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Sci Signal. 2015 Apr 14;8(372):ra34. doi: 10.1126/scisignal.aaa5903.

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

Author information

1
Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
2
Division of Hematology-Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
3
Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI 53706, USA.
4
Department of Pediatrics, Center for Pediatric Biomedical Research, University of Rochester Medical Center, Rochester, NY 14642, USA.
5
Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02142, USA.
6
Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Division of Hematology-Oncology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA. Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA. bpaw@rics.bwh.harvard.edu.

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. 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.

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PMID:
25872869
PMCID:
PMC4402725
DOI:
10.1126/scisignal.aaa5903
[Indexed for MEDLINE]
Free PMC Article

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