Scara5 Is a Ferritin Receptor Mediating Non-Transferrin Iron Delivery

Abstract

Summary Developing organs require iron for a myriad of functions, but embryos deleted of the major adult transport protein, transferrin or its receptor transferrin receptor1 (TfR1−/−) initiate organogenesis, suggesting that non-transferrin pathways are important. To examine these pathways, we developed chimeras composed of fluorescence-tagged TfR1−/− cells and untagged wild type cells. In the kidney, TfR1−/− cells populated capsule and stroma, mesenchyme and nephron, but were underrepresented in ureteric bud tips. Consistently, TfR1 provided transferrin to the ureteric bud, but not to the capsule or the stroma. Instead of transferrin, we found that the capsule internalized ferritin. Since the capsule expressed a novel receptor called Scara5, we tested its role in ferritin uptake and found that Scara5 bound serum ferritin and stimulated its endocytosis from the cell surface with consequent iron delivery. These data implicate cell type-specific mechanisms of iron traffic in organogenesis, which alternatively utilize transferrin or non-transferrin iron delivery pathways.

Identification of iron-loaded ferritin as an essential mitogen for cell proliferation and postembryonic development in Drosophila

“…For example, serum ferritin regulates vascular remodeling and angiogenesis, suggesting a role for serum ferritin in cell proliferation [23]. Recently, two ferritin receptors, Tim-2, which binds ferritin heavy chain [24,25], and Scara5, which binds ferritin light chain [26], have been identified. The mammalian ferritin receptors bind serum ferritin, stimulate its endocytosis from the cell surface with consequent iron delivery, and thus promote cell proliferation and organogenesis [23].…”

Cell sensitivity to oxidative stress is influenced by ferritin autophagy

“…Ferritin can also be taken up by a recently found ferritin receptor called Scara5 [18] and, interestingly, the H subunit of circulating ferritin even by the transferrin receptor-1 [19].…”

Apoferritin: protein nanocarrier for targeted delivery

“…However, these receptors can be found not only on cancer cell membranes but also on the surface of many healthy cells [98], such as TfR1 in kidney cells. Therefore, it is better to modify the surface of apoferritin with actively targeting moieties, which can also increase its size.…”