| Phosphorylation of the eukaryotic initiation factor 2 (eIF2) α subunit is a well-documented mechanism to downregulate protein synthesis under a variety of stress conditions. eIF2 binds GTP and Met-tRNAi and transfers Met-tRNA to the 40S subunit to form the 43S preinitiation complex. eIF2 promotes a new round of translation initiation by exchanging GDP for GTP, a reaction catalyzed by eIF2B. Kinases that are activated by viral infection (PKR), endoplasmic reticulum stress (PERK/PEK), amino acid deprivation (GCN2), or heme deficiency (HRI) can phosphorylate the α subunit of eIF2. This phosphorylation stabilizes the eIF2-GDP-eIF2B complex and inhibits the turnover of eIF2B. Induction of PKR by IFN-γ and TNF-α induces potent phosphorylation of eIF2α at Ser51.eIF2B, a guanine nucleotide exchange factor, is composed of 5 subunits, the largest of which is eIF2B-epsilon (7). Multiple in vivo phosphorylation sites have been identified on eIF2B-epsilon (8). Casein Kinase II can phosphorylate eIF2B-epsilon at Ser717/718 to allow for association with its substrate eIF2. Phosphorylation at Ser544 allows GSK-3 to phosphorylate the key regulatory site Ser540. A fifth eIF2B-epsilon phosphorylation site, Ser466, can be phosphorylated by casein kinase I. |
