Erythropoiesis, the process of red blood cell production, is highly dependent on iron uptake via transferrin and its receptor, transferrin receptor 1 (TfR1), but the mechanisms governing the proper recycling of TfR1 in relation to cellular iron demands remain elusive. Here, we identify human TMEM187, a Golgi transmembrane protein of unknown function, as a novel negative regulator of erythropoiesis. Lack of TMEM187 in a cell model initiates erythropoiesis without the normal induction protocol and accelerates iron uptake. Following the induction protocol, TMEM187 ablation leads to premature erythroid maturation, resulting in early phosphatidylserine ectopia and cell membrane fragility, hallmarks of cellular senes... More
Erythropoiesis, the process of red blood cell production, is highly dependent on iron uptake via transferrin and its receptor, transferrin receptor 1 (TfR1), but the mechanisms governing the proper recycling of TfR1 in relation to cellular iron demands remain elusive. Here, we identify human TMEM187, a Golgi transmembrane protein of unknown function, as a novel negative regulator of erythropoiesis. Lack of TMEM187 in a cell model initiates erythropoiesis without the normal induction protocol and accelerates iron uptake. Following the induction protocol, TMEM187 ablation leads to premature erythroid maturation, resulting in early phosphatidylserine ectopia and cell membrane fragility, hallmarks of cellular senescence that renders the cells susceptible to macrophage recognition and phagocytosis. In zebrafish embryos, tmem187 deletion leads to enhanced early erythropoiesis, although the phenotype is later compensated, whereas hematopoietic stem-cell expression of human TMEM187 in mice, which lack endogenously a homologous gene, resulted in compromised erythropoiesis and moderate anemia. Mechanistically, we demonstrate that TMEM187 interacts with RAB11 to restrain endosomal recycling, interfering with RAB11-GRAB association that activates RAB11. Consequently, TMEM187 modulates TfR1 recycling to the cell membrane to fine-tune iron uptake efficiency for erythropoiesis. Our findings reveal a novel modulatory pathway in which TMEM187 plays a crucial role in regulating erythroid differentiation, maturation, and senescence, providing a previously unexplored perspective of TMEM187's physiological function.
