TMEM187 is a novel brakelike modulator in the regulation of erythropoiesis

Abstract

Abstract Erythropoiesis, the process of red blood cell production, is highly dependent on iron uptake by transferrin and its receptor, transferrin receptor 1 (TfR1). However, 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 cell models 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 render the cells susceptible to macrophage recognition and phagocytosis. In zebrafish embryos, tmem187 deletion leads to enhanced early erythropoiesis, although this phenotype is later compensated, whereas hematopoietic stem cell expression of human TMEM187 in mice, which lack a homologous gene endogenously, results in compromised erythropoiesis and moderate anemia. Mechanistically, we demonstrate that TMEM187 interacts with RAB11A to restrain endosomal recycling by interfering with RAB11A–GRAB association, involved with endosomal vesicle back to the plasma membrane, that activates RAB11A. 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 on TMEM187's physiological function.