Pharmacological Targeting of RIG-I Selectively Activates the Integrated Stress Response

The integrated stress response (ISR) is a eukaryotic pathway that attenuates global protein synthesis while allowing selective translation of specific mRNAs, which together can reestablish homeostasis following an acute stress. Diverse pathologic insults activate one or more of the four ISR kinases, which selectively phosphorylate eIF2a to induce translational and transcriptional adaptation of multiple biological functions. Recent results suggest that enhancing ISR kinase activity could ameliorate pathologies linked to numerous diseases, including many neurodegenerative disorders. However, few pharmacological strategies exist to selectively activate ISR kinases and downstream adaptive signaling. Here, we describe compound A8 and its cyclized metabolite CC81 as highly-selective ISR activators that activate the heme-regulated inhibitor (HRI) ISR kinase through a mechanism involving binding of the cytosolic pattern recognition receptor RIG-I. Our results establish a pharmacological strategy to selectively activate HRI-dependent ISR signaling by targeting RIG-I, revealing new mechanistic options for ameliorating etiologically diverse diseases through ISR activation.