API

Relationship: 1729

Title

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Protein Adduct Formation leads to Unfolded Prortein Response

Upstream event

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Protein Adduct Formation

Downstream event

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Unfolded Prortein Response

Key Event Relationship Overview

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AOPs Referencing Relationship

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AOP Name Adjacency Weight of Evidence Quantitative Understanding
CYP2E1 activation and formation of protein adducts leading to neurodegeneration adjacent Moderate Moderate

Taxonomic Applicability

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Sex Applicability

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Life Stage Applicability

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Key Event Relationship Description

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Covalent binding of metabolites or other molecules, such as HNE, with key ER proteins can induce ER stress or can cause oxidative damage in the ER. The mechanism is not completely understood. The principle is that modified proteins are not able to be folded in the correct way, leading to accumulation of unfolded proteins in the ER. Another possibility is that key proteins in the ER are altered, which inhibits their function. Ultimately the ER homeostasis will be disturbed, which leads to ER stress and the activation of UPR.

Evidence Supporting this KER

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HNE-modified proteins are detected after lipid peroxidation, as is described in KER 4. More recent research showed that the modified proteins by HNE are also ER proteins, such as protein disulphide isomerase, glucose regulated protein 58/78 and heat shock protein 60. To confirm whether protein-HNE adducts can induce ER stress and UPR, changes in the PERK pathway were monitored. After HNE treatment in rat aortic smooth muscle cells the expression in the PERK pathway increased. Cumaoglu et al. performed a study related to diabetes, and also found that a higher concentration of HNE in cells lead to a higher expression of PERK. Moreover, other proteasomes function in the cell can be carbonylated by CYP2E1 dependent oxidant stress.

For toxicants which can directly form protein adducts which leads to UPR is not much known, certainly not about the mechanism. Cisplatin can bind to microsomal compartments which induce ER stress and ultimately UPR. Metabolites of cyclosporin and acetaminophen can also bind to microsomal compartments with the same effect as cisplatin.

Acetaldehyde and malondialdehyde (product lipid peroxidation) can react together and can form MAA-adducts. There is no direct link with UPR, but the MAA-adducts are very stable. MAA modified proteins are found in the lungs and skin. Further research is needed to detect whether the can interact with ER proteins.

Biological Plausibility

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The biological plausibility can be found in literature, but mechanism is not known. For ethanol, the metabolite acetaldehyde specifically, there is no direct link between protein adduct and UPR

Empirical Evidence

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Uncertainties and Inconsistencies

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Quantitative Understanding of the Linkage

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Response-response Relationship

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Time-scale

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Known modulating factors

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Known Feedforward/Feedback loops influencing this KER

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Domain of Applicability

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References

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Sapkota, M. & Wyatt, T. A. Alcohol, aldehydes, adducts and airways. Biomolecules 5, 2987–3008 (2015).

Tuma, D. J. Role of malondialdehyde-acetaldehyde adducts in liver injury. Free Radical Biology and Medicine 32, 303–308 (2002).

Foufelle, F. & Fromenty, B. Role of endoplasmic reticulum stress in drug-induced toxicity. Pharmacol. Res. Perspect. 4, e00211 (2016).

Haberzettl, P. & Hill, B. G. Oxidized lipids activate autophagy in a JNK-dependent manner by stimulating the endoplasmic reticulum stress response. Redox Biol. 1, 56–64 (2013).

Galligan, J. J. et al. Oxidative stress-mediated aldehyde adduction of GRP78 in a mouse model of alcoholic liver disease: Functional independence of ATPase activity and chaperone function. Free Radic. Biol. Med. 73, 411–420 (2014).

Cumaoglu, A., Arıcıoglu, A. & Karasu, C. Redox status related activation of endoplasmic reticulum stress and apoptosis caused by 4-hydroxynonenal exposure in INS-1 cells. Toxicol. Mech. Methods 24, 362–367 (2014).

Kessova, I. G. & Cederbaum, A. I. The effect of CYP2E1-dependent oxidant stress on activity of proteasomes in HepG2 cells. J Pharmacol Exp Ther 315, 304–312 (2005).

Huličiak, M. et al. Covalent binding of cisplatin impairs the function of Na +/K +-ATPase by binding to its cytoplasmic part. Biochem. Pharmacol. 83, 1507–1513 (2012).

Sadrieh, N. & Thomas, P. E. Characterization of rat cytochrome P450 isozymes involved in the covalent binding of cyclosporin A to microsomal proteins. Toxicol. Appl. Pharmacol. 127, 222–232 (1994).

Shin, N. Y., Liu, Q., Stamer, S. L. & Liebler, D. C. Protein targets of reactive electrophiles in human liver microsomes. Chem. Res. Toxicol. 20, 859–867 (2007).