Fig. 1

GRP78 in UPR and stress response. During ER stress, when misfolded proteins accumulate in the ER, GRP78 binds to the misfolded proteins, keeping them foldable and releasing three ER transmembrane proteins. The three proteins (IRE1, PERK, and ATF6) are activated to initiate the UPR signaling cascades. Activated IRE1 cleaves unspliced XBP1 mRNA, and the cleaved mRNA is then translated into the transcription factor XBP1s. PERK dimerizes, trans-autophosphorylates, and then phosphorylates eIF2α to inhibit protein translation. Phosphorylated eIF2α also activates the transcription factor, ATF4. ATF6 is transferred from the ER to the Golgi complex. ATF6 is cleaved in the Golgi by SiP1 and SiP2 proteases, releasing a cytosolic basic leucine zipper (bZIP) domain, which is transferred to the nucleus. Three transcription factors, including ATF4, XBP1s, and ATF6, synergistically control the expression of adaptive genes related to ERAD, ER-chaperones, pro-apoptotic CHOP, and autophagy, to maintain steady-state. In addition, activated PERK phosphorylates NRF2, thereby generating an antioxidant response to inhibit ROS accumulation