Low protein synthesis is a feature of somatic stem cells that promotes regeneration in multiple tissues. Modest increases in protein synthesis impair stem cell function, but the mechanisms by which this occurs are largely unknown. We determine that low protein synthesis within hematopoietic stem cells (HSCs) is associated with elevated proteome quality in vivo. HSCs contain less misfolded and unfolded proteins than myeloid progenitors. Increases in protein synthesis cause HSCs to accumulate misfolded and unfolded proteins. To test how proteome quality affects HSCs, we examine Aarssti/sti mice that harbor a tRNA editing defect that increases amino acid misincorporation. Aarssti/sti mice exhibit reduced HSC numbers, increased proliferation, and diminished serial reconstituting activity. Misfolded proteins overwhelm the proteasome within Aarssti/sti HSCs, which is associated with increased c-Myc abundance. Deletion of one Myc allele partially rescues serial reconstitution defects in Aarssti/sti HSCs. Thus, HSCs are dependent on low protein synthesis to maintain proteostasis, which promotes their self-renewal.

中文翻译：

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蛋白质组质量的适度下降会损害造血干细胞的自我更新。

低蛋白合成是体干细胞的特征，它促进了多种组织的再生。蛋白质合成的适度增加会损害干细胞的功能，但这种机制的发生在很大程度上尚不清楚。我们确定造血干细胞（HSCs）中的低蛋白合成与体内蛋白质组质量提高有关。与骨髓祖细胞相比，HSC包含的错误折叠和未折叠的蛋白质更少。蛋白质合成的增加导致HSC积聚错误折叠和未折叠的蛋白质。为了测试蛋白质组质量如何影响HSC，我们检查了Aarssti / sti小鼠，它们具有tRNA编辑缺陷，该缺陷会增加氨基酸错误掺入。Aarssti / sti小鼠表现出降低的HSC数量，增加的增殖和减少的系列重组活性。错误折叠的蛋白质使Aarssti / sti HSC中的蛋白酶体不堪重负，这与c-Myc丰度增加有关。删除一个Myc等位基因可部分挽救Aarssti / sti HSC中的连续重组缺陷。因此，HSC依赖于低蛋白合成来维持蛋白稳态，从而促进其自我更新。