The effects of tRNA editing deficiency on hematopoietic stem cells

To test how translational control of proteome quality affects stem cell function, we examined Aarssti/sti mice that harbor a mutation in the alanyl-tRNA synthetase, which causes a tRNA editing defect that increases amino acid misincorporation errors during translation. Aarssti/sti mice exhibited reduced HSC numbers, increased HSC proliferation and significantly diminished HSC serial reconstituting activity in vivo, but did not exhibit defects within restricted progenitors. Modest accumulation of misfolded proteins partially overwhelmed the capacity of the proteasome within HSCs, which was associated with stabilization and increased abundance of c-Myc. Conditional deletion of a single copy of Myc partially rescued serial reconstitution defects in Aarssti/sti HSCs. HSCs are thus dependent on the maintenance of proteome quality and homeostasis to preserve their self-renewal activity in vivo.

为探究蛋白质组质量的翻译调控对干细胞功能的影响，我们对携带丙氨酰-tRNA合成酶（alanyl-tRNA synthetase）突变的Aarssti/sti小鼠开展了相关实验。该突变会引发tRNA编辑缺陷，进而导致翻译过程中氨基酸错掺错误的发生率升高。Aarssti/sti小鼠的造血干细胞（hematopoietic stem cell, HSC）数量减少、增殖水平升高，且体内连续重建造血活性显著受损，但受限祖细胞未出现相关功能缺陷。错误折叠蛋白的轻度积累会超出造血干细胞内蛋白酶体的处理能力，该现象与c-Myc蛋白的稳定性提升及丰度增加密切相关。单拷贝Myc的条件性敲除可部分挽救Aarssti/sti小鼠造血干细胞的连续重建造血缺陷。由此可见，造血干细胞依赖蛋白质组质量与稳态的维持，以保留其体内自我更新活性。

搜集汇总

背景与挑战

背景概述

该数据集研究tRNA编辑缺陷对造血干细胞功能的影响，使用小鼠模型通过RNA-Seq技术分析转录组数据。数据集包含6个样本，比较了Aarssti/sti突变型和野生型造血干细胞，揭示了蛋白质质量控制缺陷导致干细胞自我更新能力下降，并涉及c-Myc通路的调控机制。