E3泛素连接酶Cul5调节小鼠稳态造血干细胞功能。

Siera A Tomishima,Dale D Kim,Nadia Porter,Ipsita Guha,Asif A Dar,Yohaniz Ortega-Burgos,Jennifer Roof,Hossein Fazelinia,Lynn A Spruce,Christopher S Thom,Robert L Bowman,Paula M Oliver
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引用次数: 0

摘要

造血干细胞(HSC)自我更新与分化之间的平衡对于确保长期再生能力至关重要,同时允许对需要增加造血输出的事件做出反应。造血干细胞及其后代的增殖分化受细胞因子信号下游的JAK/STAT通路控制。E3泛素连接酶,如Cullin 5 (Cul5),可以通过降解信号中间体调节JAK/STAT信号。在这里,我们报告了造血细胞(Cul5Vav-Cre)中缺乏Cul5的小鼠,HSPCs的数量增加,脾肿大和髓外造血。Cul5Vav-Cre小鼠的分化倾向于骨髓和巨核细胞,导致白细胞增多、贫血和血小板增多。Cul5Vav-Cre小鼠增加HSC增殖和循环,与CXCR4表面表达降低有关。在骨髓细胞中,我们发现LRRC41与CUL5共免疫沉淀,反之亦然,支持CRL5与LRRC41形成复合物。我们发现在IL-3刺激期间Cul5Vav-Cre hsc中LRRC41和STAT5的积累,支持Cul5对它们的调节。Cul5Vav-Cre骨髓HSPCs的全细胞蛋白质组(WCP)分析发现,许多STAT5靶基因和相关途径上调。最后,ruxolitinib对Cul5Vav-Cre小鼠正常造血的JAK1/2抑制作用。这些研究证明了Cul5在造血干细胞功能、干细胞命运决定和IL-3信号传导调节中的功能。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
The E3 ubiquitin ligase Cul5 regulates hematopoietic stem cell function for steady-state hematopoiesis in mice.
The balance of hematopoietic stem cell (HSC) self-renewal versus differentiation is essential to ensure long-term repopulation capacity while allowing response to events that require increased hematopoietic output. Proliferation and differentiation of HSCs and their progeny is controlled by the JAK/STAT pathway downstream of cytokine signaling. E3 ubiquitin ligases, like Cullin 5 (Cul5), can regulate JAK/STAT signaling by degrading signaling intermediates. Here we report that mice lacking Cul5 in hematopoietic cells (Cul5Vav-Cre) have increased numbers of HSPCs, splenomegaly, and extramedullary hematopoiesis. Differentiation in Cul5Vav-Cre mice is myeloid- and megakaryocyte-biased, resulting in leukocytosis, anemia and thrombocytosis. Cul5Vav-Cre mice increased HSC proliferation and circulation, associated with a decrease in CXCR4 surface expression. In bone marrow cells, we identified LRRC41 co-immunoprecipitated with CUL5, and vice versa, supporting that CRL5 forms a complex with LRRC41. We identified an accumulation of LRRC41 and STAT5 in Cul5Vav-Cre HSCs during IL-3 stimulation, supporting their regulation by Cul5. Whole cell proteome (WCP) analysis of HSPCs from Cul5Vav-Cre bone marrow identified upregulation of many STAT5 target genes and associated pathways. Finally, JAK1/2 inhibition with ruxolitinib normalized hematopoiesis in Cul5Vav-Cre mice. These studies demonstrate the function of Cul5 in HSC function, stem cell fate decisions, and regulation of IL-3 signaling.
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