Fig. 1: Dimerizable PERK enables tunable and selective control of the ISR. | Nature Communications

Fig. 1: Dimerizable PERK enables tunable and selective control of the ISR.

From: Specific activation of the integrated stress response uncovers regulation of central carbon metabolism and lipid droplet biogenesis

Fig. 1

a Schematic illustrating the inputs and outputs of the ISR. The ISR incorporates input from various cellular stress sensors to increase the levels of p-eIF2, the central input into the pathway. Its major outputs include a reduction in protein synthesis, the formation of SGs, and the induction of a specialized gene expression program that is in part mediated by the translational induction of the transcription factor ATF4. b Schematic illustrating the pharmacogenetic Dmr-PERK tool. Upon addition of a small molecule dimerizer, Dmr-PERK phosphorylates eIF2 and activates the ISR. c AlphaLISA measurement of the ratio of p-eIF2/eIF2 in Dmr-PERK U2OS cells following 2 h of dimerizer treatment at the indicated concentrations. Error bars show mean ± SD of three technical replicates. d Quantification of OP-Puromycin incorporation (left axis) and G3BP1-positive SGs (right axis) co-labeled in Dmr-PERK cells following 4 h of dimerizer treatment at the indicated concentration. Error bars depict mean ± SD of three technical replicates e Heatmap of protein coding gene expression in untreated (UT) Dmr-PERK cells or in cells treated with dimerizer (Dmr, 0.2 nM), thapsigargin (Tg, 100 nM), or arsenite (Ars, 0.05 mM), for the indicated amount of time. Columns show the mean expression of three replicates relative to the mean expression at t = 0 on a log2 scale. f Heatmap of genes described in e that have a significantly different time-dependent response between dimerizer (Dmr) and thapsigargin (Tg) treatments. Selected GO terms with significant enrichment by ORA within the groups of Tg-responsive genes are indicated. g Heatmap of genes described in e that have a significantly different time-dependent response between dimerizer (Dmr) and arsenite (Ars) treatments. Selected GO terms with significant enrichment by ORA within the groups of arsenite-responsive genes are indicated. a, b are created with BioRender.com released under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International license https://creativecommons.org/licenses/by-nc-nd/4.0/deed.en. Source data are provided as a Source Data file.

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