Translational control by heme-regulated elF2α kinase during erythropoiesis

Abstract

Purpose of reviewHRI is the heme-regulated elF2α kinase that phosphorylates the α-subunit of elF2. Although the role of HRI in inhibiting globin synthesis in erythroid cells is well established, broader roles of HRI in translation have been uncovered recently. This review is to summarize the new discoveries of HRI in stress erythropoiesis and in fetal γ-globin expression.Recent findingsHRI and activating transcription factor 4 (ATF4) mRNAs are highly expressed in early erythroblasts. Inhibition of protein synthesis by HRI-phosphorylated elF2α (elF2αP) is necessary to maintain protein homeostasis in both the cytoplasm and mitochondria. In addition, HRI-elF2αP specifically enhances translation of ATF4 mRNA leading to the repression of mechanistic target of rapamycin complex 1 (mTORC1) signaling. ATF4-target genes are most highly activated during iron deficiency to maintain mitochondrial function, redox homeostasis, and to enable erythroid differentiation. HRI is therefore a master translation regulator of erythropoiesis sensing intracellular heme concentrations and oxidative stress for effective erythropoiesis. Intriguingly, HRI-elF2αP-ATF4 signaling also inhibits fetal hemoglobin production in human erythroid cells.SummaryThe primary function of HRI is to maintain protein homeostasis accompanied by the induction of ATF4 to mitigate stress. Role of HRI-ATF4 in γ-globin expression raises the potential of HRI as a therapeutic target for hemoglobinopathy.

Macrocytic anemias

“…Several cytoplasmic events during TED are unique, including: large accumulations of intracellular iron, extensive heme synthesis, balanced synthesis of α- and β-globins, assembly and accumulation of hemoglobin tetramers, conversion of aerobic to anerobic metabolism, and turnover or loss of specific organelles while assembling the erythrocyte plasma membrane and associated membrane skeleton. Increased intracellular iron and heme can be toxic via generation of reactive oxygen species (ROS) [36], while a stoichiometric balance of four hemes and two α- and two β-chain globins as components of hemoglobin is tightly regulated to avoid proteotoxicity [37]. In CFU-Es and Pro-EBs, increased iron importation induces heme synthesis that precedes globin synthesis, which is controlled by both heme and the zinc-finger erythroid transcription factor GATA1 [38].…”

“…Heme incorporated into hemoglobin does not generate ROS, and heme oxygenase decreases intracellular free heme. Heme also regulates translation of many mRNAs during TED, including those encoding globin chains, by binding heme-regulated eIF2α kinase (Heme-Regulated Inhibitor; HRI) [37]. Activity of eIF2α, the major translation initiation factor during TED, is downregulated via phosphorylation, and heme binding HRI decreases eIF2α phosphorylation, thereby increasing translation of globin mRNAs.…”

TMPRSS6 as a Therapeutic Target for Disorders of Erythropoiesis and Iron Homeostasis

“…Intracellular iron controls heme synthesis via the iron-regulatory proteins that inhibit translation by binding to the 5′-untranslated region of the mRNA encoding the rate-limiting enzyme of heme synthesis, erythroid-specific 5-aminolevulinate synthase (eALAS, a.k.a., ALAS2) [ 11 ]. The intracellular concentration of heme in turn translationally regulates the synthesis of globin chains, coordinating the stoichiometric requirements for normal Hb production [ 12 ]. Accordingly, erythrocytes produced under iron-deficient conditions contain less hemoglobin per cell than those produced under iron-sufficient conditions.…”

“…Under the same conditions, the translation of globin chains and some other erythrocyte proteins is inhibited by heme-regulated inhibitor (HRI, heme-regulated eIF2α-kinase) [ 41 ]. Here HRI also cross-talks with the mammalian target of rapamycin (mTOR) pathway to inhibit erythroblast protein synthesis during iron deficiency [ 12 ].…”

The Role and Therapeutic Potential of the Integrated Stress Response in Amyotrophic Lateral Sclerosis

“…Classically identified as a red blood cell modulator that adjusts globin mRNA translation to heme levels [ 48 , 49 ], new discoveries have illustrated a much broader regulatory role for this kinase, particularly in the central nervous system. Recently, Alvarez-Castelao and coworkers identified HRI as the main sensor and responder to deficiencies in the ubiquitin proteasome degradation.…”