Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA, USA.
Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.
Nat Chem Biol. 2020 Oct;16(10):1052-1061. doi: 10.1038/s41589-020-0584-z. Epub 2020 Jul 20.
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.
IRE1/XBP1s 信号通路的激活是纠正内质网（ER）稳态缺陷的有前途的策略，这些缺陷与多种疾病有关。然而，迄今为止，尚无鉴定出的该途径的药理学激活剂可通过选择性激活 IRE1/XBP1s 信号来进行 ER 蛋白稳态重塑。在这里，我们使用高通量筛选来鉴定非毒性化合物，这些化合物通过 IRE1/XBP1s 的激活来诱导 ER 蛋白稳态重塑。我们采用转录谱分析严格证实，我们优先考虑的化合物可选择性地激活 IRE1/XBP1s 信号，而不激活其他细胞应激反应信号通路。此外，我们证明我们的化合物通过 IRE1 依赖性机制改善了不稳定的淀粉样前体蛋白（APP）变体的 ER 蛋白稳态，并减少了细胞模型中 APP 相关的线粒体毒性。这些结果确立了高度选择性的 IRE1/XBP1s 激活化合物，可广泛用于定义 IRE1/XBP1s 活性在健康和疾病背景下对 ER 蛋白稳态调节的功能重要性。
