Science 348, 239–242 (2015);
The accumulation of unfolded proteins triggers the unfolded protein response (UPR), which incorporates a more global stress response, the integrated stress response (ISR). The ISR is triggered by phosphorylation of the α subunit of translation initiation factor 2, inhibiting eIF2B, the guanine nucleotide exchange factor (GEF) for the eIF2 complex. The ISR thereby restores proteostasis by globally attenuating translation, mitigating the risk of proteotoxicity. Guanabenz (GBZ) and ISRIB are two small molecules that have been used to probe the ISR pathway. GBZ increases levels of phosphorylated eIF2α by inhibiting the regulatory subunit, PPP1R15A, of the eIF2α phosphatase, thereby delaying translation recovery and protecting cells from otherwise lethal proteotoxicity. ISRIB potently reverses the effects of eIF2α phosphorylation, but its precise target was not known. Because GBZ also targets the α2-adrenergic receptor, its utility as a therapeutic or as a specific eIF2α phosphatase probe is limited. Das et al. therefore synthesized a GBZ derivative, Sephin1, with the same selectivity and activity but without off-target liability.Through this unique targeting of the phosphatase regulatory subunit, these authors found that Sephin1 could prevent the molecular, morphological and motor defects in mouse models of two protein-misfolding diseases, Charcot-Marie-Tooth disease type 1B (CMT-1B) and amyotrophic lateral sclerosis (ALS). To define ISRIB's target, Sekine et al. isolated ISRIB-resistant cell lines and looked for mutations within eIF2B and eIF2, as they had biochemical evidence that ISRIB counteracts the effects of eIF2α phosphorylation on translation at the level of GEF activity by eIF2B. The ISRIB-resistant mutations all affected the delta subunit of eIF2B, which fits the biochemical observations of Sidrauski et al. These studies highlight the druggability of the ISR and utility of its modifiers as potential therapeutics and as probes.
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Bucci, M. Proteostasis: Found in translation. Nat Chem Biol 11, 380 (2015). https://doi.org/10.1038/nchembio.1826