Eukaryotic initiation factor 2α phosphorylation mediates fetal hemoglobin induction through a post-transcriptional mechanism
Eukaryotic initiation factor 2α phosphorylation mediates fetal hemoglobin induction through a post-transcriptional mechanism
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DOI：
10.1182/blood-2013-03-491043
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发表时间：
2013-07-25
期刊：
影响因子：
20.3
通讯作者：
Lowrey, Christopher H.
中科院分区：
文献类型：
--
作者：
Hahn, Cynthia K.;Lowrey, Christopher H.
增加胎儿血红蛋白（HbF）水平的策略可以改善症状并改善β-血红蛋白病患者的生活。虽然大多数研究都集中在γ-珠蛋白基因表达的诱导作为一种方法来诱导HbF，我们假设，转录后调节HbF在控制HbF水平发挥了低估但重要的作用。在本研究中，我们研究了是否增加真核起始因子2 α（eIF 2 α）磷酸化，蛋白质翻译的关键调节，可以提高转录后的人原代红系细胞中的HbF。使用已知的eIF 2 α去磷酸化抑制剂salubrinal进行的初步分析表明，eIF 2 α磷酸化升高会增强HbF的产生，而不会改变球蛋白基因表达、增殖或细胞分化。这些结果进一步得到了eIF 2 α途径的其他药理学激活剂对HbF的转录后诱导以及负调节因子GADD 34和CReP的遗传失活的支持。此外，我们发现，这种增加HbF的新机制可以与临床相关的γ-珠蛋白基因表达的转录激活因子相结合，以增加HbF。总之，这些发现将eIF 2 α磷酸化鉴定为HbF诱导的转录后调节因子，其可以单独或组合地在β-血红蛋白病患者中被靶向。
Strategies to increase fetal hemoglobin (HbF) levels can ameliorate symptoms and improve the lives of beta-hemoglobinopathy patients. Although most studies have focused on induction of gamma-globin gene expression as an approach to induce HbF, we hypothesized that post-transcriptional regulation of HbF plays an underappreciated yet important role in controlling HbF levels. In the present study, we investigated whether increasing eukaryotic initiation factor 2 alpha (eIF2 alpha) phosphorylation, a key regulator of protein translation, could enhance HbF post-transcriptionally in human primary erythroid cells. Initial analysis using a known inhibitor of eIF2 alpha dephosphorylation, salubrinal, revealed that elevated eIF2 alpha phosphorylation enhanced HbF production without changing globin gene expression, proliferation, or cell differentiation. These results were further supported by the post-transcriptional induction of HbF by other pharmacologic activators of the eIF2 alpha pathway and by genetic inactivation of the negative regulators, GADD34 and CReP. Additionally, we found that this novel mechanism of increasing HbF could be combined with clinically relevant transcriptional activators of gamma-globin gene expression to additively enhance HbF. Taken together, these findings identify eIF2 alpha phosphorylation as a post-transcriptional regulator of HbF induction that may be pharmacologically targeted, either alone or in combination, in beta-hemoglobinopathy patients.