(A) During homeostasis when normal protein folding occurs, chaperone protein glucose-related protein (GRP)78 binds transmembrane proteins IRE1, ATF6 and PERK in the ER. (B) Following mild stress leading to misfolding of proteins, the ER initiates the UPR cascade, releasing GRP78 to chaperone proper protein folding. Activated transmembrane proteins damp down protein synthesis except for proteins required for the UPR to restore equilibrium. (C) Severe, prolonged stress to the ER can induce cell death that overwhelms the UPR and culminates in cell death through many mechanisms.