Heme-regulated Inhibitor Kinase-mediated Phosphorylation of Eukaryotic Translation Initiation Factor 2 Inhibits Translation, Induces Stress Granule Formation, and Mediates Survival upon Arsenite Exposure

Abstract

Exposure to arsenite inhibits protein synthesis and activates multiple stress signaling pathways. Although arsenite has diverse effects on cell metabolism, we demonstrated that phosphorylation of eukaryotic translation initiation factor 2 at Ser-51 on the ␣ subunit was necessary to inhibit protein synthesis initiation in arsenite-treated cells and was essential for stress granule formation. Of the four protein kinases known to phosphorylate eukaryotic translation initiation factor 2␣, only the heme-regulated inhibitor kinase (HRI) was required for the translational inhibition in response to arsenite treatment in mouse embryonic fibroblasts. In addition, HRI expression was required for stress granule formation and cellular survival after arsenite treatment. In vivo studies elucidated a fundamental requirement for HRI in murine survival upon acute arsenite exposure. The results demonstrated an essential role for HRI in mediating arsenite stress-induced phosphorylation of eukaryotic translation initiation factor 2␣, inhibition of protein synthesis, stress granule formation, and survival.

Eukaryotic initiation factor 2α kinase is a nitric oxide‐responsive mercury sensor enzyme: Potent inhibition of catalysis by the mercury cation and reversal by nitric oxide

“…Moreover, in contrast to an earlier publication that HRI plays an essential role in mediating arsenite stress-induced phosphorylation [12], arsenite had little effect on HRI activity in our experiments.…”

“…1 [12], had a marginal effect on catalytic activity in our assays (Table 1). Essentially similar results with the different cations were obtained for the N-terminal truncated mutant.…”

Hepcidin as a therapeutic tool to limit iron overload and improve anemia in β-thalassemic mice

“…Decreased iron availability likely results in more effective erythropoiesis, as less iron is available during erythroid development to generate free heme or α-globin precipitates, factors associated with shortened rbc survival. Previously presented data demonstrate that the absence of heme-regulated inhibitor (HRI) kinase, which controls Hb synthesis (25), exacerbates the β-thalassemia phenotype (26), while lack of heme exporter feline leukemia virus subgroup C cellular receptor (FLVCR), which controls heme export (27), impairs rbc formation (28). These observations, along with our new data, suggest that an excess of iron and/or heme (in addition to α-globin) in erythroid cells might be deleterious to erythropoiesis.…”

Rôle de l’heme regulated inhibitor(HRI) dans la résistance à l’apoptose

“…L'activation des voies de réponse au stress peut alors interférer avec la mort SYNTHÈSE REVUES du réticulum endoplasmique, la protéine kinase GCN2 (general control non-derepressible 2) en réponse aux radiations et à la carence en acides aminés, et, enfin, HRI (heme-regulated inhibitor) dans des conditions de déficit en hème. HRI est également activée lors d'une réponse au stress oxydant et au cours de traitements par des inhibiteurs du protéasome induisant la formation de granules de stress [7,18]. Dans cette revue, nous proposons un nouveau rôle pour HRI dans la résistance à l'apoptose, en partie par l'induction des granules de stress.…”

“…Le laboratoire du Dr. Kaufman a montré que, contrairement aux MEF de type sauvage, les MEF n'exprimant pas HRI ne forment pas de granules de stress en présence d'arsénite et meurent par apoptose [18]. Dans une étude pionnière [7], nous avons établi que l'activation de HRI est critique pour la formation des granules de stress dans des cellules cancéreuses exposées au bortézomib, un inhibiteur du protéasome approuvé pour le traitement des myélomes.…”