Figure 2. FIGURE 2: The ISR in translational reprograming.

Environmental cues are able to turn off mTORC1, thus impeding phosphorylation of 4EBP and release of eIF4E, the initiation factor responsible for m7G cap recognition; this process leads to cap-dependent translational repression. In addition, different stimuli activate the stress sensor kinases GCN2, PERK, PKR or HRI that in turn phosphorylate eIF4α. Phospo ser51 eIF4α cannot exchange anymore GDP and GTP therefore formation of the ternary complex between the small ribosomal subunit, eIF4α and the initiator tRNAMeti is inhibited. While general translation is inhibited, special/selective translation is initiated by activation of the ATF4 transcriptional program.