Protein phosphorylation plays an important role in the control of translation by eukaryotic initiation factor 2 (eIF2). eIF2 binds GTP and Met-tRNAi and transfers the Met-tRNA to the 40S subunit, to form the 43S preinitiation complex. Later in the cycle, prior to elongation, the bound GTP is hydrolyzed, releasing eIF2-GDP. For eIF2 to promote another round of initiation, GDP must be exchanged for GTP, a reaction catalyzed by eIF2B. Kinases activated by viral infection (PKR), endoplasmic reticulum stress (PERK/PEK), amino acid deprivation (GCN2), and hemin deficiency (HRI) can phosphorylate the alpha subunit of eIF2. This phosphorylation stabilizes the eIF2-GDP-eIF2B complex, inhibiting the turnover of eIF2B. The eIF2B is also inhibited by GSK-3beta phosphorylation. These events result in a shutdown of cellular protein synthesis and can lead to apoptosis.
