Selective enhancement of translation of activating transcription factor 4 (ATF4) and γ-globin mRNAs by eIF2αP in erythroid precursors. eIF2 is a heterotrimeric protein complex, which binds initiating methionyl transfer RNA and the 40S ribosomal subunit to start nascent polypeptide synthesis. HRI is the major eIF2α kinase in the erythroid lineage, and is indispensable in coordinating heme and globin synthesis as well as in combating oxidative stress. Phosphorylation of the α-subunit of eIF2 by HRI impairs the recycling of eIF2 for another round of initiation and thus inhibits translation of the vast majority of mRNAs. However, eIF2αP also selectively increases the translation of ATF4 mRNA. (A) In the 5′UTR of ATF4 mRNA, there are 2 uORFs that are preferentially translated under nonstressed conditions and prevent the downstream translational initiation in the coding sequence of ATF4 mRNA. As initiating 40S ribosomal subunits scan from the cap structure, translation starts at the uORF1. After termination of translation, the 40S subunit remains associated with mRNA and reinitiates efficiently at uORF2 under nonstressed conditions. Upon stress, elevated eIF2αP impairs the reinitiation of 40S at uORF2 due to limiting functional eIF2. Thus, 40S continues to scan downstream and initiates at the AUG codon of the coding sequence of ATF4 mRNA permitting the synthesis of ATF4 protein. (B) The homeostasis of the cellular eIF2αP level is controlled not only by the activation of HRI, but also by dephosphorylation of eIF2αP by PPase1 in order to regenerate active eIF2. CreP and GADD34 are the 2 regulatory proteins that recruit eIF2αP to PPase1 for dephosphorylation. Salubrinal, a small chemical molecule, is a selective inhibitor of dephosphorylation of eIF2αP by interfering with the recruitment of eIF2αP to PPase1. Thus, treatment of cells with salubrinal results in an increased eIF2αP level. In differentiating human erythroid cells, γ-globin translation is increased upon salubrinal treatment as shown in this Blood article.