病变提供了一个有希望的治疗策略.
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