Pharmacological targeting of RIG-I can selectively activate the integrated stress response
Year: 2025
Type: article
Abstract: The integrated stress response (ISR) is a eukaryotic stress-responsive signaling pathway that attenuates global protein synthesis while allowing selective translation of specific mRNAs, which together can reestablish homeostasis following acute stress. Diverse pathologic insults activate one or more of the four ISR kinases, which selectively phosphorylate eIF2α to mediate ISR 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 report that compound A8 can preferentially activate the ISR through the binding of the cytosolic pattern recognition receptor RIG-I, which subsequently activates the heme-regulated inhibitor (HRI) ISR kinase independent of an interferon response. The establishment of A8 and its active metabolite CC81 provides opportunities to probe the biological and therapeutic relationship between innate immune signaling and ISR activation in health and disease.
Source: Science Advances
Authors: Caroline A. Cuoco, Wen Ren, Kelsey R. Baron, Sakina Gologo, Valerie Perea, Prakhyat Mathur, Prerona Bora, Amina Ta, Alan Chu, Rama Aldakhlallah, Derek Rhoades, Christian M. Cole, Ee Phie Tan, William C. Hou, Leonard Yoon, Xiaoyan Guo, Jessica D. Rosarda, Phil S. Baran, Martin Kampmann, Lakeisha Tillery, Kristen A. Johnson, Evan T. Powers, R. Luke Wiseman, Jeffery W. Kelly
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $4,500
OpenAlex ID: W4415673302