The mTORC1/4E-BP pathway coordinates hemoglobin production with L -leucine availability

Abstract

In multicellular organisms, the mechanisms by which diverse cell types acquire distinct amino acids and how cellular function adapts to their availability are fundamental questions in biology. Here, we found that increased neutral essential amino acid (NEAA) uptake was a critical component of erythropoiesis. As red blood cells matured, expression of the amino acid transporter gene Lat3 increased, which increased NEAA import. Inadequate NEAA uptake by pharmacologic inhibition or RNAi-mediated knockdown of LAT3 triggered a specific reduction in hemoglobin production in zebrafish embryos and murine erythroid cells through the mTORC1 (mechanistic target of rapamycin complex 1)/4E-BP (eukaryotic translation initiation factor 4E-binding protein) pathway. CRISPR-mediated deletion of members of the 4E-BP family in murine erythroid cells rendered them resistant to mTORC1 and LAT3 inhibition and restored hemoglobin production. These results identify a developmental role for LAT3 in red blood cells and demonstrate that mTORC1 serves as a homeostatic sensor that couples hemoglobin production at the translational level to sufficient uptake of NEAAs, particularly L-leucine.

Improved Fetal Hemoglobin With mTOR Inhibitor–Based Immunosuppression in a Kidney Transplant Recipient With Sickle Cell Disease

“…It has been previously shown that the mTOR pathway is involved in regulating the growth and proliferation of red blood cells, both in vitro and in vivo . The mTOR complex 1 pathway has been identified as a critical regulator of red blood cell growth and proliferation . The use of mTOR inhibitors in normal and β‐thalassemia patients has increased; in vitro, the expression of fetal hemoglobin is increased to higher levels than those obtained with hydroxyurea .…”

FAM210B is an erythropoietin target and regulates erythroid heme synthesis by controlling mitochondrial iron import and ferrochelatase activity

“…To determine how Fam210b is developmentally regulated, we performed RNA sequencing (RNAseq) on transcripts from murine fetal liver erythroid cells (34) that were sorted into fractions corresponding to their stage of maturation (R1-R5) (15, [37][38][39]. Fam210b expression was up-regulated during maturation from R2 to R3, which corresponds to the developmental shift from TER119 Ϫ to TER119 ϩ expression.…”

Perspective: The Potential Role of Essential Amino Acids and the Mechanistic Target of Rapamycin Complex 1 (mTORC1) Pathway in the Pathogenesis of Child Stunting

“…mTORC1 regulates hematopoietic stem cell renewal and differentiation (108) and hematopoiesis through raptor (109). mTORC1 also regulates erythrocyte growth and proliferation (110) and hemoglobin synthesis (111). Cellular iron homeostasis is modulated by the iron-responsive element/iron-regulatory protein (IRE/IRP) regulatory network (112) and hepcidin (113).…”