This Key Event Relationship is licensed under the Creative Commons BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.

Relationship: 1865


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

Accumulation, misfolded proteins leads to Unfolded Protein Response

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 Marvin Martens (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 Do not cite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

An indication of the the relevant life stage(s) for this KER.  More help

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

The accumulation of unfolded proteins in the ER triggers the activation of sensors involved in the unfolded protein response.

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

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 activation of the UPR is well documented and known to be related to liver injury.

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

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

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
Provides sources of data that define the response-response relationships between the KEs.  More help
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


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

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.