Fig. 2

The integrated stress response. In response to various sources of cellular and environmental stress, a family of four eIF2α kinases phosphorylate (black P) eIF2α (light grey). GCN2 (yellow) responds to amino acid deficiency, HRI (blue) responds to heme deficiency in erythroid cells, and PKR (green) responds to the presence of double-stranded RNA coincident with viral infection and PERK (red) responds to endoplasmic reticulum stress. Additional stresses that phosphorylate eIF2α, for which the corresponding kinase is unknown, are indicated (grey). Phosphorylated eIF2α leads to a global repression of translation. Accumulation of a pool of mRNAs, stalled at the initiation step of translation, seed the assembly of stress granules (maroon arrow). In contrast P-eIF2α reprograms translation to favour a subset of mRNAs, such as those for activating transcription factor Atf4 (orange), that contain uORFs in their 5’UTR. P-eIF2α-dependent translation of Atf4 and subsequent nuclear localisation of ATF4 protein initiate the integrated stress response (dark green arrow), a pro-survival pathway