Fig. 2. Translational initiation in the absence or presence of stress. (Green panels) In the absence of stress, eIF2B promotes the charging of the eIF2-GTP-tRNA^Met ternary complex by exchanging GDP for GTP. When the eIF2-GTP-tRNA^Met ternary complex is available, a canonical 48S preinitiation complex is assembled at the 5' end of capped transcripts (green arrow: Normal) and scanning begins. Upon recognition of the initiation codon by the anticodon of tRNA^Met, eIF5 promotes GTP hydrolysis, and early initiation factors are displaced by the 60S ribosomal subunit. As additional ribosomes are added to the transcript, the mRNA is converted into a polysome. (Red panels) In stressed cells (red arrow: Stress), phosphorylation of eIF2 by PKR, PERK, HRI or GCN2 converts eIF2 into a competitive antagonist of eIF2B, depleting the stores of eIF2/GTP/tRNA^Met. Under these conditions, TIA-1 is included in a non-canonical, eIF2/eIF5-deficient 48S^* preinitiation complex (composed of all components of the 48S pre-initiation complex except eIF2 and eIF5) that is translationally silent. TIA-1 self-aggregation then promotes the accumulation of these complexes at discrete cytoplasmic foci known as stress granules. Blue square, eIF5; green triangle, eIF2 bound to GTP; yellow triangle, eIF2 bound to GDP; red triangle, phospho-eIF2 bound to GDP.