The J-domain of Sec63 recruits and activates BiP to bind onto IRE1α under normal conditions. Upon ER stress, BiP is released from IRE1α to bind to unfolded proteins, leading to IRE1α oligomerization and activation. Once activated, IRE1α-mediates XBP1 mRNA splicing, resulting in the production of the active transcription factor (XBP1s) that activates the expression of ER chaperones and quality control factors (not shown). During prolonged ER stress, Sec63 recruits upregulated BiP to bind onto IRE1α and hence inhibits IRE1α oligomerization and RNase activity.