API

Relationship: 1864

Title

?

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

Upstream event

?

Inhibition of N-linked glycosylation

Downstream event

?


Accumulation, misfolded proteins

Key Event Relationship Overview

?


AOPs Referencing Relationship

?

AOP Name Adjacency Weight of Evidence Quantitative Understanding
Inhibition of N-linked glycosylation leads to liver injury adjacent Not Specified Not Specified

Taxonomic Applicability

?

Sex Applicability

?

Life Stage Applicability

?

Key Event Relationship Description

?


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

Evidence Supporting this KER

?


Biological Plausibility

?

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.

Empirical Evidence

?

The ER, glycosylation is performed to newly synthesized unfolded proteins. Misfolded proteins recognized by ER- associated degradation (ERAD). (Stein et al., 2014) (Breitling and Aebi, 2013)

The terminal glucoses and mannoses in combination with lectin receptors maintain correct folding of nascent polypeptide and contribute in the elimination of misfolded proteins(Adnan et al., 2016)(Araki & Nagata, 2012)(Shao & Hegde, 2016)(Kim, Spear, & Ng, 2005) (Li, K. et al. (2011)

This quality control of protein folding is glycosylation directed. Misfolded proteins that are unglycosylated fail to be recognized by ERAD (Shental-Bechor & Levy, 2008)(Xu and Ng, 2015)

Link between N-linked glycosylation and the UPR, disrupting glycosylation enhances the degradation of ATP binding cassette (Nakajima et al., 2011)

Experiments with cDNA encoding N-gly-cosylation-deficient P-gp showed that P-gp without the glycan is stuck in subcellular compartments (Draheim et al., 2010).

Folding-incompetent proteins carrying N-glycans are extracted from futile folding cycles in the calnexin chaperone system upon intervention of EDEM1, EDEM2 and EDEM3, three ER-stress-induced members of the glycosyl hydrolase 47 family.(Olivari and Molinari, 2007)

Uncertainties and Inconsistencies

?

What is causing the misfolding?

Quantitative Understanding of the Linkage

?


Response-response Relationship

?

Time-scale

?

Known modulating factors

?

Known Feedforward/Feedback loops influencing this KER

?

Domain of Applicability

?


References

?


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.