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Unfolded Prortein Response leads to General Apoptosis
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|CYP2E1 activation and formation of protein adducts leading to neurodegeneration||adjacent||High||High||Jelle Broeders (send email)||Under development: Not open for comment. Do not cite|
Life Stage Applicability
Key Event Relationship Description
During the UPR several proteins are released from the ER. When cells have too much stress, due to ROS or other factors, and can’t restore the ER homeostasis pro-death programs are activated. This is done by the proteins IRE1, PERK and ATF-6 which are released from the ER. The main protein involved in apoptosis is CHOP, which is part of the pathway after activation of the PERK protein. But also IRE1 plays a big role in the cell death regulation.
Evidence Collection Strategy
Evidence Supporting this KER
Several studies are performed using western blotting and inhibition assays to find out which proteins are activated in UPR and which have a role in cell death. CHOP has two different roles, which can induce cell death or has a protective function for survival. CHOP is activated by ATF4, which is first activated by a phosphorylated eIF2a. eIF2a is phosphorylated by an activated PERK. IRE1 and PERK activation leads to higher expression of caspases which induce cell death, by Nf-kB and ATF4 activation respectively. Another study showed a direct link between UPR and apoptosis. DHCR24 inhibited apoptosis by interfering with ER stress which resulted in lower levels of CHOP.
That UPR can induce apoptosis is known, but the exact mechanism is not completely clear since many proteins play a role.
Uncertainties and Inconsistencies
Different forms of ER stress can lead to different UPR reactions.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Foufelle, F. & Fromenty, B. Role of endoplasmic reticulum stress in drug-induced toxicity. Pharmacol. Res. Perspect. 4, e00211 (2016).
Hiramatsu, N., Chiang, W. C., Kurt, T. D., Sigurdson, C. J. & Lin, J. H. Multiple Mechanisms of Unfolded Protein Response-Induced Cell Death. Am. J. Pathol. 185, 1800–1808 (2015).
Sano, R. & Reed, J. C. ER stress-induced cell death mechanisms. Biochimica et Biophysica Acta - Molecular Cell Research 1833, 3460–3470 (2013).
Hiramatsu, N. et al. Translational and posttranslational regulation of XIAP by eIF2 and ATF4 promotes ER stress-induced cell death during the unfolded protein response. Mol. Biol. Cell 25, 1411–1420 (2014).
Shah, A. & Kumar, A. Methamphetamine-mediated endoplasmic reticulum (ER) stress induces type-1 programmed cell death in astrocytes via ATF6, IRE1 beta and PERK pathways. Oncotarget 7, 46100–46119 (2016).
Han, J. et al. ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death. Nat. Cell Biol. 15, 481–490 (2013).
Lu, X. et al. 3 ??-hydroxysteroid-?? 24 reductase (DHCR24) protects neuronal cells from apoptotic cell death induced by Endoplasmic Reticulum (ER) stress. PLoS One 9, (2014).