Regulation of eIF4E guides a unique translational program to control erythroid maturation
Craig M. Forester, Juan A. Osés-Prieto, Nancy J. Phillips, Sohit Miglani, Xiaming Pang, Gun Woo Byeon, Rachel Demarco, Al Burlingame, Maria Barna, Davide Ruggero
Abstract
Translation control is essential in balancing hematopoietic precursors and differentiation; however, the mechanisms underlying this program are poorly understood. We found that the activity of the major cap-binding protein eIF4E is unexpectedly regulated in a dynamic manner throughout erythropoiesis that is uncoupled from global protein synthesis rates. Moreover, eIF4E activity directs erythroid maturation, and increased eIF4E expression maintains cells in an early erythroid state associated with a translation program driving the expression of PTPN6 and Igf2bp1. A cytosine-enriched motif in the 5' untranslated region is important for eIF4E-mediated translation specificity. Therefore, selective translation of key target genes necessary for the maintenance of early erythroid states by eIF4E highlights a unique mechanism used by hematopoietic precursors to rapidly elicit erythropoietic maturation upon need.