A J-Protein Co-chaperone Recruits BiP to Monomerize IRE1 and Repress the Unfolded Protein Response

Cell. 2017 Dec 14;171(7):1625-1637.e13. doi: 10.1016/j.cell.2017.10.040. Epub 2017 Nov 30.


When unfolded proteins accumulate in the endoplasmic reticulum (ER), the unfolded protein response (UPR) increases ER-protein-folding capacity to restore protein-folding homeostasis. Unfolded proteins activate UPR signaling across the ER membrane to the nucleus by promoting oligomerization of IRE1, a conserved transmembrane ER stress receptor. However, the coupling of ER stress to IRE1 oligomerization and activation has remained obscure. Here, we report that the ER luminal co-chaperone ERdj4/DNAJB9 is a selective IRE1 repressor that promotes a complex between the luminal Hsp70 BiP and the luminal stress-sensing domain of IRE1α (IRE1LD). In vitro, ERdj4 is required for complex formation between BiP and IRE1LD. ERdj4 associates with IRE1LD and recruits BiP through the stimulation of ATP hydrolysis, forcibly disrupting IRE1 dimers. Unfolded proteins compete for BiP and restore IRE1LD to its default, dimeric, and active state. These observations establish BiP and its J domain co-chaperones as key regulators of the UPR.

Keywords: Allosteric Regulation; Biological Feedback; Endoplasmic Reticulum; Fluorescence Resonance Energy Transfer; HSP70 Heat-Shock Proteins; Protein Dimerization; Protein Folding; Repressor Protein; Stress; Unfolded Protein Response.

MeSH terms

  • Animals
  • Cricetinae
  • Endoplasmic Reticulum / metabolism
  • Endoplasmic Reticulum Chaperone BiP
  • Endoribonucleases / metabolism*
  • HSP40 Heat-Shock Proteins / metabolism*
  • Heat-Shock Proteins / metabolism*
  • Humans
  • Membrane Proteins / metabolism*
  • Molecular Chaperones / metabolism*
  • Protein Folding
  • Protein Serine-Threonine Kinases / metabolism*
  • Unfolded Protein Response*


  • DNAJB9 protein, human
  • Endoplasmic Reticulum Chaperone BiP
  • HSP40 Heat-Shock Proteins
  • Heat-Shock Proteins
  • Membrane Proteins
  • Molecular Chaperones
  • ERN1 protein, human
  • Protein Serine-Threonine Kinases
  • Endoribonucleases