Building on previous work which showed that the small molecule ISRIB potently blocks the integrated stress response (Sidrauski et al., 2013), we report on ISRIB's remarkable specificity and fast action in vivo, underscoring its proposed direct effect on translation.
Boosting the function of translation factor eIF2B by chronic small molecule administration prevents pathology in a neurodegenerative model of Vanishing White Matter disease characterized by a maladaptive stress response.
Genetic lesions that compromise the ribosome P-stalk implicate direct signalling from the ribosome to the translation initiation factor eIF2 kinase GCN2 in the cellular response to amino acid starvation.
ATF4 is a metabolic effector of mTORC1 signaling, co-opted to induce gene targets involved in amino acid synthesis, uptake, and tRNA charging, contributing to mTORC1-driven protein and glutathione synthesis.
Phosphorylated translation initiation factor eIF2, a potent inhibitor of protein synthesis in eukaryotic cells, is also inhibitory to protein synthesis when bound to GTP and initiator tRNA broadening the reach and immediacy of eIF2-mediated control.