The CKS1/CKS2 proteostasis axis is crucial to maintain hematopoietic stem cell function

Long-term hematopoietic stem cells are rare, highly quiescent stem cells of the hematopoietic system with life-long self-renewal potential and the ability to transplant and reconstitute the entire hematopoietic system of conditioned recipients. Most of our understanding of these rare cells has relied on cell surface identification, epigenetic and transcriptomic analyses. Our knowledge of protein synthesis, folding, modification and degradation – broadly termed protein homeostasis or “proteostasis” – in these cells is still in its infancy. Here we report the requirement of the small phospho-binding adaptor proteins, the cyclin dependent kinase subunits (Cks1 and Cks2), for maintaining ordered hematopoiesis and long-term hematopoietic stem cell reconstitution. Cks1 and Cks2 are critical regulators of a myriad of key intracellular signalling pathways that govern hematopoietic stem cell biology and together they balance protein homeostasis and restrain reactive oxygen species to ensure healthy hematopoietic stem cell function.

长期造血干细胞（long-term hematopoietic stem cells）是造血系统中一类罕见的高度静息干细胞，具备终身自我更新能力，且可移植并重建经预处理受体的完整造血系统。目前学界对这类稀有细胞的认知大多基于细胞表面标识鉴定、表观基因组学与转录组学分析。而学界对这类细胞中蛋白质合成、折叠、修饰与降解过程（广义上统称为蛋白质稳态（protein homeostasis）或"proteostasis"）的认知仍处于起步阶段。本研究阐明了小型磷酸结合衔接蛋白——细胞周期蛋白依赖性激酶亚基（Cks1与Cks2）在维持造血系统有序稳态与长期造血干细胞重建中的必需作用。Cks1与Cks2是调控诸多关键细胞内信号通路的核心调节因子，这些通路直接调控造血干细胞的生物学特性；二者协同维持蛋白质稳态，并抑制活性氧（reactive oxygen species），以保障造血干细胞的健康功能。