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.

Vanishing White Matter Disease mutations compromise the function of the essential translation initiation factor eIF2B by destabilizing the holoenzyme, and the small molecule ISRIB reverses their pathogenic effect by promoting complex formation.

A drug-like molecule called ISRIB, which activates the translation initiation factor eIF2B, antagonizes stress responses as diverse as protein misfolding and nutrient deprivation, and restores protein synthesis, enhancing memory.

Integrated stress response-induced expression of ATF4 and its transactivation of SOX9 causes aberrant chondrocyte differentiation and skeletal defects which can be alleviated by modulating initiation-factor eIF2α phosphorylation translation control.

eIF2-P activates the integrated stress response by inducing a conformational change in eIF2B that decreases substrate (eIF2) binding and reduces eIF2B's catalytic activity.

A compound that prevents stressors such as UV light and viral infection from downregulating protein synthesis inside cells improves memory performance in mice.

Genetically induced conformational modulation of eIF2B activates the Integrated Stress Response by impairing nucleotide exchange.

Inhibition of the integrated stress response restores neuronal and immune dysfunction and alleviates memory deficits in aged mice.

Two seemingly distinct cellular stress response pathways that contribute to neurodegeneration after axonal insults are now revealed to be under the control of a single master regulator of the neuronal injury response, the kinase DLK.

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.