Releasing the brake on protein synthesis in hematopoietic stem cells
| Autor: | Davide Ruggero, Craig M. Forester |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Eukaryotic Large Ribosomal Subunit
Protein subunit Cell Translation (biology) Cell Differentiation Cell Biology Biology Hematopoietic Stem Cells Article Cell biology Haematopoiesis medicine.anatomical_structure Genetics medicine Protein biosynthesis Molecular Medicine Eukaryotic Small Ribosomal Subunit Stem cell |
| Zdroj: | Cell Stem Cell |
| ISSN: | 1875-9777 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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