Upstream eventUnfolded Prortein Response
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Inhibition of N-linked glycosylation leads to liver injury||adjacent||Not Specified||Not Specified|
Life Stage Applicability
Key Event Relationship Description
After UPR activation the downstream target of this pathway, CHOP, triggers apoptosis.
Evidence Supporting this KER
Hepatocyte apoptosis in response to UPR activation is well documented.Chop is the downstream target that gets activated by the UPR.(Puthalakath et al., 2007) It plays a major role in the induction of cell death (Marciniak et al., 2004)(Liu et al., 2014)
Chop induces apoptosis through the control of target genes (B’chir et al., 2014);(Teske et al., 2013)
Chop deficiency can reduce the extent of cell death after ER stress (Tamaki et al., 2008)(Hiramatsu et al., 2014)
Forced expression of CHOP increases the induction of cell death (Han et al., 2013) also in hepatocytes. (Uzi et al., 2013)(Rao et al., 2015)(Pfaffenbach et al., no date)
mRNA expression of CHOP can be measured (Kandel-Kfir et al., 2015)
(Dara, Ji and Kaplowitz, 2011); (Oyadomari and Mori, 2004); (Urra et al., 2013); (Hetz, 2012); (Sano and Reed, 2013); (Gorman et al., 2012); (Li et al., 2014);
Uncertainties and Inconsistencies
Due to the complex feedback loops within the UPR it is difficult to make this KER linear. CHOP is also involved in autophagy.
Quantitative Understanding of the Linkage
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
B’chir, W. et al. (2014) ‘Dual role for CHOP in the crosstalk between autophagy and apoptosis to determine cell fate in response to amino acid deprivation’, Cellular Signalling. Elsevier Inc., 26(7), pp. 1385–1391. doi: 10.1016/j.cellsig.2014.03.009.
Dara, L., Ji, C. and Kaplowitz, N. (2011) ‘The contribution of endoplasmic reticulum stress to liver diseases’, Hepatology, 53(5), pp. 1752–1763. doi: 10.1002/hep.24279.
Gorman, A. M. et al. (2012) ‘Stress management at the ER: Regulators of ER stress-induced apoptosis’, Pharmacology and Therapeutics. Elsevier Inc., 134(3), pp. 306–316. doi: 10.1016/j.pharmthera.2012.02.003.
Han, J. et al. (2013) ‘ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death’, Nature Cell Biology. doi: 10.1038/ncb2738.
Hetz, C. (2012) ‘The unfolded protein response: controlling cell fate decisions under ER stress and beyond’, Nature reviews. Molecular cell biology. Nature Publishing Group, 13(2), pp. 89–102. doi: 10.1038/nrm3270.
Hiramatsu, N. et al. (2014) ‘Translational and posttranslational regulation of XIAP by eIF2 and ATF4 promotes ER stress-induced cell death during the unfolded protein response’, Molecular Biology of the Cell, 25(9), pp. 1411–1420. doi: 10.1091/mbc.E13-11-0664.
Kandel-Kfir, M., Almog, T., Shaish, A., Shlomai, G., Anafi, L., Avivi, C., … Kamari, Y. (2015). Interleukin-1α deficiency attenuates endoplasmic reticulum stress-induced liver damage and CHOP expression in mice. Journal of Hepatology. https://doi.org/10.1016/j.jhep.2015.05.012
Li, Y. et al. (2014) ‘New insights into the roles of CHOP-induced apoptosis in ER stress Structure and Properties of C/EBP Homologous Protein Roles of CHOP in ER Stress-Mediated Apoptosis’, Acta Biochim Biophys Sin, 46(8), pp. 629–640. doi: 10.1093/abbs/gmu048.Review.
Liu, K. et al. (2014) ‘CHOP mediates ASPP2-induced autophagic apoptosis in hepatoma cells by releasing beclin-1 from Bcl-2 and inducing nuclear translocation of Bcl-2’, Cell Death and Disease. doi: 10.1038/cddis.2014.276.
Marciniak, S. J. et al. (2004) ‘CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum’, Genes and Development, 18(24), pp. 3066–3077. doi: 10.1101/gad.1250704.
Ohoka, N. et al. (2005) ‘TRB3, a novel ER stress-inducible gene, is induced via ATF4-CHOP pathway and is involved in cell death’, EMBO Journal, 24(6), pp. 1243–1255. doi: 10.1038/sj.emboj.7600596.
Oyadomari, S. and Mori, M. (2004) ‘Roles of CHOP/GADD153 in endoplasmic reticulum stress.’, Cell death and differentiation, 11(4), pp. 381–389. doi: 10.1038/sj.cdd.4401373.
Pfaffenbach, K. T. et al. (2010) ‘Linking endoplasmic reticulum stress to cell death in hepatocytes : roles of C / EBP homologous protein and chemical chaperones in palmitate-mediated cell death’, Am J Physiol Endocrinol Metab, 298, pp. 1027–1035. doi: 10.1152/ajpendo.00642.2009.
Pfaffenbach, K. T. et al. (no date) ‘Linking endoplasmic reticulum stress to cell death in hepatocytes: roles of C/EBP homologous protein and chemical chaperones in palmitate-mediated cell death’.
Puthalakath, H. et al. (2007) ‘ER Stress Triggers Apoptosis by Activating BH3-Only Protein Bim’, Cell. doi: 10.1016/j.cell.2007.04.027.
Rao, J. et al. (2015) ‘C/EBP homologous protein (CHOP) contributes to hepatocyte death via the promotion of ERO1α signalling in acute liver failure’, Biochem. J, 466, pp. 369–378. doi: 10.1042/BJ20140412.
Sano, R. and Reed, J. C. (2013) ‘ER stress-induced cell death mechanisms’, Biochimica et Biophysica Acta - Molecular Cell Research. Elsevier B.V., 1833(12), pp. 3460–3470. doi: 10.1016/j.bbamcr.2013.06.028.
Tamaki, N. et al. (2008) ‘CHOP deficiency attenuates cholestasis-induced liver fibrosis by reduction of hepatocyte injury.’, American journal of physiology. Gastrointestinal and liver physiology, 294(2), pp. G498-505. doi: 10.1152/ajpgi.00482.2007.
Teske, B. F. et al. (2013) ‘CHOP induces activating transcription factor 5 (ATF5) to trigger apoptosis in response to perturbations in protein homeostasis’, Molecular Biology of the Cell. doi: 10.1091/mbc.E13-01-0067.
Urra, H. et al. (2013) ‘When ER stress reaches a dead end’, Biochimica et Biophysica Acta - Molecular Cell Research. Elsevier B.V., 1833(12), pp. 3507–3517. doi: 10.1016/j.bbamcr.2013.07.024.
Uzi, D. et al. (2013) ‘CHOP is a critical regulator of acetaminophen-induced hepatotoxicity’, Journal of Hepatology. European Association for the Study of the Liver, 59(3), pp. 495–503. doi: 10.1016/j.jhep.2013.04.024.
Yi, L. et al. (2014) ‘Quercetin enhances apoptotic effect of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in ovarian cancer cells through reactive oxygen species (ROS) mediated CCAAT enhancer-binding protein homologous protein (CHOP)-death receptor 5 pathway’, Cancer Science, 105(5), pp. 520–527. doi: 10.1111/cas.12395.
Zhang, J. et al. (2015) ‘Hepatocyte autophagy is linked to C/EBP-homologous protein, Bcl2-interacting mediator of cell death, and BH3-interacting domain death agonist gene expression’, Journal of Surgical Research. Elsevier Inc, 195(2), pp. 588–595. doi: 10.1016/j.jss.2015.01.039.