Serine/threonine-protein kinase/endoribonuclease IRE1
IRE1-mediated unfolded protein response
A J-Protein Co-chaperone Recruits BiP to Monomerize IRE1 and Repress the Unfolded Protein Response.
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 (IRE1<sup>LD</sup>). In vitro, ERdj4 is required for complex formation between BiP and IRE1<sup>LD</sup>. ERdj4 associates with IRE1<sup>LD</sup> and recruits BiP through the stimulation of ATP hydrolysis, forcibly disrupting IRE1 dimers. Unfolded proteins compete for BiP and restore IRE1<sup>LD</sup> to its default, dimeric, and active state. These observations establish BiP and its J domain co-chaperones as key regulators of the UPR.