The mTORC1/4E-BP pathway coordinates hemoglobin production with L-leucine availability
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 erythropoies...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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American Association for the Advancement of Science (AAAS)
2017
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| Online Access: | http://hdl.handle.net/1721.1/108695 https://orcid.org/0000-0002-7029-7415 |
| _version_ | 1826216617179086848 |
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| author | 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. Eisenstein, R. S. Cantor, A. B. Paw, B. H. Lodish, Harvey F |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology 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. Eisenstein, R. S. Cantor, A. B. Paw, B. H. Lodish, Harvey F |
| author_sort | Chung, J. |
| collection | MIT |
| description | 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. |
| first_indexed | 2024-09-23T16:49:58Z |
| format | Article |
| id | mit-1721.1/108695 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T16:49:58Z |
| publishDate | 2017 |
| publisher | American Association for the Advancement of Science (AAAS) |
| record_format | dspace |
| spelling | mit-1721.1/1086952022-10-03T08:38:07Z 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. Eisenstein, R. S. Cantor, A. B. Paw, B. H. Lodish, Harvey F Massachusetts Institute of Technology. Department of Biology Whitehead Institute for Biomedical Research Lodish, Harvey F 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. National Institutes of Health (U.S.) (P01 HL032262) 2017-05-05T14:47:25Z 2017-05-05T14:47:25Z 2015-04 2015-01 Article http://purl.org/eprint/type/JournalArticle 1945-0877 1937-9145 http://hdl.handle.net/1721.1/108695 Chung, J. et al. “The mTORC1/4E-BP Pathway Coordinates Hemoglobin Production with L-Leucine Availability.” Science Signaling 8.372 (2015): ra34-ra34. https://orcid.org/0000-0002-7029-7415 en_US http://dx.doi.org/10.1126/scisignal.aaa5903 Science Signaling Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf American Association for the Advancement of Science (AAAS) PMC |
| spellingShingle | 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. Eisenstein, R. S. Cantor, A. B. Paw, B. H. Lodish, Harvey F The mTORC1/4E-BP pathway coordinates hemoglobin production with L-leucine availability |
| title | The mTORC1/4E-BP pathway coordinates hemoglobin production with L-leucine availability |
| title_full | The mTORC1/4E-BP pathway coordinates hemoglobin production with L-leucine availability |
| title_fullStr | The mTORC1/4E-BP pathway coordinates hemoglobin production with L-leucine availability |
| title_full_unstemmed | The mTORC1/4E-BP pathway coordinates hemoglobin production with L-leucine availability |
| title_short | The mTORC1/4E-BP pathway coordinates hemoglobin production with L-leucine availability |
| title_sort | mtorc1 4e bp pathway coordinates hemoglobin production with l leucine availability |
| url | http://hdl.handle.net/1721.1/108695 https://orcid.org/0000-0002-7029-7415 |
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