Proapoptotic BAX and BAK modulate the unfolded protein response by a direct interaction with IRE1α

Accumulation of misfolded protein in the endoplasmic reticulum (ER) triggers an adaptive stress response-termed the unfolded protein response (UPR)-mediated by the ER transmembrane protein kinase and endoribonuclease inositol-requiring enzyme-1 alpha (IRE1 alpha). We investigated UPR signaling events in mice in the absence of the proapoptotic BCL-2 family members BAX and BAK [double knockout (DKO)]. DKO mice responded abnormally to tunicamycin-induced ER stress in the liver, with extensive tissue damage and decreased expression of the IRE1 substrate X-box-binding protein 1 and its target genes. ER-stressed DKO cells showed deficient IRE1a signaling. BAX and BAK formed a protein complex with the cytosolic domain of IRE1 alpha that was essential for IRE1 alpha activation. Thus, BAX and BAK function at the ER membrane to activate IRE1 alpha signaling and to provide a physical link between members of the core apoptotic pathway and the UPR.