Fig. 1. Endoplasmic reticulum (ER) stress induces the unfolded protein response signaling by three types of ER stress sensors: inositol-requiring enzyme 1 (IRE1), protein kinase RNA-like ER kinase (PERK) and activating transcription factor 6 (ATF6). Misfolded proteins sequestrate glucose-regulated protein 78 kDa (Grp78), thus allowing activation of three ER membrane-associated proteins. Activated IRE1 cleaves X box-binding protein 1 (XBP1) mRNA to a spliced form (XBP1s) that is translated to gene sets involved in ER-associated protein degradation (ERAD), ER chaperones, lipid biosynthesis and glycosylation. Along with selective XBP1 mRNA splicing, other mRNA are degraded through regulated IRE1-dependent decay (RIDD). In addition, IRE1 activates c-Jun N-treminal kinase (JNK) and p38 by IRE1-tumor necrosis factor receptor associated factor 2 (TRAF2)-apoptotic signaling kinase-1 (ASK1) complex and induce apoptosis by inhibiting anti-apoptotic proteins. Activation of PERK phosphorylates eukaryotic translation initiator factor 2α (eIF2α), selective induction of ATF4 and its downstream protein C/EBP homologous protein (CHOP), resulting in apoptosis. This pathway is negatively regulated by a phosphate complex protein phosphate 1c (PP1c) and stress-induced regulatory subunit DNA damage-inducible protein 34 kDA (GADD34). In addition PERK also activates nuclear factor erythroid 2-related factor 2 (NRF2), which induce antioxidant responses. ATF6 is translocated into golgi where it is cleaved by the site 1 and site 2 protease to release the transcription factor that regulates chaperones expression, transcription of genes with an ER stress response elements (ERSE), ERAD and CHOP.