Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Division of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Cell Stem Cell. 2021 Jul 1;28(7):1275-1290.e9. doi: 10.1016/j.stem.2021.02.008. Epub 2021 Mar 11.
Impaired ribosome function is the underlying etiology in a group of bone marrow failure syndromes called ribosomopathies. However, how ribosomes are regulated remains poorly understood, as are approaches to restore hematopoietic stem cell (HSC) function loss because of defective ribosome biogenesis. Here we reveal a role of the E3 ubiquitin ligase HectD1 in regulating HSC function via ribosome assembly and protein translation. Hectd1-deficient HSCs exhibit a striking defect in transplantation ability and ex vivo maintenance concomitant with reduced protein synthesis and growth rate under stress conditions. Mechanistically, HectD1 ubiquitinates and degrades ZNF622, an assembly factor for the ribosomal 60S subunit. Hectd1 loss leads to accumulation of ZNF622 and the anti-association factor eIF6 on 60S, resulting in 60S/40S joining defects. Importantly, Znf622 depletion in Hectd1-deficient HSCs restored ribosomal subunit joining, protein synthesis, and HSC reconstitution capacity. These findings highlight the importance of ubiquitin-coordinated ribosome assembly in HSC regeneration.
核糖体功能障碍是一组被称为核糖体病的骨髓衰竭综合征的潜在病因。然而，核糖体如何被调节以及如何恢复由于核糖体生物发生缺陷导致的造血干细胞（HSC）功能丧失仍然知之甚少。在这里，我们揭示了 E3 泛素连接酶 HectD1 通过核糖体组装和蛋白质翻译来调节 HSC 功能的作用。Hectd1 缺陷的 HSCs 在移植能力和体外维持方面表现出明显的缺陷，同时在应激条件下蛋白质合成和生长速率降低。在机制上，HectD1 泛素化和降解 ZNF622，这是核糖体 60S 亚基的组装因子。Hectd1 的缺失导致 ZNF622 和反关联因子 eIF6 在 60S 上的积累，导致 60S/40S 结合缺陷。重要的是，在 Hectd1 缺陷的 HSCs 中耗尽 Znf622 恢复了核糖体亚基结合、蛋白质合成和 HSC 重建能力。这些发现强调了泛素协调的核糖体组装在 HSC 再生中的重要性。
