HectD1 controls hematopoietic stem cell regeneration by coordinating ribosome assembly and protein synthesis.
HectD1 controls hematopoietic stem cell regeneration by coordinating ribosome assembly and protein synthesis.
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DOI：
10.1016/j.stem.2021.02.008
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发表时间：
2021-07-01
期刊：
影响因子：
23.9
通讯作者：
Tong W
中科院分区：
文献类型：
--
作者：
Lv K;Gong C;Antony C;Han X;Ren JG;Donaghy R;Cheng Y;Pellegrino S;Warren AJ;Paralkar VR;Tong W
核糖体功能受损是一组称为核糖体病的骨髓衰竭综合征的根本病因。然而，核糖体是如何调控的仍然知之甚少，由于核糖体生物发生缺陷而恢复造血干细胞(HSC)功能的方法也是如此。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显著的缺陷，在应激条件下伴随着蛋白质合成和生长速度的降低。从机制上讲，HectD1泛素化并降解ZNF622，ZNF622是核糖体60S亚单位的组装因子。HectD1缺失导致ZNF622和抗结合因子eIF6在60s上积累，导致60s/40s连接缺陷。重要的是，在Hectd1缺陷的HSCs中，缺失了Znf622，恢复了核糖体亚基连接、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。童和他的同事发现了泛素依赖的核糖体组装和蛋白质合成调节在造血干细胞再生中的关键作用。E3连接酶Hectd1的缺失，通过促进其底物ZNF622在应激期间保留在再生的造血干细胞中，损害了核糖体亚单位的连接和蛋白质翻译的效率。
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 attributable to defective ribosome biogenesis. Here we reveal a role for 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 a 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 led to an accumulation of ZNF622 and the anti-association factor eIF6 on the 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. Tong and colleagues uncover a key role for ubiquitin-dependent regulation of ribosomal assembly and protein synthesis in hematopoietic stem cell regeneration. Depletion of an E3 ligase, Hectd1, impairs ribosomal subunit joining and protein translation efficiency by promoting retention of its substrate ZNF622 in regenerating hematopoietic stem cells during stress.
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