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

• Published in: Cell 2017-12, Vol.171 (7), p.1625-1637.e13
• Main Authors: Amin-Wetzel, Niko, Saunders, Reuben A., Kamphuis, Maarten J., Rato, Claudia, Preissler, Steffen, Harding, Heather P., Ron, David
• Format: Article
• Language: English
• Subjects: Allosteric Regulation; Animals; Biological Feedback; Cricetinae; Endoplasmic Reticulum; Endoplasmic Reticulum - metabolism; Endoribonucleases - metabolism; Fluorescence Resonance Energy Transfer; Heat-Shock Proteins - metabolism; HSP40 Heat-Shock Proteins - metabolism; HSP70 Heat-Shock Proteins; Humans; Membrane Proteins - metabolism; Molecular Chaperones - metabolism; Protein Dimerization; Protein Folding; Protein-Serine-Threonine Kinases - metabolism; Repressor Protein; Stress; Unfolded Protein Response
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2017.10.040

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. [Display omitted] •The endoplasmic reticulum co-chaperone ERdj4 selectively represses IRE1 signaling•ERdj4 associates with the IRE1 luminal domain and recruits the Hsp70 BiP•Recruited BiP hydrolyzes ATP to disrupt the active IRE1 luminal domain dimer•Unfolded proteins compete for the repressive machinery to restore IRE1 dimers Molecular basis for the regulation of the unfolded protein response by chaperones and misfolded proteins.