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A vital sugar code for ricin toxicity

A vital sugar code for ricin toxicity

Authors :
Julian Jude
Johannes Stadlmann
Andreas Leibbrandt
Ulrich Elling
Tove Irene Klokk
Karl Mechtler
Kirsten Sandvig
Josef M. Penninger
Christian Koerner
Johannes Zuber
James C. Paulson
Cory D. Rillahan
Jasmin Taubenschmid
Christian Thiel
Thorsten Marquardt
Markus Jost
Source :
Cell Research
Publication Year :
2017
Publisher :
Springer Science and Business Media LLC, 2017.

Abstract

Ricin is one of the most feared bioweapons in the world due to its extreme toxicity and easy access. Since no antidote exists, it is of paramount importance to identify the pathways underlying ricin toxicity. Here, we demonstrate that the Golgi GDP-fucose transporter Slc35c1 and fucosyltransferase Fut9 are key regulators of ricin toxicity. Genetic and pharmacological inhibition of fucosylation renders diverse cell types resistant to ricin via deregulated intracellular trafficking. Importantly, cells from a patient with SLC35C1 deficiency are also resistant to ricin. Mechanistically, we confirm that reduced fucosylation leads to increased sialylation of Lewis X structures and thus masking of ricin-binding sites. Inactivation of the sialyltransferase responsible for modifications of Lewis X (St3Gal4) increases the sensitivity of cells to ricin, whereas its overexpression renders cells more resistant to the toxin. Thus, we have provided unprecedented insights into an evolutionary conserved modular sugar code that can be manipulated to control ricin toxicity.

Details

ISSN :
17487838 and 10010602
Volume :
27
Database :
OpenAIRE
Journal :
Cell Research
Accession number :
edsair.doi.dedup.....76ed7ed4bf947ca70a06848daece062b
Full Text :
https://doi.org/10.1038/cr.2017.116