QRICH1 dictates the outcome of ER stress through transcriptional control of proteostasis

• Published in: Science (American Association for the Advancement of Science) Vol. 371; no. 6524
• Main Authors: You, Kwontae, Wang, Lingfei, Chou, Chih-Hung, Liu, Kai, Nakata, Toru, Jaiswal, Alok, Yao, Junmei, Lefkovith, Ariel, Omar, Abdifatah, Perrigoue, Jacqueline G, Towne, Jennifer E, Regev, Aviv, Graham, Daniel B, Xavier, Ramnik J
• Format: Journal Article
• Language: English
• Published: United States The American Association for the Advancement of Science 01.01.2021
• Subjects: Activating transcription factor 6; Adaptation; Adaptive control; Animals; Apoptosis; Biopsy; Cell death; Cell fate; Cell survival; Cells, Cultured; Chromatin; Colon; Context; CRISPR; Divergence; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; eIF-2 Kinase - metabolism; Endoplasmic reticulum; Endoplasmic Reticulum Stress - genetics; Enterocytes; Environmental stress; Epithelial cells; Epithelium; Eukaryotic Initiation Factor-2 - metabolism; Feedback (Response); Gene Expression Regulation; Gene regulation; Gene sequencing; Genomes; Golgi apparatus; Homeostasis; Humans; Immunoprecipitation; Inflammation; Inflammation - genetics; Inflammation - metabolism; Inflammation - pathology; Inflammatory bowel diseases; Intestinal Mucosa - metabolism; Intestinal Mucosa - pathology; Intestine; Kinases; Liver; Meta Analysis; Mice; Modules; Molecular modelling; Mortality; Organoids; Pathology; Protein biosynthesis; Protein kinase; Protein synthesis; Proteins; Proteostasis - genetics; Recovery; Ribonucleic acid; RNA; RNA-Seq; Single-Cell Analysis; Survival; Tissues; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription, Genetic; Translation; Ulcerative colitis; Unfolded Protein Response - genetics
• ISSN: 0036-8075; 1095-9203
• 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.