Journal
CELL STEM CELL
Volume 28, Issue 7, Pages 1275-+Publisher
CELL PRESS
DOI: 10.1016/j.stem.2021.02.008
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Funding
- National Institute of Health [R01DK127738, R01HL095675]
- Department of Defense
- St. Baldrick's Foundation
- Alex's Lemonade Research Foundation
- Basser Center for BRCA Research
- NIH [R35 GM138035]
- Blood Cancer UK [12048]
- United Kingdom Medical Research Council [MR/T012412/1]
- Kay Kendall Leukaemia Fund
- Wellcome Trust strategic award [100140]
- Wellcome Trust
- MRC
- Connor Wright Project, the Cambridge National Institute for Health Research Biomedical Research Centre
- European Cooperation in Science and Technology (COST) Action [CA18233]
- Scientific and Technical Foundation of Shanxi Province [2020JM-015]
- MRC [MR/T012412/1] Funding Source: UKRI
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This study reveals the role of the E3 ubiquitin ligase HectD1 in regulating HSC function through ribosome assembly and protein translation. Deficiency of HectD1 leads to accumulation of ZNF622 and eIF6 on 60S, resulting in 60S/40S joining defects. Depletion of Znf622 in Hectdl-deficient HSCs restores ribosomal subunit joining and protein synthesis, highlighting the importance of ubiquitin-coordinated ribosome assembly in HSC regeneration.
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. Hectdi-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 Hectdl-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.
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