摘要 : Purpose of review HRI is the heme-regulated elF2 alpha kinase that phosphorylates the alpha-subunit of elF2. Although the role of HRI in inhibiting globin synthesis in erythroid cells is well established, broader roles of HRI in t... 展开 Purpose of review HRI is the heme-regulated elF2 alpha kinase that phosphorylates the alpha-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 gamma-globin expression. Recent findings HRI and activating transcription factor 4 (ATF4) mRNAs are highly expressed in early erythroblasts. Inhibition of protein synthesis by HRI-phosphorylated elF2 alpha (elF2 alpha P) is necessary to maintain protein homeostasis in both the cytoplasm and mitochondria. In addition, HRI-elF2 alpha P 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-elF2 alpha P-ATF4 signaling also inhibits fetal hemoglobin production in human erythroid cells. Summary The primary function of HRI is to maintain protein homeostasis accompanied by the induction of ATF4 to mitigate stress. Role of HRI-ATF4 in gamma-globin expression raises the potential of HRI as a therapeutic target for hemoglobinopathy. 收起