Cul4A is required for hematopoietic stem-cell engraftment and self-renewal.
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.
Li
Binghui
B
Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Jia
Nan
N
Waning
David L
DL
Yang
Feng-Chun
FC
Haneline
Laura S
LS
Chun
Kristin T
KT
D000818:Animals; D049109:Cell Proliferation; D046528:Chimerism; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism*; D006085:Graft Survival; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic
C491940:Cul4a protein, mouse; D044842:Cullin Proteins