2. Academic Validation
  3. Pharmacologic IRE1/XBP1s activation confers targeted ER proteostasis reprogramming

Pharmacologic IRE1/XBP1s activation confers targeted ER proteostasis reprogramming

  • Nat Chem Biol. 2020 Oct;16(10):1052-1061. doi: 10.1038/s41589-020-0584-z.
Julia M D Grandjean 1,  Aparajita Madhavan 1,  Lauren Cech 1,  Bryan O Seguinot 1,  Ryan J Paxman 2,  Emery Smith 3,  Louis Scampavia 3,  Evan T Powers 2,  Christina B Cooley 4,  Lars Plate 5,  Timothy P Spicer 3,  Jeffery W Kelly 2 6,  R Luke Wiseman 7
Affiliations

Affiliations

  • 1 Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA.
  • 2 Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
  • 3 Scripps Research Molecular Screening Center, The Scripps Research Institute, Jupiter, FL, USA.
  • 4 Department of Chemistry, Trinity University, San Antonio, TX, USA.
  • 5 Departments of Chemistry and Biological Sciences, Vanderbilt University, Nashville, TN, USA.
  • 6 The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, USA.
  • 7 Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA. [email protected].
PMID: 32690944 DOI: 10.1038/s41589-020-0584-z
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.

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