A critical role for mTORC1 in erythropoiesis and anemia

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Abstract

Red blood cells (RBC) must coordinate their rate of growth and proliferation with the availability of nutrients, such as iron, but the signaling mechanisms that link nutritional state to RBC growth are incompletely understood. We performed a screen for cell types that have high levels of signaling through mTORC1, a protein kinase that couples nutrient availability to cell growth. This screen revealed that reticulocytes show high levels of phosphorylated ribosomal protein S6, a downstream target of mTORC1. We found that mTORC1 activity in RBCs is regulated by dietary iron, and that genetic activation or inhibition of mTORC1 results in macrocytic or microcytic anemia, respectively. Finally, ATP competitive mTOR inhibitors reduced RBC proliferation and were lethal after treatment with phenylhydrazine, an inducer of hemolysis. These results identify the mTORC1 pathway as a critical regulator of RBC growth and proliferation, and establish that perturbations in this pathway result in anemia.

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Zachary A Knight

University of California, San Francisco, San Francisco, United States

Competing interests
The authors declare that no competing interests exist.
Sarah F Schmidt

Howard Hughes Medical Institute, The Rockefeller University, New York, United States

Competing interests
The authors declare that no competing interests exist.
Kivanc Birsoy

Whitehead Institute for Biomedical Research, Cambridge, United States

Competing interests
The authors declare that no competing interests exist.
Keith Tan

Howard Hughes Medical Institute, The Rockefeller University, New York, United States

Competing interests
The authors declare that no competing interests exist.
Jeffrey M Friedman

Howard Hughes Medical Institute, The Rockefeller University, New York, United States

For correspondence
friedj@rockefeller.edu

Competing interests
The authors declare that no competing interests exist.

Ethics

Animal experimentation: All procedures were carried out in accordance with the National Institutes of Health Guidelines on the Care and Use of Animals and approved by the Rockefeller University Institutional Animal Care and Use Committee (Protocol #12530).

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.