Research ArticlePhysiology

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

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Science Signaling  14 Apr 2015:
Vol. 8, Issue 372, pp. ra34
DOI: 10.1126/scisignal.aaa5903

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Red cells need leucine to make hemoglobin

Inhibitors of the protein complex mTORC1 are used in the clinic, but they can cause anemia. Limitation of nutrients, such as amino acids, inhibits mTORC1 activity, which reduces protein synthesis by enhancing the activity of the translation inhibitor protein 4E-BP. The oxygen-carrying protein complex hemoglobin in red blood cells contains globin proteins, which have a particularly high percentage of leucine residues, leading Chung et al. to investigate the role of mTORC1 in hemoglobin production. Deficiency or inhibition of LAT3, an uptake transporter for l-leucine, prevented hemoglobin production in zebrafish and mouse red blood cells. Inadequate l-leucine uptake prevented the translation of globin-encoding transcripts. Thus, red cell function critically depends on 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. 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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