Essential role of FBXL5-mediated cellular iron homeostasis in maintenance of hematopoietic stem cells.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 28714470.
- Also identified by DOI 10.1038/ncomms16114 and PMC identifier 5520054.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Hematopoietic stem cells (HSCs) are maintained in a hypoxic niche to limit oxidative stress. Although iron elicits oxidative stress, the importance of iron homeostasis in HSCs has been unknown. Here we show that iron regulation by the F-box protein FBXL5 is required for HSC self-renewal. Conditional deletion of Fbxl5 in mouse HSCs results in cellular iron overload and a reduced cell number. Bone marrow transplantation reveals that FBXL5-deficient HSCs are unable to reconstitute the hematopoietic system of irradiated recipients as a result of stem cell exhaustion. Transcriptomic analysis shows abnormal activation of oxidative stress responses and the cell cycle in FBXL5-deficient mouse HSCs as well as downregulation of FBXL5 expression in HSCs of patients with myelodysplastic syndrome. Suppression of iron regulatory protein 2 (IRP2) accumulation in FBXL5-deficient mouse HSCs restores stem cell function, implicating IRP2 as a potential therapeutic target for human hematopoietic diseases associated with FBXL5 downregulation.
Medical subject headings
- Cell Self Renewal
- F-Box Proteins
- Hematopoietic Stem Cells
- Homeostasis
- Iron
- Myelodysplastic Syndromes
- Oxidative Stress
- Ubiquitin-Protein Ligase Complexes