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Event: 1604

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Inhibition of N-linked glycosylation

Short name

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Biological Context

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Level of Biological Organization
Molecular

Cell term

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Organ term

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor). Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Overview

AOPs Including This Key Event

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AOP Name	Role of event in AOP	Point of Contact	Author Status	OECD Status
Inhibition of N-linked glycosylation leads to liver injury	MolecularInitiatingEvent	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 Do not cite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 KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help

Life Stages

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Sex Applicability

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

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

The ER, glycosylation is performed to newly synthesized unfolded proteins. Misfolded proteins recognized by ER- associated degradation (ERAD). (Stein, Ruggiano, Carvalho, & Rapoport, 2014)

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

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

Glycosylation inhibition can be achieved through direct inhibition of the biosynthesis or the processing of N-Linked oligosaccharide chains. Enzymes that synthesize N-linked oligosaccharide chain are targets for inhibition of glycosylation.

Tunicamycin inhibits N-Linked glycosylation by blocking the transfer of N-acetylglucosamine-1-phosphate (GlcNAc-1-P) from UDP-GlcNAc to dolichol-P. Amphomycin, a lipopeptide, inhibits dolichol-P-mannose synthesis by apparently forming complexes with the carrier lipid dolichol-P. (Mcdowell et al., 1988) Elbein et al 1987,Varki et al 2009)

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

Glycosylation mutants (Esko et al 2017)

Efficacy of inhibition of the oligosaccharide processing can be measured by TCA precipitation or endo H digestion analysis of radiolabeled cells. (Powell, 1995) (Kim et al., 2005)

Alteration in levels of protein glycosylation can be measured using a lectin microarray. (Liu et al., 2017)

Bioluminescent N-linked-glycosylation reporters (Contessa et al., 2012)

Domain of Applicability

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References

List of the literature that was cited for this KE 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.

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.

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.

Buckley, B. J. and Whorton, A. R. (1997) ‘Tunicamycin increases intracellular calcium levels in bovine aortic endothelial cells’, Am.J.Physiol, 273(0002–9513 (Print)), pp. C1298–C1305.

Contessa, J. N. et al. (2012) ‘Biosynthesis is a Novel Target for Cancer Therapy’, 16(12), pp. 3205–3214. doi: 10.1158/1078-0432.CCR-09-3331.Molecular.

Elbein, A.D., Pan, Y.T., Solf, R., and Vosbeck, K. (1983). Effect of swasinone, an inhibitor of glyciprotein processing, on cultured mammalian cells. J. Cell Physiol. 115:265-275.

Esko JD, Stanley P. Glycosylation Mutants of Cultured Mammalian Cells. 2017. In: Varki A, Cummings RD, Esko JD, et al., editors. Essentials of Glycobiology [Internet]. 3rd edition. Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press; 2015-2017. Chapter 49.

Esko JD, Bertozzi C, Schnaar RL. Chemical Tools for Inhibiting Glycosylation. 2017. In: Varki A, Cummings RD, Esko JD, et al., editors. Essentials of Glycobiology [Internet]. 3rd edition. Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press; 2015-2017. Chapter 55.

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.

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: 10.1099/mic.0.047712-0.

Lopez-Sambrooks, C. et al. (2016) ‘Oligosaccharyltransferase inhibition induces senescence in RTK-driven tumor cells’, Nature Chemical Biology, 12(12), pp. 1023–1030. doi: 10.1038/nchembio.2194.

Mcdowell, W. et al. (1988) ‘in influenza-virus-infected cells by x-D-mannopyranosylmethyl-’, 255, pp. 991–998.

Powell, L. (1995) ‘Inhibition of N-Linked Glycosylation’, Current Protocols in Immunology, 12(1995), pp. 1–12.

Salzberger, W. et al. (2015) ‘Influence of glycosylation inhibition on the binding of KIR3DL1 to HLA-B∗57:01’, PLoS ONE. doi: 10.1371/journal.pone.0145324.

Schwarz, F. and Aebi, M. (2011) ‘Mechanisms and principles of N-linked protein glycosylation’, Current Opinion in Structural Biology. Elsevier Ltd, 21(5), pp. 576–582. doi: 10.1016/j.sbi.2011.08.005.

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.

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.

Varki A, Cummings RD, Esko JD, et al., editors. Essentials of Glycobiology. 2nd edition. Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press; 2009. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1908/

Wojtowicz, K. et al. (2012) ‘Inhibitors of N-glycosylation as a potential tool for analysis of the mechanism of action and cellular localisation of glycoprotein P’, Acta Biochimica Polonica, 59(4), pp. 445–450.