ECC1 is an erythroid Ca2+ channel that inhibits KLF1 during terminal erythropoiesis.

Abstract

Terminal erythropoiesis, the final stage of red blood cell maturation, is regulated by the erythropoietin (EPO)- JAK2-STAT5 pathway, which controls KLF1 expression. We identify ECC1 as a novel EPO-responsive Ca2+ channel that negatively regulates KLF1 transcription. EPO-activated ECC1 induces CaTF2 phosphorylation, nuclear translocation, and transcriptional inactivation of KLF1. Using HUDEP-2, and human pluripotent stem cells (hPSCs)-derived CD71+ erythroblasts, we observe ECC1 downregulation and reduced Ca2+ levels during terminal erythropoiesis. Forced inactivation of ECC1 enhances erythroid-specific genes by promoting KLF1 gene expression and accelerates erythroid maturation, increasing globin expression and enucleation. In late terminal erythropoiesis, as ECC1 levels decrease, KLF1 regulation shifts from ECC1-dependent CaTF2 to ECC1- independent JAK2-STAT5, thereby enhancing KLF1 transcription and erythroid maturation. This study uncovers a novel EPO-ECC1-Ca2+-CaTF2-KLF1 inhibitory signaling pathway, advancing our understanding of KLF1 gene regulation and suggesting strategies for increasing clinical RBC production by enhancing erythrocyte maturation.