The mTORC1/4E-BP pathway coordinates hemoglobin production with L-leucine availability
Name
Lodish_The mtorc1.pdf
Size
1.24 MB
Format
Adobe PDF
Checksum (MD5)
ce118a789306d93c07f730f7f93f011f
Author(s)
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.
Date Issued
April 2015
Journal
Science Signaling
Publisher
American Association for the Advancement of Science (AAAS)
Citation
Chung, J. et al. “The mTORC1/4E-BP Pathway Coordinates Hemoglobin Production with L-Leucine Availability.” Science Signaling 8.372 (2015): ra34-ra34.
Version
Author's final manuscript
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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Whitehead Institute for Biomedical Research
Terms of Use
Creative Commons Attribution-Noncommercial-Share Alike
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1126/scisignal.aaa5903
