Figure 1.

Key steps in the initiation phase of mRNA translation. The initiation step in translation involves the binding of the ternary complex, consisting of eukaryotic initiation factor 2 (eIF2) associated with GTP and the initiator form of methionyl-tRNA (met-tRNAi), to the 40S ribosomal subunit to form the 43S preinitiation complex. The eIF4F•eIF4B complex in association with mRNA subsequently binds to form the 48S preinitiation complex. The 40S ribosomal subunit then scans along the 5’-untranslated region of the mRNA and stops at an AUG start codon, triggering hydrolysis of GTP bound to eIF2 to GDP leading to release of the eIF2•GDP and eIF4F•eIF4B complexes. The GDP bound to eIF2 is exchanged for GTP by eIF2B and the eIF4F•eIF4B complex binds to another mRNA to re-start the process. GCN2 phosphorylates eIF2 on its α-subunit, converting it from a substrate of eIF2B into a competitive inhibitor, leading to decreased ternary complex formation. mTORC1 promotes assembly of the eIF4F complex through phosphorylation of the eIF4E binding proteins (4E-BPs) and programmed cell death 4 (PDCD4). Phosphorylation of 4E-BP by mTORC1 releases it from the eIF4E•4E-BP complex, allowing eIF4E to bind to eIF4G. Similarly, phosphorylation of PDCD4 by p70S6K1 (which is also activated by mTORC1) frees eIF4A from the eIF4A•PDCD4 complex, allowing it to bind to eIF4G. In addition, p70S6K1 phosphorylates eIF4B, thereby enhancing its stimulatory activity toward eIF4A.