Figure 4. The mechanism of regulation of ATF4 and ATF5 mRNA translation.

(a) Diagram shows the sizes, spacing and disposition of the two upstream open reading frames (uORFs) in human, mouse, rat, cow and chicken activating transciption factor 4 (ATF4) mRNAs and the four mammalian ATF5 mRNAs^{62, 63}. (b) The pattern of translation in control (unstressed) conditions when eIF2-GTP-Met-tRNA_i ternary complexes (eIF2-TCs) are abundant. Small (40S) ribosomal subunits with associated eIF2-TCs (blue) scan the mRNA in the direction shown by the short horizontal arrows, and nascent protein chains are shown by the black zig-zag line associated with the large (60S) ribosomal subunit. If eIF2-TCs are abundant, most of the 40S subunits that resume scanning after uORF1 translation will acquire a new eIF2-TC in time to initiate translation of uORF2, and ribosomes that translate this second uORF will be unable to initiate at the ATF4/5 AUG because uORF2 is rather too long to allow rescanning, and also because it would require backwards scanning which doesn’t appear to occur over significant distances⁵⁹. (c) Pattern of translation in stressed conditions (for example, thapsigargin treatment), when eIF2-TC availability is low due to eIF2 phosphorylation by activated PERK. Consequently, most of the 40S subunits that resume scanning after translating uORF1 acquire a new eIF2-TC only after they have passed the uORF2 initiation codon, but in time to initiate at the next AUG which is at the start of the ATF ORF in both cases.