Phosphorylation of eIF2alpha at serine 51 is a single covalent modification that changes which messenger RNAs are translated. The mechanism depends on the fact that eIF2 delivers the initiator methionine transfer RNA to the ribosome as part of a ternary complex with GTP. After initiation, the GTP is hydrolyzed and eIF2-GDP must be recycled to eIF2-GTP by the guanine nucleotide exchange factor eIF2B.
Phosphorylated eIF2alpha binds eIF2B tightly and inhibits it. With eIF2B sequestered, eIF2-GDP cannot be recycled fast enough, ternary complex becomes limiting, and global cap-dependent initiation falls. This is the suppression half of the response, and it conserves amino acids and energy at a moment when the cell may be short of both.
Selective translation of specific transcripts is the second half. Transcripts such as ATF4 contain short upstream open reading frames in their 5-prime leaders. When ternary complex is abundant, ribosomes initiate at these upstream frames and terminate before reaching the main coding sequence, so little ATF4 is made. When ternary complex is scarce, ribosomes scan past the upstream frames and initiate at the main ATF4 start codon instead. The result is that a global reduction in initiation increases ATF4 protein. ATF4 then drives transcription of amino acid transporters, antioxidant enzymes, and the pro-apoptotic factor CHOP.
This is the clearest example in the chapter of translational reprogramming as an adaptive output. The cell does not simply slow translation; it changes the ratio of what is made, favoring regulators that can restore balance and, if the stress persists, favoring CHOP and the transition toward apoptosis.