A Molecular Mechanism for Turning off IRE1α Signaling During Endoplasmic Reticulum Stress

Misfolded proteins in the endoplasmic reticulum (ER) activate IRE1 endoribonuclease in mammalian cells, which mediates XBP1 mRNA splicing to produce an active transcription factor. This promotes the expression of specific genes to alleviate ER stress and thereby attenuating IRE1. Although sustained activation of IRE1 is linked to human diseases, it is not clear how IRE1 is attenuated during ER stress. Here, we identify that Sec63 is a subunit of the previously identified IRE1/Sec61 translocon complex. We find that Sec63 recruits and activates BiP ATPase through its luminal J-domain to bind onto IRE1. This leads to inhibition of higher-order oligomerization and attenuation of IRE1 RNase activity during prolonged ER stress. In Sec63 deficient cells, IRE1 remains activated for a long time despite the presence of excess BiP in the ER. Thus, our data suggest that the Sec61 translocon bridges IRE1 with Sec63/BiP to regulate the dynamics of IRE1 signaling in cells.