Response of EIF2AK1 (HRI) to heme deficiency

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R-HSA-9648895
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Pathway
Species
Homo sapiens
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The kinases of the integrated stress response phosphorylate EIF2S1 (eIF2-alpha) to regulate cellular translation. The kinases comprise PERK (also called EIF2AK3), which responds to unfolded protein in the endoplasmic reticulum; EIF2AK2 (also called PKR), which responds to cytosolic double-stranded RNA; EIF2AK4 (also called GCN2), which responds to amino acid deficiency; and EIF2AK1 (also called heme-regulated inhibitor, HRI, and heme-controlled repressor, HCR), which responds to heme deficiency and cytosolic unfolded protein. Each molecule of EIF2AK1 binds two molecules of heme, one bound near the N-terminus and one bound at the kinase insert (KI) domain that inhibits the kinase activity of EIF2AK1 (inferred from the rabbit homolog in Chefalo et al. 1998, Rafie-Kolpin et al. 2000, inferred from the mouse homolog in Misanova et al. 2006, Hirai et al. 2007, Igarashi et al. 2008). Dissociation of heme from the KI domain activates the kinase activity of EIF2AK1, which autophosphorylates (inferred from the mouse homolog in Bauer et al. 2001, Rafie-Kolpin et al. 2003, Igarashi et al. 2011) and then phosphorylates EIF2S1 (Bhavnani et al. 2018, inferred from the rabbit homologs in Chefalo et al. 1998, Rafie-Kolpin et al. 2000, inferred from the mouse homologs in Lu et al. 2001, Rafie-Kolpin et al. 2003, Igarashi et al. 2011).
Phosphorylated EIFS1 causes a reduction in general cellular translation and thereby coordinates globin synthesis with heme availability during erythropoiesis (inferred from mouse knockout in Han et al. 2001, reviewed in Chen et al. 2014). Translation of mitochondrial and cytosolic ribosomal proteins is most severely reduced, causing a decrease in cellular protein synthesis (inferred from mouse homologs in Zhang et al. 2019). Lack of EIF2AK1 causes accumulation of unfolded globins devoid of heme and consequent anemia in iron-deficient mice (inferred from mouse knockout in Han et al. 2001). Activation of the cytoplasmic unfolded protein response and impaired mitochondrial respiration are also observed in HRI deficiency (inferred from mouse homologs in Zhang et al. 2019).
Phosphorylation of EIFS1 activates translation of certain mRNAs such as ATF4, ATF5, and DDIT3 (CHOP) that have upstream ORFs (inferred from mouse homologs in Harding et al. 2000). ATF4 in turn activates programs of gene expression that ameliorate effects of the stress to maintain mitochondrial function, redox homeostasis, and erythroid differentiation (inferred from mouse homologs in Zhang et al. 2019). Unresolved stress, however, can eventually lead to apoptosis regulated by DDIT3. EIF2AK1 also represses mTORC1 (mechanistic target of mechanistic target of rapamycin complex 1) signaling via ATF4-mediated induction of GRB10 as a feedback mechanism to attenuate erythropoietin-mTORC1-stimulated ineffective erythropoiesis in iron deficiency anemia (inferred from mouse homologs in Zhang et al. 2018 and Zhang et. al. 2019).
EIF2AK1 is also activated by heat shock, arsenite (oxidative stress), and osmotic stress (inferred from mouse homologs in Lu et al. 2001). The mechanisms by which these stresses act on EIF2AK1 are independent of heme but are not yet fully elucidated. Furthermore, EIF2AK1 is involved in the production of human fetal hemoglobin, and EIF2AK1-mediated stress response has emerged as a potential therapeutic target for hemoglobinopathies (reviewed in Chen and Zhang 2019).
In addition to regulation of erythropoiesis, EIF2AK1 shows effects outside of the erythroid lineage, including requirement for the maturation and functions of macrophages (inferred from mouse homologs in Liu et al. 2007), reduction in endoplasmic reticulum stress in hepatocytes, activation of hepatic expression of fibroblast growth factor, and mediation of translation of GRIN2B (GluN2B. a subunit of the NMDA receptor) and BACE1 in the nervous system (reviewed in Burwick and Aktas 2017). HRI-integrated stress response is activated in human cancer cell lines and primary multiple myeloma cells, and has emerged as a molecular target of anticancer agents (reviewed in Burwick and Aktas 2017; reviewed in Chen and Zhang 2019).

