Pharmacological targeting of RIG-I can selectively activate the integrated stress response
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.
Authors
- William C. Hou (ORCID: https://orcid.org/0009-0009-8635-438X)
- Derek Rhoades (ORCID: https://orcid.org/0000-0002-9536-424X)
- Amina Ta
- Caroline A. Cuoco (ORCID: https://orcid.org/0009-0002-0690-6391)
- Rama Aldakhlallah (ORCID: https://orcid.org/0009-0008-5833-0244)
- Prerona Bora (ORCID: https://orcid.org/0000-0002-3489-6146)
- Ee Phie Tan (ORCID: https://orcid.org/0000-0003-1352-0366)
- Kelsey R Baron (ORCID: https://orcid.org/0000-0002-6275-7522)
- Leonard Yoon (ORCID: https://orcid.org/0000-0002-8663-5757)
- Kristen Johnson (ORCID: https://orcid.org/0000-0003-0788-7217)
- Phil S. Baran (ORCID: https://orcid.org/0000-0001-9193-9053)
- Jessica D. Rosarda (ORCID: https://orcid.org/0000-0002-2742-7413)
- Valerie Perea
- Xiaoyan Guo (ORCID: https://orcid.org/0000-0002-9388-484X)
- Evan T. Powers (ORCID: https://orcid.org/0000-0001-8185-8487)
- Martin Kampmann (ORCID: https://orcid.org/0000-0002-3819-7019)
- Jeffery W. Kelly (ORCID: https://orcid.org/0000-0001-8943-3395)
- R. Luke Wiseman (ORCID: https://orcid.org/0000-0001-9287-6840)
- Christian M. Cole (ORCID: https://orcid.org/0009-0002-3946-3574)
- Prakhyat Mathur (ORCID: https://orcid.org/0000-0002-3129-4465)
- Alan Chu (ORCID: https://orcid.org/0000-0002-6669-9649)
- Wen Ren
- Lakeisha Tillery
- Sakina Gologo (ORCID: https://orcid.org/0009-0000-3479-1160)
Institutions
- Scripps Research Institute (US)
- Uniformed Services University of the Health Sciences (US)
- University of California, San Francisco (US)
- Institute for Neurodegenerative Disorders (US)
- California Institute for Biomedical Research (US)
Publication Details
- Journal
- Science Advances
- Published
- 2025-10-29
- DOI
- https://doi.org/10.1126/sciadv.adt3014
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 0.00