ER stress (UPR pathway) Simple review

  Cellular stress conditions, such as glucose deprivation,depletion of ER Ca2+ stores, exposure to free radicals, and accumulation of unfolded/misfolded proteins, disrupt the proper function of the ER and initiates cell stress response, the unfolded protein response (UPR).

 UPR is characterized by the activation of three ER transmembrane effector proteins: PKR-like ER kinase (PERK), inositol requiring enzyme 1 (IRE1), and the activating transcription factor-6 (ATF-6).

 One major pathway of UPR is the suppression of most protein translations through phosphorylation of eukaryotic translation initiation factor 2 subunit a (eIf2a) by PERK.

 Another pathway is the upregulated expression of ER-localized molecular chaperones, such as glucoseregulated protein 78 (GRP78/Bip), GRP94 and other molecular chaperones like heat shock proteins (HSPs).

 However, prolonged ER stress may activate an ER stress-dependent apoptotic pathway
by induction of caspases-12 and CHOP (C/EBP homologous protein, growth arrest and DNA damage inducible gene 153, GADD153).

Fig 1. Mechanism of transcriptional induction of CHOP in ER stress. Under ER stress conditions, BiP binds to unfolded proteins and thereby renders each ER stress transducers including PERK, ATF6 and Ire1 to be activated. Activated PERK phosphorylates eIF2, which results in translational induction of ATF4. BiP-free pATF6(p) is transported to the Golgi apparatus and pATF6(N) is released by proteolysis. Activated Ire1 cleaves XBP-1 mRNA precursor to mature XBP-1 mRNA by unique splicing. XBP-1 mRNA precursor is also upregulated by pATF6(N). On ER stress, the transcriptional induction of CHOP is regulated at least by four cis-acting elements, AARE1, AARE2, ERSE1 and ERSE2. ATF4, pATF6(N) and XBP-1 are known to activate transcription of CHOP. ATF4 binds to AARE1 and AARE2. ATF2 and ATF3 can bind to the CHOP AARE. However, the role of ATF2 and ATF3 in induction of CHOP during ER stress is unclear. Both pATF6(N) and XBP-1 bind to the CACG part of ERSE1 and ERSE2. NF-Y constitutively binds to the CCAAR part of ERSE1 and ERSE2

(a) Pathways of NO-induced cell death. Excessive NO leads to cell death through DNA damage or ER stress. DNA damage causes cell death via the apoptosis pathway mediated by activation of p53 or via the necrosis pathway mediated by activation of PARP, which results in depletion of NAD+ and ATP. While high amounts of NO cause DNA damage, lower amounts of NO cause ER stress without DNA damage in some cell types such as pancreatic -cell, which has developed ER. NO depletes ER Ca2+, which results in accumulation of unfolded proteins in the ER, and leads to apoptosis via induction of CHOP and activation of JNK and caspase-12.