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The Cytosolic Protein G0S2 Maintains Quiescence in Hematopoietic Stem Cells

机译:胞质蛋白G0S2在造血干细胞中保持静止

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摘要

Bone marrow hematopoietic stem cells (HSCs) balance proliferation and differentiation by integrating complex transcriptional and post-translational mechanisms regulated by cell intrinsic and extrinsic factors. We found that transcripts of G0/G1 switch gene 2 (G0S2) are enriched in lineage− Sca-1+ c-kit+ (LSK) CD150+ CD48− CD41− cells, a population highly enriched for quiescent HSCs, whereas G0S2 expression is suppressed in dividing LSK CD150+ CD48− cells. Gain-of-function analyses using retroviral expression vectors in bone marrow cells showed that G0S2 localizes to the mitochondria, endoplasmic reticulum, and early endosomes in hematopoietic cells. Co-transplantation of bone marrow cells transduced with the control or G0S2 retrovirus led to increased chimerism of G0S2-overexpressing cells in femurs, although their contribution to the blood was reduced. This finding was correlated with increased quiescence in G0S2-overexpressing HSCs (LSK CD150+ CD48−) and progenitor cells (LS−K). Conversely, silencing of endogenous G0S2 expression in bone marrow cells increased blood chimerism upon transplantation and promoted HSC cell division, supporting an inhibitory role for G0S2 in HSC proliferation. A proteomic study revealed that the hydrophobic domain of G0S2 interacts with a domain of nucleolin that is rich in arginine-glycine-glycine repeats, which results in the retention of nucleolin in the cytosol. We showed that this cytosolic retention of nucleolin occurs in resting, but not proliferating, wild-type LSK CD150+ CD48− cells. Collectively, we propose a novel model of HSC quiescence in which elevated G0S2 expression can sequester nucleolin in the cytosol, precluding its pro-proliferation functions in the nucleolus.
机译:骨髓造血干细胞(HSC)通过整合受细胞内在和外在因素调控的复杂转录和翻译后机制来平衡增殖和分化。我们发现G0 / G1转换基因2(G0S2)的转录本在谱系-Sca-1 + c-kit +(LSK)CD150 + CD48- CD41-细胞中富集,该细胞高度富集静态HSC,而G0S2表达在分裂LSK CD150 + CD48-细胞。使用逆转录病毒表达载体在骨髓细胞中进行功能获得的分析表明,G0S2定位于造血细胞中的线粒体,内质网和早期内体。用对照或G0S2逆转录病毒转导的骨髓细胞共移植导致股骨中过表达G0S2的细胞嵌合性增加,尽管它们对血液的贡献减少了。此发现与过表达G0S2的HSC(LSK CD150 + CD48-)和祖细胞(LS-K)的增加有关。相反,沉默内源性G0S2在骨髓细胞中的表达会增加移植后的血液嵌合性并促进HSC细胞分裂,从而支持G0S2在HSC增殖中的抑制作用。蛋白质组学研究表明,G0S2的疏水域与富含精氨酸-甘氨酸-甘氨酸重复序列的核仁素域相互作用,从而导致核仁素保留在胞质溶胶中。我们证明了核仁素的这种胞质保留发生在静止的而非增殖的野生型LSK CD150 + CD48-细胞中。总的来说,我们提出了一种新的HSC静止模型,其中升高的G0S2表达可以将核仁蛋白螯合在胞质溶胶中,从而排除其在核仁中的增殖功能。

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