Abstract
IRE1α is a conserved branch of the unfolded protein response (UPR) that detects unfolded proteins in the lumen of the endoplasmic reticulum (ER) and propagates the signal to the cytosol. We have previously shown that IRE1α forms a complex with the Sec61 translocon to cleave its substrate mRNAs (Plumb et al., 2015). This complex also regulates IRE1α activation dynamics during ER stress in cells (Sundaram et al., 2017), but the underlying mechanism is unclear. Here, we show that Sec63 is a subunit of the IRE1α/Sec61 translocon complex. Sec63 recruits and activates BiP ATPase through its luminal J-domain to bind onto IRE1α. This Sec63-mediated BiP binding to IRE1α suppresses the formation of higher-order oligomers of IRE1α, leading to proper attenuation of IRE1α RNase activity during persistent ER stress. Thus, our data suggest that the Sec61 translocon bridges IRE1α with Sec63/BiP to regulate the dynamics of IRE1α activity in cells.