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.

激活未折叠蛋白反应 (UPR) 的 IRE1/XBP1s 信号臂是一种很有前途的策略，可以纠正与多种疾病有关的内质网 (ER) 蛋白稳态缺陷。然而，迄今为止，没有发现该途径的药理学激活剂适合通过选择性激活 IRE1/XBP1s 信号进行 ER 蛋白稳态重塑。在这里，我们使用高通量筛选来识别通过 IRE1/XBP1s 激活诱导 ER 蛋白稳态重塑的无毒化合物。我们使用转录分析来严格确认我们的优先化合物选择性地激活 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 依赖机制改善淀粉样前体蛋白 (APP) 不稳定变体的 ER 蛋白稳定，并减少细胞模型中与 APP 相关的线粒体毒性。这些结果建立了高度选择性的 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。