UPR proteins IRE1 and PERK switch BiP from chaperone to ER stress sensor

BiP is a major ER chaperone and suggested to act as primary sensor in the activation of the unfolded protein response (UPR). How BiP operates as a molecular chaperone and as an ER stress sensor is unknown. Here, by reconstituting components of human UPR, ER stress and BiP chaperone systems, we discover that the interaction of BiP with the luminal domains (LD) of UPR proteins, IRE1 and PERK, switch BiP from its chaperone cycle into an ER stress sensor cycle by preventing the binding of its cochaperones, with loss of ATPase stimulation. Furthermore, misfolded proteindependent dissociation of BiP from IRE1 is primed by ATP but not ADP. Our data elucidate a previously unidentified mechanistic cycle of BiP function that explains its ability to act as a Hsp70 chaperone and ER stress sensor