Pharmacologic IRE1/XBP1s activation confers targeted ER proteostasis reprogramming.

Nature Chemical Biology
Julia M D GrandjeanR Luke Wiseman

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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Citations

Jul 25, 2020·Nature Chemical Biology·Nadia Cummins, Rebecca C Taylor
Sep 6, 2020·The Journal of Biological Chemistry·Julia M D Grandjean, R Luke Wiseman
Feb 11, 2021·Biomedicines·Natalia SiweckaIreneusz Majsterek
Feb 6, 2021·Molecular Therapy : the Journal of the American Society of Gene Therapy·René L VidalClaudio Hetz
Feb 24, 2021·Nature Reviews. Cardiology·Jun RenYingmei Zhang
Mar 4, 2021·Biomolecules·Talya ShachamGerardo Z Lederkremer
Aug 31, 2020·Trends in Cancer·Diana Pelizzari RaymundoEric Chevet
Aug 19, 2021·Endocrinology·Michael A KalwatMelanie H Cobb
Sep 25, 2021·Nature Chemical Biology·Hannah C FeldmanDustin J Maly

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Methods Mentioned

BETA
electrophoresis
RNA-seq
nuclear magnetic resonance
ELISA
PCR
transfection
protein assay
Infrared Imaging
dot blots
enzyme-linked immunosorbent assay

Software Mentioned

RiboPro
LI
RQ Manager
CellTiterGlo
DESeq
Library MCS
COR Image Studio
ChemAxon JChem Suite
ArrayStar
ImageQuant

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