Figure 1. Eukaryotic Cap-Dependent Translation Initiation and Key Regulatory Pathways.

Initiation begins with the assembly of the 43S preinitiation complex (PIC), consisting of the 40S small ribosomal subunit, eIF1, eIF1A, eIF3, eIF5, and the ternary complex eIF2-GTP-Met-tRNA_i. The PIC is recruited to the 5’ cap of the mRNA by the eIF4F complex (eIF4E, eIF4G, and eIF4A) and eIF4B. Circularization of the mRNA is promoted by interaction between eIF4G and PABP. The mRNA is scanned in a 5’ to 3’ direction until a start (AUG) codon is recognized, triggering the release of eIF1, inorganic phosphate (Pi), eIF5, and eIF2-GDP. The joining of the 60S ribosomal subunit to the PIC and release of several initiation factors, including eIF1A, is catalyzed by eIF5B, leading to the formation of the elongation-competent 80S ribosome. eIF2-GDP is recycled to eIF2-GTP by the exchange factor eIF2B. Under stress conditions, phosphorylation of the α-subunit of eIF2 (eIF2α) impairs recycling and ternary complex formation. Translation initiation is also regulated by mTOR, which can directly or indirectly phosphorylate eIF4G, eIF4B, 4E-BP, and PDCD4, promoting cap-dependent initiation.