ZFIN ID: ZDB-PUB-150416-8
The mTORC1/4E-BP pathway coordinates hemoglobin production with L-leucine availability
Chung, J., Bauer, D.E., Ghamari, A., Nizzi, C.P., Deck, K.M., Kingsley, P.D., Yien, Y.Y., Huston, N.C., Chen, C., Schultz, I.J., Dalton, A.J., Wittig, J.G., Palis, J., Orkin, S.H., Lodish, H.F., Eisenstein, R.S., Cantor, A.B., Paw, B.H.
Date: 2015
Source: Science signaling   8: ra34 (Journal)
Registered Authors: Paw, Barry
Keywords: none
MeSH Terms:
  • Amino Acid Transport Systems, Basic/genetics
  • Amino Acid Transport Systems, Basic/metabolism
  • Animals
  • Animals, Genetically Modified
  • CRISPR-Cas Systems
  • Carrier Proteins/genetics
  • Carrier Proteins/metabolism*
  • Cell Line, Tumor
  • Cells, Cultured
  • Embryo, Mammalian/blood supply
  • Embryo, Mammalian/embryology
  • Embryo, Mammalian/metabolism
  • Embryo, Nonmammalian/embryology
  • Embryo, Nonmammalian/metabolism
  • Erythroid Cells/metabolism
  • Erythropoiesis/genetics
  • Eukaryotic Initiation Factors/genetics
  • Eukaryotic Initiation Factors/metabolism*
  • Gene Expression Regulation, Developmental
  • HEK293 Cells
  • Hemoglobins/genetics
  • Hemoglobins/metabolism*
  • Humans
  • Immunoblotting
  • Leucine/metabolism*
  • Mice
  • Microscopy, Confocal
  • Multiprotein Complexes/genetics
  • Multiprotein Complexes/metabolism*
  • Phosphoproteins/genetics
  • Phosphoproteins/metabolism*
  • RNA Interference
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction/genetics
  • TOR Serine-Threonine Kinases/genetics
  • TOR Serine-Threonine Kinases/metabolism*
  • Zebrafish
PubMed: 25872869 Full text @ Sci. Signal.
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. 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 (mammalian 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.