BiP-bound and nonclustered mode of Ire1 evokes a weak but sustained unfolded protein response

Genes Cells. 2013 Apr;18(4):288-301. doi: 10.1111/gtc.12035. Epub 2013 Feb 6.


In eukaryotic cells under nonstressed conditions, the endoplasmic reticulum (ER)-located molecular chaperone BiP is associated with an ER-membrane protein Ire1 to inhibit its self-association. While ER stress leads Ire1 to form transiently BiP-unbound clusters, which strongly evoke the unfolded protein response (UPR), here we propose an alternative activation status of Ire1. When yeast cells are physiologically ER-stressed by inositol depletion for a prolonged time, the UPR is weakly activated in a sustained manner after a transient peak of activation. During persistent stress, Ire1 foci disappear, while Ire1 continues to be self-associated. Under these conditions, Ire1 may be activated as a homo-dimer, as it shows considerable activity even when carrying the W426A mutation, which allows Ire1 to form homo-dimers but not clusters. Unlike the Ire1 clusters, the nonclustered active form seems to be associated with BiP. An Ire1 mutant not carrying the BiP-association site continued to form clusters and to be activated strongly even after long-term stress. Similar observations were obtained when cells were ER-stressed by dithiothreitol. We thus propose that upon persistent ER stress, Ire1 is weakly and continuously activated in a nonclustered form through its (re)association with BiP, which disperses the Ire1 clusters.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Endoplasmic Reticulum / metabolism
  • Endoplasmic Reticulum Stress
  • Fungal Proteins / genetics
  • Fungal Proteins / metabolism*
  • HSP70 Heat-Shock Proteins / genetics
  • HSP70 Heat-Shock Proteins / metabolism*
  • Inositol / deficiency
  • Membrane Glycoproteins / chemistry
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Mutation, Missense
  • Protein Binding
  • Protein Multimerization
  • Protein Serine-Threonine Kinases / chemistry
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Protein Unfolding
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins / chemistry
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Unfolded Protein Response*


  • Fungal Proteins
  • HSP70 Heat-Shock Proteins
  • KAR2 protein, yeast
  • Membrane Glycoproteins
  • Saccharomyces cerevisiae Proteins
  • Inositol
  • IRE1 protein, S cerevisiae
  • Protein Serine-Threonine Kinases