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

Science. 2021 Jan 1;371(6524):eabb6896. doi: 10.1126/science.abb6896.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Apoptosis
  • Cells, Cultured
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Endoplasmic Reticulum Stress / genetics*
  • Eukaryotic Initiation Factor-2 / metabolism
  • Gene Expression Regulation*
  • Humans
  • Inflammation / genetics
  • Inflammation / metabolism*
  • Inflammation / pathology
  • Intestinal Mucosa / metabolism
  • Intestinal Mucosa / pathology
  • Mice
  • Organoids
  • Proteostasis / genetics*
  • RNA-Seq
  • Single-Cell Analysis
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription, Genetic
  • Unfolded Protein Response / genetics*
  • eIF-2 Kinase / metabolism

Substances

  • DNA-Binding Proteins
  • Eukaryotic Initiation Factor-2
  • QRICH1 protein, human
  • Transcription Factors
  • PERK kinase
  • eIF-2 Kinase