Enhanced ribosome biogenesis and protein synthesis are required for cell proliferation. During hematopoietic regeneration, hematopoietic stem cells (HSCs) proliferate rapidly to replenish the hematopoietic system. How HSCs respond and regulate ribosome biogenesis and protein synthesis during regeneration remains unclear. Here, we analyzed the expression of a series of ubiquitin-specific-proteases (USPs) during HSC regeneration. We found USP4 expression is significantly increased in proliferating HSCs. Further functional and mechanistic investigations revealed a crucial regulatory function of USP4 in HSC regeneration and leukemia progression by modulating ribosome biogenesis and protein synthesis. USP4 deubiquitinates and stabilizes PES1 to facilitate ribosome biogenesis and protein synthesis in proliferative HSCs and leukemic cells. Usp4 deletion significantly decreases protein synthesis, proliferation and reconstitution capacity of HSCs. Usp4 inhibition suppresses ribosome biogenesis and proliferation of leukemic cells, and prolongs the survival of AML (Acute myeloid leukemia) mice. These findings provide a new insight into the response mechanism of ribosome biogenesis and protein synthesis in HSCs, and their contribution to leukemia progression.

增强的核糖体生物发生和蛋白质合成是细胞增殖所必需的。在造血再生过程中，造血干细胞 （HSC） 迅速增殖以补充造血系统。HSC 在再生过程中如何响应和调节核糖体生物发生和蛋白质合成仍不清楚。在这里，我们分析了 HSC 再生过程中一系列泛素特异性蛋白酶 （USP） 的表达。我们发现 USP4 表达在增殖的 HSC 中显着增加。进一步的功能和机制研究揭示了 USP4 通过调节核糖体生物发生和蛋白质合成在 HSC 再生和白血病进展中的关键调节功能。USP4 去泛素化和稳定 PES1，以促进增殖性 HSC 和白血病细胞中的核糖体生物发生和蛋白质合成。Usp4 缺失显着降低 HSC 的蛋白质合成、增殖和重建能力。Usp4 抑制抑制白血病细胞的核糖体生物发生和增殖，并延长 AML （急性髓性白血病） 小鼠的存活时间。这些发现为 HSC 中核糖体生物发生和蛋白质合成的反应机制及其对白血病进展的贡献提供了新的见解。