A coordinated translational control mediated by eEF2 phosphorylation safeguards erythroid differentiation

Translational control is crucial for maintaining cellular homeostasis, yet the distinct features and regulatory requirements governing protein synthesis during erythropoiesis remain unclear. Here, we identify significant phosphorylation of eukaryotic elongation factor 2 (eEF2) at threonine 56 during erythroid differentiation, which reduces protein synthesis and acts as a molecular brake to prevent unchecked erythropoiesis, as evidenced by elevated red blood cell counts in peripheral blood and increased incidence of thrombosis in eEF2_T56M mice, which are deficient in eEF2 phosphorylation.To dissect the translational programs regulating erythropoiesis mediated by eEF2 phosphorylation, we applied parallel RNA-sequencing (RNA-seq) and ribosome profiling (Ribo-seq) to Ter119+ erythroblasts isolated from WT and eEF2_T56M fetal livers to comprehensively analyze the translational regulatory networks during murine hematopoiesis.