1. Pharmacologic IRE1/XBP1s activation confers targeted ER proteostasis reprogramming
- Author
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Timothy P. Spicer, R. Luke Wiseman, Christina B. Cooley, Lauren Cech, Louis Scampavia, Bryan O. Seguinot, Lars Plate, Evan T. Powers, Julia M. D. Grandjean, Jeffery W. Kelly, Aparajita Madhavan, Emery Smith, and Ryan J Paxman
- Subjects
0303 health sciences ,biology ,Cellular Reprogramming Techniques ,Chemistry ,Endoplasmic reticulum ,030302 biochemistry & molecular biology ,HEK 293 cells ,Cell Biology ,Cell biology ,03 medical and health sciences ,Proteostasis ,Unfolded protein response ,Amyloid precursor protein ,biology.protein ,Signal transduction ,Molecular Biology ,Chemical genetics ,030304 developmental biology - Abstract
Activation of the IRE1/XBP1s signaling arm of the unfolded protein response (UPR) is a promising strategy to correct defects in endoplasmic reticulum (ER) proteostasis implicated in diverse diseases. However, no pharmacologic activators of this pathway identified to date are suitable for ER proteostasis remodeling through selective activation of IRE1/XBP1s signaling. Here, we use high-throughput screening to identify non-toxic compounds that induce ER proteostasis remodeling through IRE1/XBP1s activation. We employ transcriptional profiling to stringently confirm that our prioritized compounds selectively activate IRE1/XBP1s signaling without activating other cellular stress-responsive signaling pathways. Furthermore, we demonstrate that our compounds improve ER proteostasis of destabilized variants of amyloid precursor protein (APP) through an IRE1-dependent mechanism and reduce APP-associated mitochondrial toxicity in cellular models. These results establish highly selective IRE1/XBP1s activating compounds that can be widely employed to define the functional importance of IRE1/XBP1s activity for ER proteostasis regulation in the context of health and disease.
- Published
- 2020