HRI coordinates translation necessary for protein homeostasis and mitochondrial function in erythropoiesis
- Massachusetts Institute of Technology, United States
- Boston Children's Hospital, Harvard Medical School, United States
Abstract
Iron and heme play central roles in red blood cell production. However, the underlying mechanisms remain incompletely understood. HRI is a heme-regulated kinase that controls translation by phosphorylating eIF2a. 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 integrated stress response mRNAs during iron deficiency in vivo. Moreover, we find that translation of mRNAs encoding cytosolic and mitochondrial ribosomal proteins are substantially repressed by HRI in iron deficiency, causing a decrease in cytosolic and mitochondrial protein synthesis. The absence of HRI in 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 enable erythroid differentiation. We further identify GRB10 as a previously unappreciated regulator of terminal erythropoiesis.
Data availability
All sequencing data have been deposited in GEO under accession code GSE119365.
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Author details
Funding
National Institute of Diabetes and Digestive and Kidney Diseases (RO1 DK087984)
- Jane-Jane Chen
National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK103794)
- Vijay G Sankaran
National Heart, Lung, and Blood Institute (R33 HL120791)
- Vijay G Sankaran
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: Mice were maintained at the Massachusetts Institute of Technology (MIT) animal facility, and all experiments were carried out using protocols (#1015-099-18) approved by the Division of Comparative Medicine, MIT.
Copyright
© 2019, Zhang et al.
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.
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HRI coordinates translation necessary for protein homeostasis and mitochondrial function in erythropoiesis
eLife 8:e46976.
https://doi.org/10.7554/eLife.46976
