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. 2004 Jul 26;101(31):11269–11274. doi: 10.1073/pnas.0400541101

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Copyright © 2004, The National Academy of Sciences

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Fig. 5. — Model for ATF4 translational control by its leader sequences. The ATF4 mRNA is illustrated as a straight line that has uORFs 1 and 2 that are presented as boxes. The shading of the small ribosomal subunit indicates its association with eIF2-GTP bound . After translation of the positive-acting uORF1, ribosomes retain the capacity to reinitiate translation at a downstream ORF. The basis for this reinitiation capacity is currently not clear. In the related GCN4 translation mechanism, the termination context of the analogous uORF1 is thought to facilitate the retention of the small ribosomal subunit with the GCN4 mRNA (1, 12, 28). After translation of the ATF4 uORF1, the 40S ribosomal subunits are proposed to resume scanning in a 5′ to 3′ direction along the ATF4 transcript. When eIF2-GTP bound is plentiful during nonstressed conditions, the small ribosomal subunits quickly acquire the eIF2 ternary complex and, coupled with the 60S ribosome, reinitiate translation at uORF2. After translation of this inhibitory uORF2, ribosomes dissociate from the ATF4 mRNA, thereby reducing expression of the ATF4-coding region. When cells are subjected to ER stress or to nutrient deprivation, the levels of eIF2 phosphorylation are enhanced leading to reduced eIF2-GTP levels. After translation of uORF1, there is an increased time required for reacquisition of eIF2-GTP coupled that allows a portion of the scanning 40S ribosomal subunits to scan through the negative-acting uORF2. While scanning the mRNA-leader region from beginning of uORF2 to the initiation codon of the ATF4-coding region, ribosomes reacquire the eIF2 ternary complex, facilitating translational expression of ATF4. When uORF1 is mutated, ribosomes scanning from the 5′ end of the ATF4 mRNA will initiate translation at uORF2. After translation of the inhibitory uORF2, ribosomes dissociate from the ATF4 mRNA, thus lowering translation of the ATF4-coding region even when eIF2-GTP levels are reduced in response to cellular stress. When the distance between uORF1 and uORF2 is increased compared to WT, most ribosomes are competent for reinitiation before reaching uORF2, thereby reducing ATF4 translation independent of eIF2-GTP availability.

Inline graphic — Model for ATF4 translational control by its leader sequences. The ATF4 mRNA is illustrated as a straight line that has uORFs 1 and 2 that are presented as boxes. The shading of the small ribosomal subunit indicates its association with eIF2-GTP bound . After translation of the positive-acting uORF1, ribosomes retain the capacity to reinitiate translation at a downstream ORF. The basis for this reinitiation capacity is currently not clear. In the related GCN4 translation mechanism, the termination context of the analogous uORF1 is thought to facilitate the retention of the small ribosomal subunit with the GCN4 mRNA (1, 12, 28). After translation of the ATF4 uORF1, the 40S ribosomal subunits are proposed to resume scanning in a 5′ to 3′ direction along the ATF4 transcript. When eIF2-GTP bound is plentiful during nonstressed conditions, the small ribosomal subunits quickly acquire the eIF2 ternary complex and, coupled with the 60S ribosome, reinitiate translation at uORF2. After translation of this inhibitory uORF2, ribosomes dissociate from the ATF4 mRNA, thereby reducing expression of the ATF4-coding region. When cells are subjected to ER stress or to nutrient deprivation, the levels of eIF2 phosphorylation are enhanced leading to reduced eIF2-GTP levels. After translation of uORF1, there is an increased time required for reacquisition of eIF2-GTP coupled that allows a portion of the scanning 40S ribosomal subunits to scan through the negative-acting uORF2. While scanning the mRNA-leader region from beginning of uORF2 to the initiation codon of the ATF4-coding region, ribosomes reacquire the eIF2 ternary complex, facilitating translational expression of ATF4. When uORF1 is mutated, ribosomes scanning from the 5′ end of the ATF4 mRNA will initiate translation at uORF2. After translation of the inhibitory uORF2, ribosomes dissociate from the ATF4 mRNA, thus lowering translation of the ATF4-coding region even when eIF2-GTP levels are reduced in response to cellular stress. When the distance between uORF1 and uORF2 is increased compared to WT, most ribosomes are competent for reinitiation before reaching uORF2, thereby reducing ATF4 translation independent of eIF2-GTP availability.