Hematopoietic Stem and Progenitor Cells Exhibit Stage-Specific Translational Programs via mTOR- and CDK1-Dependent Mechanisms.,Cell Stem Cell

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Hematopoietic Stem and Progenitor Cells Exhibit Stage-Specific Translational Programs via mTOR- and CDK1-Dependent Mechanisms.
Cell Stem Cell ( IF 19.8 ) Pub Date : 2020-05-07 , DOI: 10.1016/j.stem.2019.12.006
Christina C Spevak ₁ , Harold K Elias ₁ , Lavanya Kannan ₁ , Mohamed A E Ali ₁ , Gaëlle H Martin ₁ , Shanmugapriya Selvaraj ₁ , William S Eng ₁ , Amanda Ernlund ₂ , Vinagolu K Rajasekhar ₃ , Carolien M Woolthuis ₄ , Guangjie Zhao ₁ , Caryn J Ha ₁ , Robert J Schneider ₂ , Christopher Y Park ₁

Affiliation

Hematopoietic stem cells (HSCs) require highly regulated rates of protein synthesis, but it is unclear if they or lineage-committed progenitors preferentially recruit transcripts to translating ribosomes. We utilized polysome profiling, RNA sequencing, and whole-proteomic approaches to examine the translatome in LSK (Lin-Sca-1+c-Kit+) and myeloid progenitor (MP; Lin-Sca-1-c-Kit+) cells. Our studies show that LSKs exhibit low global translation but high translational efficiencies (TEs) of mRNAs required for HSC maintenance. In contrast, MPs activate translation in an mTOR-independent manner due, at least in part, to proteasomal degradation of mTOR by the E3 ubiquitin ligase c-Cbl. In the near absence of mTOR, CDK1 activates eIF4E-dependent translation in MPs through phosphorylation of 4E-BP1. Aberrant activation of mTOR expression and signaling in c-Cbl-deficient MPs results in increased mature myeloid lineage output. Overall, our data demonstrate that hematopoietic stem and progenitor cells (HSPCs) undergo translational reprogramming mediated by previously uncharacterized mechanisms of translational regulation.

中文翻译：

造血干细胞和祖细胞通过 mTOR 和 CDK1 依赖机制表现出特定阶段的转化程序。

造血干细胞 (HSC) 需要高度调节的蛋白质合成速率，但尚不清楚它们或谱系承诺的祖细胞是否优先招募转录物来翻译核糖体。我们利用多核糖体分析、RNA 测序和全蛋白质组学方法来检查 LSK (Lin-Sca-1+c-Kit+) 和骨髓祖细胞 (MP; Lin-Sca-1-c-Kit+) 细胞中的翻译组。我们的研究表明，LSK 表现出低全局翻译，但 HSC 维护所需的 mRNA 翻译效率 (TE) 高。相反，MPs 以独立于 mTOR 的方式激活翻译，至少部分是由于 E3 泛素连接酶 c-Cbl 对 mTOR 的蛋白酶体降解。在几乎没有 mTOR 的情况下，CDK1 通过 4E-BP1 的磷酸化激活 MPs 中的 eIF4E 依赖性翻译。c-Cbl 缺陷型 MPs 中 mTOR 表达和信号传导的异常激活导致成熟骨髓谱系输出增加。总体而言，我们的数据表明，造血干细胞和祖细胞 (HSPC) 经历了由以前未表征的翻译调控机制介导的翻译重编程。

更新日期：2020-05-07

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