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Inhibition of N-linked glycosylation leads to Accumulation, misfolded proteins
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||Marvin Martens (send email)||Under development: Not open for comment. Do not cite|
Life Stage Applicability
Key Event Relationship Description
Inhibition of glycosylation leads to an accumulation of misfolded proteins in the ER.
Evidence Supporting this KER
The inhibition compromises the Glycosylation-directed quality control of the ER associated degradation (ERAD) leading to a build up of misfolded proteins. N-linked glycosylation is crucial for correct recognition and clearance of misfolded proteins. Their ability to bypass clearance leads to the build up of misfolded proteins.
Uncertainties and Inconsistencies
What is causing the misfolding?
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Adnan, H. et al. (2016) ‘Endoplasmic reticulum-targeted subunit toxins provide a new approach to rescue misfolded mutant proteins and revert cell models of genetic diseases’, PLoS ONE, 11(12), pp. 1–19. doi:10.1371/journal.pone.0166948
Araki, K. and Nagata, K. (2012) ‘SUP: Protein folding and quality control in the ER.’, Cold Spring Harbor perspectives in biology, 4(8), p. a015438. doi:10.1101/cshperspect.a015438
Breitling, J. and Aebi, M. (2013) ‘N-linked protein glycosylation in the endoplasmic reticulum’, Cold Spring Harbor Perspectives in Biology, 5(8), pp. 1–15. doi: 10.1101/cshperspect.a013359.
Draheim, V., Reichel, A., Weitschies, W., & Moenning, U. (2010). N-glycosylation of ABC transporters is associated with functional activity in sandwich-cultured rat hepatocytes. European Journal of Pharmaceutical Sciences, 41(2), 201–209. https://doi.org/10.1016/j.ejps.2010.06.005
Kim, W., Spear, E. D. and Ng, D. T. W. (2005) ‘Yos9p detects and targets misfolded glycoproteins for ER-associated degradation’, Molecular Cell, 19(6), pp. 753–764. doi: 10.1016/j.molcel.2005.08.010
Stein, A. et al. (2014) ‘Key Steps in ERAD of Luminal ER Proteins Reconstituted with Purified Components’, Cell. doi: 10.1016/j.cell.2014.07.050.
Li, K. et al. (2011) ‘Repression of N-glycosylation triggers the unfolded protein response (UPR) and overexpression of cell wall protein and chitin in aspergillus fumigatus’, Microbiology, 157(7), pp. 1968–1979. doi:
Shao, S. and Hegde, R. S. (2016) ‘Target Selection during Protein Quality Control’, Trends in Biochemical Sciences. Elsevier Ltd, 41(2), pp. 124–137. doi: 10.1016/j.tibs.2015.10.007.
Shental-Bechor, D. and Levy, Y. (2008) ‘Effect of glycosylation on protein folding: A close look at thermodynamic stabilization’, Proceedings of the National Academy of Sciences, 105(24), pp. 8256–8261. doi: 10.1073/pnas.0801340105.
Nakajima, S. et al. (2011) ‘Selective Abrogation of BiP/GRP78 Blunts Activation of NF- B through the ATF6 Branch of the UPR: Involvement of C/EBP and mTOR-Dependent Dephosphorylation of Akt’, Molecular and Cellular Biology. doi: 10.1128/MCB.00939-10.
Olivari, S., & Molinari, M. (2007). Glycoprotein folding and the role of EDEM1, EDEM2 and EDEM3 in degradation of folding-defective glycoproteins. FEBS Letters, 581(19), 3658–3664. https://doi.org/10.1016/j.febslet.2007.04.070
Xu, C. and Ng, D. T. W. (2015) ‘Glycosylation-directed quality control of protein folding’, Nature Reviews Molecular Cell Biology. Nature Publishing Group, 16(12), pp. 742–752. doi: 10.1038/nrm4073.