Stress sensor Ire1 deploys a divergent transcriptional program in response to lipid bilayer stress

J Cell Biol. 2020 Jul 6;219(7):e201909165. doi: 10.1083/jcb.201909165.

Abstract

Membrane integrity at the endoplasmic reticulum (ER) is tightly regulated, and its disturbance is implicated in metabolic diseases. Using an engineered sensor that activates the unfolded protein response (UPR) exclusively when normal ER membrane lipid composition is compromised, we identified pathways beyond lipid metabolism that are necessary to maintain ER integrity in yeast and in C. elegans. To systematically validate yeast mutants that disrupt ER membrane homeostasis, we identified a lipid bilayer stress (LBS) sensor in the UPR transducer protein Ire1, located at the interface of the amphipathic and transmembrane helices. Furthermore, transcriptome and chromatin immunoprecipitation analyses pinpoint the UPR as a broad-spectrum compensatory response wherein LBS and proteotoxic stress deploy divergent transcriptional UPR programs. Together, these findings reveal the UPR program as the sum of two independent stress responses, an insight that could be exploited for future therapeutic intervention.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biosensing Techniques
  • Caenorhabditis elegans / genetics*
  • Caenorhabditis elegans / metabolism
  • Caenorhabditis elegans Proteins / genetics*
  • Caenorhabditis elegans Proteins / metabolism
  • Chromatin / chemistry
  • Chromatin / metabolism
  • Endoplasmic Reticulum
  • Endoplasmic Reticulum Stress / genetics*
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Genes, Reporter
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Heat-Shock Proteins / genetics*
  • Heat-Shock Proteins / metabolism
  • Homeostasis / genetics
  • Intracellular Membranes / metabolism
  • Intracellular Membranes / ultrastructure
  • Lipid Bilayers / chemistry*
  • Lipid Bilayers / metabolism
  • Lipid Metabolism / genetics
  • Luminescent Proteins / genetics
  • Luminescent Proteins / metabolism
  • Membrane Glycoproteins / genetics*
  • Membrane Glycoproteins / metabolism
  • Protein-Serine-Threonine Kinases / genetics*
  • Protein-Serine-Threonine Kinases / metabolism
  • Saccharomyces cerevisiae / genetics*
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins / genetics*
  • Saccharomyces cerevisiae Proteins / metabolism
  • Transcription, Genetic
  • Unfolded Protein Response*

Substances

  • Caenorhabditis elegans Proteins
  • Chromatin
  • Heat-Shock Proteins
  • Hsp-4 protein, C elegans
  • Lipid Bilayers
  • Luminescent Proteins
  • Membrane Glycoproteins
  • Saccharomyces cerevisiae Proteins
  • red fluorescent protein
  • Green Fluorescent Proteins
  • IRE1 protein, S cerevisiae
  • Protein-Serine-Threonine Kinases