Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Science. 2021 Jan 1;371(6524). doi: 10.1126/science.abb6896.
Tissue homeostasis is perturbed in a diversity of inflammatory pathologies. These changes can elicit endoplasmic reticulum (ER) stress, protein misfolding, and cell death. ER stress triggers the unfolded protein response (UPR), which can promote recovery of ER proteostasis and cell survival or trigger programmed cell death. Here, we leveraged single-cell RNA sequencing to define dynamic transcriptional states associated with the adaptive versus terminal UPR in the mouse intestinal epithelium. We integrated these transcriptional programs with genome-scale CRISPR screening to dissect the UPR pathway functionally. We identified QRICH1 as a key effector of the PERK-eIF2α axis of the UPR. QRICH1 controlled a transcriptional program associated with translation and secretory networks that were specifically up-regulated in inflammatory pathologies. Thus, QRICH1 dictates cell fate in response to pathological ER stress.
组织内稳态在多种炎症性病理中受到干扰。这些变化会引起内质网 (ER) 应激、蛋白质错误折叠和细胞死亡。ER 应激会触发未折叠蛋白反应 (UPR)，这可以促进 ER 蛋白平衡和细胞存活的恢复，或触发程序性细胞死亡。在这里，我们利用单细胞 RNA 测序来定义与小鼠肠上皮细胞中适应性与终末 UPR 相关的动态转录状态。我们将这些转录程序与基因组规模的 CRISPR 筛选相结合，从功能上解析 UPR 途径。我们确定 QRICH1 是 UPR 中 PERK-eIF2α 轴的关键效应因子。QRICH1 控制着与翻译和分泌网络相关的转录程序，这些程序在炎症性病理中特异性地上调。因此，QRICH1 决定了细胞在应对病理性 ER 应激时的命运。
