Hematopoietic Stem and Progenitor Cells Exhibit Stage-Specific Translational Programs via mTOR- and CDK1-Dependent Mechanisms.
Hematopoietic Stem and Progenitor Cells Exhibit Stage-Specific Translational Programs via mTOR- and CDK1-Dependent Mechanisms.
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DOI：
10.1016/j.stem.2019.12.006
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发表时间：
2020-05-07
期刊：
影响因子：
23.9
通讯作者：
Park, Christopher Y.
中科院分区：
文献类型：
--
作者：
Spevak, Christina C.;Elias, Harold K.;Kannan, Lavanya;Ali, Mohamed A. E.;Martin, Gaelle H.;Selvaraj, Shanmugapriya;Eng, William S.;Ernlund, Amanda;Rajasekhar, Vinagolu K.;Woolthuis, Carolien M.;Zhao, Guangjie;Ha, Caryn J.;Schneider, Robert J.;Park, Christopher Y.
造血干细胞（HSC）需要高度调节的蛋白质合成速率，但目前尚不清楚它们或谱系定型祖细胞是否优先招募转录本翻译核糖体。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+）和髓系祖细胞（MP; Lin-Sca-1-c-Kit+）中的翻译组。我们的研究表明，LSK表现出低的整体翻译，但高翻译效率（TE）的HSC维持所需的mRNA。相比之下，MP以mTOR非依赖性方式激活翻译，至少部分是由于E3泛素连接酶c-Cbl对mTOR的蛋白酶体降解。在几乎不存在mTOR的情况下，CDK 1通过4 E-BP 1的磷酸化激活MP中的eIF 4 E依赖性翻译。c-Cbl缺陷型MP中mTOR表达和信号传导的异常激活导致成熟髓系输出增加。总体而言，我们的数据表明，HSPCs进行翻译重编程介导的翻译调控机制以前未知。造血干细胞和祖细胞（HSPCs）中蛋白质合成的调控机制知之甚少。Spevak，Elias及其同事提供了小鼠HSPC中翻译组的全面表征，并表明mTOR和CDK 1依赖性机制在造血发育的不同步骤中激活翻译。
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 a 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 HSPCs undergo translational reprogramming mediated by previously uncharacterized mechanisms of translational regulation. The mechanisms that regulate protein synthesis in hematopoietic stem and progenitor cells (HSPCs) are poorly understood. Spevak, Elias and colleagues provide a comprehensive characterization of the translatome in mouse HSPCs and show that mTOR and CDK1 dependent mechanisms activate translation during distinct steps in hematopoietic development.
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影响因子：
14.9
作者：
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通讯作者：
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影响因子：
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