Erythroid expression of the heme-regulated eIF-2 alpha kinase.

Crosby, John S.; Lee, K; London, Irving M.; Chen, J J

doi:10.1128/mcb.14.6.3906

Cited by 72 publications

(42 citation statements)

References 49 publications

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“…We have shown previously that HRI is predominantly expressed in the erythroid lineage (29). This is the first demonstration to our knowledge that HRI protein is expressed at a substantial level in nonerythroid cells.…”

Section: Iron Homeostasis and Hepcidin Expression In Hri Deficiencysupporting

confidence: 55%

The function of heme-regulated eIF2α kinase in murine iron homeostasis and macrophage maturation

Liu¹,

Suragani²,

Wang³

et al. 2007

J. Clin. Invest.

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Heme-regulated eIF2α kinase (HRI) plays an essential protective role in anemias of iron deficiency, erythroid protoporphyria, and β-thalassemia. In this study, we report that HRI protein is present in murine macrophages, albeit at a lower level than in erythroid precursors. Hri -/-mice exhibited impaired macrophage maturation and a weaker antiinflammatory response with reduced cytokine production upon LPS challenge. The level of production of hepcidin, an important player in the pathogenesis of the anemia of inflammation, was significantly decreased in Hri -/-mice, accompanied by decreased splenic macrophage iron content and increased serum iron content. Hepcidin expression was also significantly lower, with a concomitant increase in serum iron in Hri -/-mice upon LPS treatment. We also demonstrated an impairment of erythrophagocytosis by Hri -/-macrophages both in vitro and in vivo under chronic hemolytic anemia, providing evidence for the role of HRI in recycling iron from senescent red blood cells. This work demonstrates that HRI deficiency attenuates hepcidin expression and iron homeostasis in mice, indicating a potential role for HRI in the anemia of inflammation.

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Section: Iron Homeostasis and Hepcidin Expression In Hri Deficiencysupporting

confidence: 55%

The function of heme-regulated eIF2α kinase in murine iron homeostasis and macrophage maturation

Liu¹,

Suragani²,

Wang³

et al. 2007

J. Clin. Invest.

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“…However, HRI Ϫ/Ϫ fetal liver cells failed to respond to arsenite despite the response to amino acid and serum starvation. In nonerythroid cells, PKR is likely the eIF2␣ kinase activated by arsenite, since little or no HRI is expressed in nonerythroid cells (13). It has been reported that PKR is activated by arsenite in murine interleukin-3-dependent NFS/N1.H7 cells (21) and NIH 3T3 and MEF cells (30).…”

Section: Discussionmentioning

confidence: 99%

Translation Initiation Control by Heme-Regulated Eukaryotic Initiation Factor 2α Kinase in Erythroid Cells under Cytoplasmic Stresses

Han

Chen

2001

Molecular and Cellular Biology

288

264

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Cytoplasmic stresses, including heat shock, osmotic stress, and oxidative stress, cause rapid inhibition of protein synthesis in cells through phosphorylation of eukaryotic initiation factor 2␣ (eIF2␣) by eIF2␣ kinases. We have investigated the role of heme-regulated inhibitor (HRI), a heme-regulated eIF2␣ kinase, in stress responses of erythroid cells. We have demonstrated that HRI in reticulocytes and fetal liver nucleated erythroid progenitors is activated by oxidative stress induced by arsenite, heat shock, and osmotic stress but not by endoplasmic reticulum stress or nutrient starvation. While autophosphorylation is essential for the activation of HRI, the phosphorylation status of HRI activated by different stresses is different. The contributions of HRI in various stress responses were assessed with the aid of HRI-null reticulocytes and fetal liver erythroid cells. HRI is the only eIF2␣ kinase activated by arsenite in erythroid cells, since HRI-null cells do not induce eIF2␣ phosphorylation upon arsenite treatment. HRI is also the major eIF2␣ kinase responsible for the increased eIF2␣ phosphorylation upon heat shock in erythroid cells. Activation of HRI by these stresses is independent of heme and requires the presence of intact cells. Both hsp90 and hsc70 are necessary for all stress-induced HRI activation. However, reactive oxygen species are involved only in HRI activation by arsenite. Our results provide evidence for a novel function of HRI in stress responses other than heme deficiency.Protein synthesis in intact reticulocytes and their lysates is dependent on the availability of heme. In heme deficiency, protein synthesis is inhibited, with a marked decrease in the formation of 40S-eukaryotic initiation factor 2 (eIF2)-MettRNA f GTP (43S preinitiation complex) and with increased phosphorylation of the ␣ subunit of eIF2. eIF2 is an initiation factor which binds GTP and Met-tRNA f and is required for the formation of the 43S initiation complex. The phosphorylation of eIF2␣ in heme deficiency is the result of the activation of heme-regulated inhibitor (HRI), which is a heme-regulated eIF2␣ kinase (8, 9). The mechanism of inhibition of translation initiation by the phosphorylation of eIF2␣ has been studied extensively (18,19). In brief, the recycling of eIF2 in initiation requires the exchange of bound GDP for GTP. Under physiological conditions, eIF2 has a 400-fold-greater affinity for GDP than for GTP. The exchange of tightly bound GDP for GTP requires eIF2B, which is rate limiting and is present at 15 to 25% of the amount of eIF2. When eIF2␣ is phosphorylated, the binding of eIF2(␣P)-GDP to the regulatory subcomplex of eIF2B is much tighter than the binding of eIF2-GDP to eIF2B (25). This tighter interaction of phosphorylated eIF2 with eIF2B prevents the GDP-GTP exchange activity of eIF2B. In this manner, once the amount of phosphorylated eIF2 exceeds the amount of eIF2B, the shutoff of protein synthesis occurs.Phosphorylation of eIF2␣ was later found to be a common regulatory mechanism of protein tr...

