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骨发育过程中的代谢重新连接是tRNA m7G相关的原始矮体的基础

Qiwen Li¹, Shuang Jiang¹, Kexin Lei¹

¹State Key Laboratory of Oral Diseases and National Center for Stomatology and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.

The Journal of clinical investigation

|September 10, 2024

概括

失去N7-甲基瓜诺辛 (m7G) tRNA修饰会破坏细胞代谢和骨发育,导致原始矮体. 恢复α-谷氨酸 (αKG) 改善了缺乏m7G修饰的小鼠的骨缺陷.

科学领域:

分子生物学分子生物学
生物化学生物化学
遗传学是一个遗传学.

背景情况:

转移RNAs (tRNAs) 经历了蛋白质翻译所必需的化学修饰.
对tRNAs的N7-甲基瓜诺辛 (m7G) 修改对于细胞功能至关重要.
缺乏m7GtRNA修饰与原始矮体有关,但机制尚不清楚.

研究的目的:

阐明损失m7GtRNA修饰导致原始矮体的机制.
研究m7G修饰在细胞代谢和骨发育中的作用.
为了确定m7G相关疾病的潜在治疗点.

主要方法:

在小鼠中,有条件删除Mettl1 (催化酶) 或Wdr4 (架构蛋白) 突变.
对tRNA修饰水平,mRNA翻译和细胞代谢的分析.
评估内分泌骨形成和骨质积累.
用α-谷氨酸 (αKG) 进行代谢分析和体内救援实验.

主要成果:

失去m7G修饰损害了内分泌骨形成和骨质.
Mettl1淘汰减少了m7G修饰的tRNA,抑制了细胞骨和Rho GTPase信号mRNA的翻译.
细胞代谢得到增强,受损的Rho GTPase信号上调BCAT1并限制αKG.
在Mettl1缺乏的小鼠中,αKG补充可以挽救骨缺陷.
通过综合应激反应 (ISR) 和mTORC1信号观察到全球翻译调节.

结论:

通过调节细胞代谢,m7G tRNA 修饰对骨发育至关重要.
通过代谢重新连接,m7G tRNA 修饰的损伤导致了原始矮体.
暂停翻译启动作为响应tRNA失调的质量控制机制.

关键词:

骨生物学骨生物学骨的发育骨的发育代谢过程中的代谢.翻译翻译翻译翻译

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