Figure 2

The UPR is negatively regulated by GRP78/Bip, which associates with the three proximal sensors, IRE1, PERK and ATF6. GRP78 binds to the luminal domains of IRE1 and PERK and prevents their dimerization and activation. GRP78 associates with ATF6 and prevents its translocation to the Golgi for further activation. In the presence of misfolded proteins, GRP78 dissociates from the sensors and binds the misfolded proteins, thus releasing the sensors from negative inhibition. The three sensors coordinately regulate the UPR through their various signaling pathways.