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“…Furthermore, NOC-9 markedly enhanced Effect of NO on HRI Activity in Non-erythroid Cells-Possible regulatory roles for HRI in nonerythroid cells have yet to be explored in detail. Although HRI expression was previously believed to be specific to erythroid cells (4,38,39), mRNA encoding HRI has been reported to be expressed in several nonerythroid tissues (40,41). A search of the data base of expressed sequence tags, dbEST (Table I) indicated that HRI mRNA is expressed in a wide variety of nonerythroid cells and tissues, as well as a variety of tumors.…”

Section: Regulation Of Hri By No and Comentioning

confidence: 99%

The Heme-regulated Eukaryotic Initiation Factor 2α Kinase

Uma

Yun

Matts

2001

Journal of Biological Chemistry

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Nitric oxide (NO) has been reported to inhibit protein synthesis in eukaryotic cells by increasing the phosphorylation of the ␣-subunit of eukaryotic initiation factor (eIF) 2. However, the mechanism through which this increase occurs has not been characterized. In this report, we examined the effect of the diffusible gases nitric oxide (NO) and carbon monoxide (CO) on the activation of the heme-regulated eIF2␣ kinase (HRI) in rabbit reticulocyte lysate. Spectral analysis indicated that both NO and CO bind to the N-terminal heme-binding domain of HRI. Although NO was a very potent activator of HRI, CO markedly suppressed NO-induced HRI activation. The NO-induced activation of HRI was transduced through the interaction of NO with the N-terminal heme-binding domain of HRI and not through S-nitrosylation of HRI. We postulate that the regulation of HRI activity by diffusible gases may be of wider physiological significance, as we further demonstrate that NO generators increase eIF2␣ phosphorylation levels in NT2 neuroepithelial and C2C12 myoblast cells and activate HRI immunoadsorbed from extracts of these non-erythroid cell lines.Over 2 decades ago, the heme-regulated inhibitor (HRI) 1 of protein chain initiation in rabbit reticulocyte lysate (RRL) was identified as a heme-regulated protein kinase that phosphorylated the ␣-subunit of eukaryotic initiation factor eIF2 (reviewed in Refs. 1-3). eIF2 delivers Met-tRNA i in a complex with GTP to 43 S ribosomal initiation complexes and is released as a complex with GDP at the completion of the initiation cycle. Recycling of eIF2⅐GDP and the formation of eIF2⅐GTP⅐Met-tRNA i complexes requires the action of the guanine nucleotide exchange factor, eIF2B. Under heme-deficient conditions, HRI is activated and phosphorylates eIF2. Phosphorylated eIF2 avidly binds eIF2B, sequestering eIF2B in a poorly dissociable complex, which subsequently leads to the inhibition of the initiation of translation, as eIF2⅐GDP complexes that are present in excess of eIF2B fail to recycle. Thus, HRI functions to coordinate globin synthesis with heme availability in RRL.The amino acid sequence deduced from HRI cDNA indicates that it is composed of at least five distinct domains (4). The unique N-terminal domain of HRI contains ϳ165 amino acids. The second and fourth domains contain conserved sequence motifs I-V and motifs VI-XI, which comprise the N-terminal and C-terminal catalytic lobes of protein kinases, respectively. The third and fifth domains are also unique, consisting of ϳ140 amino acids that are inserted between the two conserved kinase lobes and ϳ50 amino acids at the C terminus, respectively.HRI is a hemoprotein that contains two distinct of hemebinding sites (5-7). Heme binding to the first site is stable, and remains associated with purified HRI, whereas heme-binding to the second site is reversible and appears to be responsible for the rapid heme-induced down-regulation of HRI activity . We have recently demonstrated that the N-terminal domain of HRI contains the stable heme-binding...

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Erythroid expression of the heme-regulated eIF-2 alpha kinase.

Cited by 72 publications

References 49 publications

The function of heme-regulated eIF2α kinase in murine iron homeostasis and macrophage maturation

The function of heme-regulated eIF2α kinase in murine iron homeostasis and macrophage maturation

Translation Initiation Control by Heme-Regulated Eukaryotic Initiation Factor 2α Kinase in Erythroid Cells under Cytoplasmic Stresses

The Heme-regulated Eukaryotic Initiation Factor 2α Kinase

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