Literature References
PubMed ID Title Journal Year
24714526 Translational control by heme-regulated eIF2α kinase during erythropoiesis

Chen, JJ

Curr. Opin. Hematol. 2014
29101239 HRI coordinates translation by eIF2αP and mTORC1 to mitigate ineffective erythropoiesis in mice during iron deficiency

Zhang, S, Macias-Garcia, A, Velazquez, J, Paltrinieri, E, Kaufman, RJ, Chen, JJ

Blood 2018
11560503 Multiple autophosphorylation is essential for the formation of the active and stable homodimer of heme-regulated eIF2alpha kinase

Bauer, BN, Rafie-Kolpin, M, Lu, L, Han, A, Chen, JJ

Biochemistry 2001
12767237 Autophosphorylation of threonine 485 in the activation loop is essential for attaining eIF2alpha kinase activity of HRI

Rafie-Kolpin, M, Han, AP, Chen, JJ

Biochemistry 2003
11689689 Translation initiation control by heme-regulated eukaryotic initiation factor 2alpha kinase in erythroid cells under cytoplasmic stresses

Lu, L, Han, AP, Chen, JJ

Mol. Cell. Biol. 2001
31033440 HRI coordinates translation necessary for protein homeostasis and mitochondrial function in erythropoiesis

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

Elife 2019
18450746 Elucidation of the heme binding site of heme-regulated eukaryotic initiation factor 2alpha kinase and the role of the regulatory motif in heme sensing by spectroscopic and catalytic studies of mutant proteins

Igarashi, J, Murase, M, Iizuka, A, Pichierri, F, Martinkova, M, Shimizu, T

J. Biol. Chem. 2008
9874252 Heme-regulated eIF-2alpha kinase purifies as a hemoprotein

Chefalo, PJ, Oh, J, Rafie-Kolpin, M, Kan, B, Chen, JJ

Eur. J. Biochem. 1998
23354059 The eIF2α kinases: their structures and functions

Donnelly, N, Gorman, AM, Gupta, S, Samali, A

Cell. Mol. Life Sci. 2013
28814160 Elucidation of molecular mechanism of stability of the heme-regulated eIF2α kinase upon binding of its ligand, hemin in its catalytic kinase domain

Bhavnani, V, Kaviraj, S, Panigrahi, P, Suresh, CG, Yapara, S, Pal, J

J. Biomol. Struct. Dyn. 2018
21223507 Autophosphorylation of heme-regulated eukaryotic initiation factor 2α kinase and the role of the modification in catalysis

Igarashi, J, Sasaki, T, Kobayashi, N, Yoshioka, S, Matsushita, M, Shimizu, T

FEBS J. 2011
17597215 Identification of Cys385 in the isolated kinase insertion domain of heme-regulated eIF2 alpha kinase (HRI) as the heme axial ligand by site-directed mutagenesis and spectral characterization

Hirai, K, Martinkova, M, Igarashi, J, Saiful, I, Yamauchi, S, El-Mashtoly, S, Kitagawa, T, Shimizu, T

J. Inorg. Biochem. 2007
11726526 Heme-regulated eIF2alpha kinase (HRI) is required for translational regulation and survival of erythroid precursors in iron deficiency

Han, AP, Yu, C, Lu, L, Fujiwara, Y, Browne, C, Chin, G, Fleming, M, Leboulch, P, Orkin, SH, Chen, JJ

EMBO J. 2001
10671563 Two heme-binding domains of heme-regulated eukaryotic initiation factor-2alpha kinase. N terminus and kinase insertion

Rafie-Kolpin, M, Chefalo, PJ, Hussain, Z, Hahn, J, Uma, S, Matts, RL, Chen, JJ

J. Biol. Chem. 2000
31554636 Heme-regulated eIF2alpha kinase in erythropoiesis and hemoglobinopthies

Chen, JJ, Zhang, S

Blood 2019
17932563 The function of heme-regulated eIF2alpha kinase in murine iron homeostasis and macrophage maturation

Liu, S, Suragani, RN, Wang, F, Han, A, Zhao, W, Andrews, NC, Chen, JJ

J. Clin. Invest. 2007
11106749 Regulated translation initiation controls stress-induced gene expression in mammalian cells

Harding, HP, Novoa, I, Zhang, Y, Zeng, H, Wek, R, Schapira, M, Ron, D

Mol. Cell 2000
16893190 Characterization of heme-regulated eIF2alpha kinase: roles of the N-terminal domain in the oligomeric state, heme binding, catalysis, and inhibition

Miksanova, M, Igarashi, J, Minami, M, Sagami, I, Yamauchi, S, Kurokawa, H, Shimizu, T

Biochemistry 2006
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