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Pharmacologic IRE1/XBP1s activation confers targeted ER proteostasis reprogramming
Julia M D Grandjean1, Aparajita Madhavan1, Lauren Cech1
1Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA.
Nature Chemical Biology
|July 22, 2020
Summary
Researchers identified novel compounds that selectively activate the IRE1/XBP1s pathway, crucial for endoplasmic reticulum (ER) proteostasis. These compounds show promise for treating diseases linked to ER dysfunction and amyloid precursor protein (APP) toxicity.
Area of Science:
- Molecular Biology
- Cellular Biology
- Pharmacology
Background:
- The unfolded protein response (UPR) pathway, particularly the IRE1/XBP1s arm, is a key regulator of endoplasmic reticulum (ER) proteostasis.
- Dysfunctional ER proteostasis is implicated in various diseases, making therapeutic modulation of this pathway a significant goal.
- Existing pharmacologic activators lack the selectivity required for precise ER proteostasis remodeling.
Purpose of the Study:
- To identify novel, non-toxic compounds that selectively activate the IRE1/XBP1s signaling pathway.
- To confirm the selective activation of IRE1/XBP1s signaling without off-target effects on other stress pathways.
- To evaluate the therapeutic potential of these compounds in cellular models of ER proteostasis defects and associated toxicity.
Main Methods:
- High-throughput screening of chemical libraries to identify potential activators.
- Transcriptional profiling to rigorously assess pathway selectivity.
- Cellular assays to evaluate ER proteostasis of destabilized amyloid precursor protein (APP) variants.
- Mitochondrial toxicity assays in cellular models.
Main Results:
- Identification of non-toxic compounds that induce ER proteostasis remodeling via IRE1/XBP1s activation.
- Confirmation of selective IRE1/XBP1s activation using transcriptional profiling, excluding other stress pathways.
- Demonstration that identified compounds improve ER proteostasis of destabilized APP variants through an IRE1-dependent mechanism.
- Reduction of APP-associated mitochondrial toxicity in cellular models.
Conclusions:
- Discovery of highly selective IRE1/XBP1s activating compounds.
- These compounds offer a valuable tool for investigating the role of IRE1/XBP1s in ER proteostasis in health and disease.
- Potential therapeutic applications for diseases characterized by ER proteostasis defects and protein misfolding.
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