Eukaryotic initiation factor 2 (eIF2) regulates global protein translation by binding to Met-tRNA and the 40S ribosome to form the pre-initiation complex. eIF2 is a heterotrimer consisting of alpha, beta, and gamma subunits. The 36kDA eIF2α subunit serves a key regulatory role. Phosphorylation of the serine residue at position 51 is able to block the formation of the pre-initiation complex and halt global protein translation. This regulatory mechanism allows cells to respond and adapt to diverse stresses such as nutrient deficiencies, viral infection, or general ER-stress. The four eIF2α kinases sense and respond to distinct types of stresses. Of these PERK (PKR-like ER kinase) phosphorylates eIF2α in response to ER-stress while GCN2 (general control non-derepressible-2) is activated in response to starvation or nutrient deficiency (1). PKR (protein kinase double-stranded RNA-dependent) phosphorylates eIF2α in response to viral infections and HRI (heme-regulated inhibitor) primarily regulates the synthesis of hemoglobin proteins in response to heme deficiency (2). This phosphorylation event can be measured using phospho-specific eIF2A antibodies and serves as an excellent tool to monitor the induction of cell stress pathways. This use is exemplified by Rojas et al. where they demonstrate inhibition of protein translation following Rotavirus infection (3). Using the phospho-specific eIF2A antibody allowed the authors to show eIF2α is phosphorylated and identify PKR as the primary kinase in this context (3). This phospho-specific eIF2A antibody has also been used to study autophagy pathways following cell starvation (1). Research published by the Bruhat group has demonstrated the utility of measuring total eIF2α levels with a general eIF2A antibody and comparing this to the phosphorylated pool of eIF2α using a phospho-specific eIF2A antibody. In this particular study this strategy aided in the dissection of autophagy induction pathways and demonstrated roles for eIF2α and ATF4 in regulating transcriptional responses (1).
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