Figure 1

ER luminal GRP78 acts as a UPR signaling regulator by binding to and maintaining the ER stress sensors (PERK, ATF6 and IRE1) in inactive forms. It also binds to and suppresses the activation of ER associated caspase-7 and -12 (C7/12). Upon ER stress, GRP78 is titrated away through binding to mal-folded proteins. This triggers the UPR, as exemplified by dimerization of PERK and IRE1, and activation of their downstream signaling pathways, leading to arrest of translation and ER associated protein degradation (ERAD). The UPR also generates the active nuclear form of ATF6, as well as ATF4, and the spliced form of XBP (XBP-1s), which act in concert with other transcriptional factors including YY1, NF-Y and TFII-I and chromatin modifiers, to activate the ER stress response element (ERSE) present on the promoters of ER stress responsive genes. A major UPR response is to induce the transcription of ER folding proteins such as the GRPs to booster the ER protein folding capacity, as well as the mitochondrial (Mito) chaperone GRP75. Stressed cells actively promote re-localization of GRP78 and GRP94 to the plasma membrane (PM), and in some instances, their secretion, and generate a cytosolic isoform of GRP78 (78va) through alternative splicing. Nonetheless, UPR can also induce transcription of the pro-apoptotic transcription factor CHOP, and following release from GRP78, caspase-7 and caspase-12 are activated, triggering apoptosis. Thus, the UPR regulates the balance between survival and cell death in stressed cells, and the up-regulation of the GRPs represents a major adaptive, protective measure through maintenance of cellular homeostasis.