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Relationship: 1864

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Inhibition of N-linked glycosylation leads to Accumulation, misfolded proteins

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes. Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

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 Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help

Sex Applicability

An indication of the the relevant sex for this KER. More help

Life Stage Applicability

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Key Event Relationship Description

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Inhibition of glycosylation leads to an accumulation of misfolded proteins in the ER.

Evidence Collection Strategy

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Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

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
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

What is causing the misfolding?

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help
Response-response Relationship
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Time-scale
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help
Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

References

List of the literature that was cited for this KER description. More help

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.