The tetraspanin CD53 protects stressed hematopoietic stem cells via promotion of DREAM complex-mediated quiescence. The tetraspanin CD53 protects stressed hematopoietic stem cells via promotion of DREAM complex-mediated quiescence

Hematopoietic stem cells (HSCs) cycle in response to inflammatory and other proliferative stressors; however, they must quickly return to quiescence to avoid exhaustion and maintain their functional integrity. The mechanisms that regulate this return to quiescence are not well understood. Here we show that the tetraspanin CD53 is markedly upregulated in HSCs in response to a variety of inflammatory and proliferative stimuli, and loss of CD53 is associated with prolonged cycling and reduced HSC function in the context of inflammatory stress. Mechanistically, CD53 promotes the activity of the DREAM transcriptional repressor complex, which downregulates genes associated with cycling and division. Proximity labeling and confocal fluorescent microscopy studies show that CD53 interacts with DREAM-associated proteins, specifically promoting the interaction between Rbl2/p130 and its phosphatase, PP2A, effectively stabilizing p130 protein availability for DREAM binding. Together, these data identify a novel mechanism by which stressed HSCs resist continued cycling. Overall design: We profiled HSCs (KSL CD48- CD150+) from the bone marrow and spleen of Cd53 KO mice and their WT littermates treated with G-CSF x 7 days or saline control

造血干细胞（Hematopoietic stem cells, HSCs）会响应炎症及其他增殖应激原而进入细胞周期循环，但它们必须快速恢复静息状态，以避免耗竭并维持功能完整性。目前学界对调控这一静息恢复过程的分子机制尚不清楚。本研究发现，四跨膜蛋白CD53在多种炎症与增殖刺激下，于HSCs中显著上调；而Cd53基因缺失会导致造血干细胞在炎症应激状态下出现周期延长、功能受损的表型。机制层面，CD53可增强DREAM转录抑制复合物的活性，该复合物能够下调与细胞周期循环及增殖分裂相关的基因。邻近标记与共聚焦荧光显微镜实验显示，CD53可与DREAM复合物相关蛋白发生相互作用，尤其可促进Rbl2/p130与其磷酸酶PP2A的结合，进而稳定p130蛋白的可获得性，以保障其与DREAM复合物的结合。综上，本研究揭示了应激状态下造血干细胞抵抗持续细胞周期循环的全新分子机制。实验整体设计：我们对经7天粒细胞集落刺激因子（G-CSF）处理或生理盐水对照处理的Cd53基因敲除（Knockout, KO）小鼠及其野生型（Wild type, WT）同窝小鼠的骨髓与脾脏中的造血干细胞（KSL CD48- CD150+）进行了表征分析。