Metabolic rewiring during bone development underlies tRNA m7G-associated primordial dwarfism.

Qiwen Li,Shuang Jiang,Kexin Lei,Hui Han,Yaqian Chen,Weimin Lin,Qiuchan Xiong,Xingying Qi,Xinyan Gan,Rui Sheng,Yuan Wang,Yarong Zhang,Jieyi Ma,Tao Li,Shuibin Lin,Chenchen Zhou,Demeng Chen,Quan Yuan
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Abstract

Translation of mRNA to protein is tightly regulated by tRNAs, which are subject to various chemical modifications that maintain the structure, stability and function. Deficiency of tRNA N7-methylguanosine (m7G) modification in patients causes a type of primordial dwarfism, but the underlying mechanism remains unknown. Here we report the loss of m7G rewires cellular metabolism, leading to the pathogenesis of primordial dwarfism. Conditional deletion of the catalytic enzyme Mettl1 or missense mutation of the scaffold protein Wdr4 severely impaired endochondral bone formation and bone mass accrual. Mechanistically, Mettl1 knockout decreased abundance of m7G-modified tRNAs and inhibited translation of mRNAs relating to cytoskeleton and Rho GTPase signaling. Meanwhile, Mettl1 knockout enhanced cellular energy metabolism despite of incompetent proliferation and osteogenic commitment. Further exploration revealed that impaired Rho GTPase signaling upregulated branched-chain amino acid transaminase 1 (BCAT1) level that rewired cell metabolism and restricted intracellular α-ketoglutarate (αKG). Supplementation of αKG ameliorated the skeletal defect of Mettl1-deficient mice. In addition to the selective translation of metabolism-related mRNAs, we further revealed that Mettl1 knockout globally regulated translation via integrated stress response (ISR) and mammalian target of rapamycin complex 1 (mTORC1) signaling. Restoring translation either by targeting ISR or mTORC1 aggravated bone defects of Mettl1-deficient mice. Overall, our study unveils a critical role of m7G tRNA modification in bone development by regulating cellular metabolism, and indicates that suspension of translation initiation as quality control mechanism in response to tRNA dysregulation.
骨骼发育过程中的代谢重构是与 tRNA m7G 相关的原始侏儒症的基础。
将 mRNA 翻译成蛋白质受到 tRNA 的严格调控,而 tRNA 会发生各种化学修饰,以保持其结构、稳定性和功能。缺乏 tRNA N7-甲基鸟苷(m7G)修饰的患者会导致一种原始侏儒症,但其潜在机制仍不清楚。在这里,我们报告了 m7G 的缺失重构了细胞代谢,导致了原始侏儒症的发病机制。催化酶Mettl1的条件性缺失或支架蛋白Wdr4的错义突变严重影响了软骨内骨的形成和骨量的增加。从机理上讲,Mettl1 基因敲除会降低 m7G 修饰的 tRNA 的丰度,抑制与细胞骨架和 Rho GTPase 信号转导有关的 mRNA 的翻译。同时,Mettl1基因敲除后,尽管细胞增殖和成骨能力不佳,但细胞能量代谢却增强了。进一步研究发现,Rho GTPase信号传导受损会上调支链氨基酸转氨酶1(BCAT1)的水平,从而重新连接细胞代谢并限制细胞内的α-酮戊二酸(αKG)。补充αKG可以改善Mettl1缺陷小鼠的骨骼缺陷。除了与代谢相关的mRNA的选择性翻译外,我们还进一步发现,Mettl1基因敲除通过综合应激反应(ISR)和哺乳动物雷帕霉素靶标复合体1(mTORC1)信号传导对翻译进行全球调控。通过靶向 ISR 或 mTORC1 恢复翻译会加重 Mettl1 缺失小鼠的骨缺陷。总之,我们的研究揭示了 m7G tRNA 修饰通过调节细胞新陈代谢在骨骼发育中的关键作用,并表明翻译启动暂停是应对 tRNA 失调的质量控制机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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