Hematopoietic Stem/Progenitor Cells Exhibit Stage-Specific Translational Programs via mTOR-and CDK1-dependent Mechanisms
| Autor: | William S. Eng, Christina C. Spevak, Caryn J. Ha, Gaëlle H. Martin, Harold Elias, Vinagolu K. Rajasekhar, Carolien M. Woolthuis, Christopher Y. Park, Lavanya Kannan, Amanda Ernlund, Guangjie Zhao, Shanmugapriya Selvaraj, Robert J. Schneider, Mohamed A.E. Ali |
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| Přispěvatelé: | Stem Cell Aging Leukemia and Lymphoma (SALL) |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Proteomics
0303 health sciences TOR Serine-Threonine Kinases Hematopoietic Stem Cell Transplantation Cell Biology Biology Hematopoietic Stem Cells Article Cell biology Ubiquitin ligase Transcriptome 03 medical and health sciences Haematopoiesis 0302 clinical medicine Translational regulation Genetics biology.protein Molecular Medicine Stem cell Progenitor cell Reprogramming 030217 neurology & neurosurgery PI3K/AKT/mTOR pathway 030304 developmental biology Signal Transduction |
| Zdroj: | Cell Stem Cell Cell stem cell, 26(5), 755-765.e7. CELL PRESS |
| ISSN: | 1934-5909 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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