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Elife. 2019 Apr 29;8. pii: e46976. doi: 10.7554/eLife.46976.

HRI coordinates translation necessary for protein homeostasis and mitochondrial function in erythropoiesis.

Author information

1
Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, United States.
2
Division of Hematology/Oncology, Boston Children's Hospital, Harvard Medical School, Boston, United States.
3
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States.
4
Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, United States.
5
Program in Biological and Biomedical Sciences, Harvard University, Cambridge, United States.
6
BioMicro Center, Massachusetts Institute of Technology, Cambridge, United States.

Abstract

Iron and heme play central roles in the production of red blood cells, but the underlying mechanisms remain incompletely understood. Heme-regulated eIF2α kinase (HRI) controls translation by phosphorylating eIF2α. Here, we investigate the global impact of iron, heme, and HRI on protein translation in vivo in murine primary erythroblasts using ribosome profiling. We validate the known role of HRI-mediated translational stimulation of integratedstressresponse mRNAs during iron deficiency in vivo. Moreover, we find that the translation of mRNAs encoding cytosolic and mitochondrial ribosomal proteins is substantially repressed by HRI during iron deficiency, causing a decrease in cytosolic and mitochondrial protein synthesis. The absence of HRI during iron deficiency elicits a prominent cytoplasmic unfolded protein response and impairs mitochondrial respiration. Importantly, ATF4 target genes are activated during iron deficiency to maintain mitochondrial function and to enable erythroid differentiation. We further identify GRB10 as a previously unappreciated regulator of terminal erythropoiesis.

KEYWORDS:

ATF4; cell biology; chromosomes; cytosolic and mitochondrial translation; erythropoiesis; gene expression; heme-regulated eIF2a kinase; integrated stress response; mitochondrial respiration; mouse

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