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Accumulation, misfolded proteins leads to Unfolded Prortein Response
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Inhibition of N-linked glycosylation leads to liver injury||adjacent||Not Specified||Not Specified||Arthur Author (send email)||Under development: Not open for comment. Do not cite|
Life Stage Applicability
Key Event Relationship Description
The accumulation of unfolded proteins in the ER triggers the activation of sensors involved in the unfolded protein response.
Evidence Collection Strategy
Evidence Supporting this KER
The activation of the UPR is well documented and known to be related to liver injury.
Uncertainties and Inconsistencies
Is there a threshold when the amount of misfolded proteins so great that the adverse outcome is triggered from the UPR?
Are all 3 branches involved in the adverse outcome? Do they need to be individually described? All the complex feedback loops make for many KERs
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Aebi, M. (2013) ‘N-linked protein glycosylation in the ER’, Biochimica et Biophysica Acta - Molecular Cell Research. Elsevier B.V., 1833(11), pp. 2430–2437. doi: 10.1016/j.bbamcr.2013.04.001.
Chambers, J. E. and Marciniak, S. J. (2014) ‘Cellular Mechanisms of Endoplasmic Reticulum Stress Signaling in Health and Disease. 2. Protein misfolding and ER stress’, AJP: Cell Physiology, 307(8), pp. C657–C670. doi: 10.1152/ajpcell.00183.2014.
Dufey, E. et al. (2014) ‘Cellular Mechanisms of Endoplasmic Reticulum Stress Signaling in Health and Disease. 1. An overview’, AJP: Cell Physiology, 307(7), pp. C582–C594. doi: 10.1152/ajpcell.00258.2014.
Gerlach, J. Q., Sharma, S. and Leister, K. J. (2012) ‘Endoplasmic Reticulum Stress in Health and Disease’, pp. 23–40. doi: 10.1007/978-94-007-4351-9.
Haze, K. et al. (1999) ‘Mammalian Transcription Factor ATF6 Is Synthesized as a Transmembrane Protein and Activated by Proteolysis in Response to Endoplasmic Reticulum Stress’, Molecular Biology of the Cell, 10(11), pp. 3787–3799. doi: 10.1091/mbc.10.11.3787.
Hetz, C. et al. (2011) ‘The Unfolded Protein Response: Integrating Stress Signals Through the Stress Sensor IRE1 ’, Physiological Reviews. doi: 10.1152/physrev.00001.2011.
Hetz, C. (2012) ‘The unfolded protein response: controlling cell fate decisions under ER stress and beyond’, Nature reviews. Molecular cell biology, 13(2), pp. 89–102. doi: 10.1038/nrm3270.
Hetz, C. and Papa, F. R. (2017) ‘The Unfolded Protein Response and Cell Fate Control’. doi: 10.1016/j.molcel.2017.06.017.
Ma, Y. and Hendershot, L. M. (2004) ‘ER chaperone functions during normal and stress conditions’, Journal of Chemical Neuroanatomy, 28(1–2), pp. 51–65. doi: 10.1016/j.jchemneu.2003.08.007.
Oyadomari, S. and Mori, M. (2004) ‘Roles of CHOP/GADD153 in endoplasmic reticulum stress’, Cell Death and Differentiation. Nature Publishing Group, 11(4), pp. 381–389. doi: 10.1038/sj.cdd.4401373.
Ramos-Castañeda, J. et al. (2005) ‘Deficiency of ATP2C1, a Golgi ion pump, induces secretory pathway defects in endoplasmic reticulum (ER)-associated degradation and sensitivity to ER stress’, Journal of Biological Chemistry, 280(10), pp. 9467–9473. doi: 10.1074/jbc.M413243200.
Ron, D. and Walter, P. (2007) ‘Signal integration in the endoplasmic reticulum unfolded protein response’, Nature Reviews Molecular Cell Biology. doi: 10.1038/nrm2199.
Vattem, K. M. and Wek, R. C. (2004) ‘Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in mammalian cells’, Proceedings of the National Academy of Sciences, 101(31), pp. 11269–11274. doi: 10.1073/pnas.0400541101.
Wang, M. and Kaufman, R. J. (2016) ‘Protein misfolding in the endoplasmic reticulum as a conduit to human disease’, Nature, 529(7586), pp. 326–335. doi: 10.1038/nature17041.
Yoshida, H. et al. (2001) ‘XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor’, Cell, 107(7), pp. 881–891. doi: 10.1016/S0092-8674(01)00611-0.