Developing red blood cells exhibit multiple, redundant systems for regulating and coordinating the uptake of iron, the synthesis of heme, and the formation of hemoglobin during terminal differentiation. We recently described the roles of poly rC-binding protein (PCBP1) and nuclear coactivator 4 (NCOA4) in mediating the flux of iron through ferritin in developing erythroid cells, with PCBP1, an iron chaperone, delivering iron to ferritin and NCOA4, an autophagic cargo receptor, directing ferritin to the lysosome for degradation and iron release. Ferritin iron flux is critical, as mice lacking these factors develop microcytic anemia. Here we report that these processes are regulated by cellular iron levels in a murine model of ex vivo terminal differentiation. PCBP1 delivers iron to ferritin via a direct protein-protein interaction. This interaction is developmentally regulated, enhanced by iron deprivation, and inhibited by iron excess, both in developing cells and in vitro. NCOA4 activity also exhibited developmental regulation and regulation by cellular iron levels. Excess iron uptake during differentiation triggered lysosomal degradation of NCOA4, which was dependent on the E3 ubiquitin ligase HERC2. Thus, developing red blood cells express a series of proteins that both mediate and regulate the flux of iron to the mitochondria.
|Number of pages||7|
|Journal||Blood Cells, Molecules, and Diseases|
|Publication status||Published - 2018 Mar|
Bibliographical noteFunding Information:
We thank Dr. Mitchell Weiss (St. Jude Children's Research Hospital, Memphis, Tennessee, USA) for the G1E-ER4 and CHO-KL cell lines. These studies were supported by the Intramural Research Program of NIDDK , NIH and the Office of Dietary Supplements, Office of the Director, NIH .
We thank Dr. Mitchell Weiss (St. Jude Children's Research Hospital, Memphis, Tennessee, USA) for the G1E-ER4 and CHO-KL cell lines. These studies were supported by the Intramural Research Program of NIDDK, NIH and the Office of Dietary Supplements, Office of the Director, NIH.
All Science Journal Classification (ASJC) codes
- Molecular Medicine
- Molecular Biology
- Cell Biology