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

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.

journal_name

Elife

journal_title

eLife

authors

Zhang S,Macias-Garcia A,Ulirsch JC,Velazquez J,Butty VL,Levine SS,Sankaran VG,Chen JJ

doi

10.7554/eLife.46976

subject

Has Abstract

pub_date

2019-04-29 00:00:00

issn

2050-084X

pii

46976

journal_volume

8

pub_type

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