2. Academic Validation
  3. 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

  • Cell Stem Cell. 2021 Jul 1;28(7):1275-1290.e9. doi: 10.1016/j.stem.2021.02.008.
Kaosheng Lv 1,  Chujie Gong 1,  Charles Antony 2,  Xu Han 1,  Jian-Gang Ren 1,  Ryan Donaghy 1,  Ying Cheng 1,  Simone Pellegrino 3,  Alan J Warren 3,  Vikram R Paralkar 2,  Wei Tong 4
Affiliations

Affiliations

  • 1 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.
  • 2 Division of Hematology-Oncology, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 3 Cambridge Institute for Medical Research, Cambridge, UK; Department of Haematology, University of Cambridge, Cambridge, UK; Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, UK.
  • 4 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. Electronic address: tongw@chop.edu.
PMID: 33711283 DOI: 10.1016/j.stem.2021.02.008
Abstract

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.

Keywords

HSC regeneration; HectD1; Polypeptide exit tunnel; ZNF622; hematopoietic stem cells; protein synthesis; ribosome assembly; ribosome biogenesis; signaling; ubiquitin.

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