Several hematopoietic stem-cell (HSC) regulators are controlled by ubiquitin-mediated proteolysis, so the ubiquitin pathway might modulate HSC function. However, this hypothesis has not been formally tested. Cul4A encodes a core subunit of one ubiquitin ligase. Whereas Cul4A-deficient embryos die in utero, Cul4A-haploinsufficient mice are viable but exhibit abnormal hematopoiesis (fewer erythroid and primitive myeloid progenitors). Given these data, we examined whether Cul4A+/- HSCs might also be impaired. Using bone marrow transplantation assays, we determined that Cul4A+/- HSCs exhibit defects in engraftment and self-renewal capacity. These studies are the first to demonstrate that ubiquitin-mediated protein degradation is important for HSC function. Further, they indicate that a Cul4A ubiquitin ligase targets for degradation one or multiple HSC regulators.
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