Figure 1.

Model of canonical and noncanonical PIC formation under various conditions. Note that the diagram is not time resolved, and hence some depicted interactions may not occur simultaneously or be competitive. (A) Assembly of the 48S PIC during normal conditions. The ternary complex joins the 40S ribosomal subunit and forms a 43S preinitiation complex. The eIF4F complex (eIF4E, eIF4A, and eIF4G) binds together with eIF4B to the 5′ cap of the mRNA. The eIF4F-bound mRNA associates with the 43S PIC, and then scans to the AUG start codon, where 48S PIC formation occurs. (B) Formation of noncanonical PICs during various stress conditions. Here, we depict three different signaling pathways that assemble noncanonical PICs: (1) mTOR inhibition by sodium selenite, amino acid (AA) starvation, rapamycin, or oxidative stress (H₂O₂), which leads to hypophosphorylation of 4E-BP, which then interacts with eIF4E and blocks translation initiation; (2) various stresses activate distinct eIF2α kinases that phosphorylate eIF2α, deplete the ternary complex, and promote the assembly of a noncanonical PIC; and (3) compounds such as pateamine A, 15-deoxy-Δ(12,14)-prostaglandin J2 (15d PGJ2), hippuristanol, silvestrol, or tiRNA target the eIF4F complex, also creating a noncanonical PIC. These noncanonical PICs differ from canonical PICs in composition and exposure of the 40S subunit interface and mRNA. These interfaces recruit RNA-BPs such as G3BP and TIA-1/R, increasing the local concentration of these proteins to promote LLPS and assembly of SG seeds. Figure modified from Jackson et al. (2010).