A vital sugar code for ricin toxicity

Jasmin Taubenschmid,Johannes Zuber,Markus Jost,Andreas Leibbrandt,Christian Koerner,Kirsten Sandvig,Johannes Stadlmann,Thorsten Marquardt,Josef M Penninger,Cory D Rillahan,Julian Jude,James C Paulson,Christian Thiel,Tove Irene Klokk,Karl Mechtler,Ulrich Elling

doi:10.1038/cr.2017.116

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.

Highlights

Ricin is a naturally occurring plant toxin produced in the seeds of Ricinus communis, the castor oil plant [1]
The toxin consists of two polypeptide chains, ricin toxin A chain (RTA) and ricin toxin B chain (RTB)
Mediated by RTB with lectin properties, ricin binds to certain carbohydrate residues on the cell surface, and is internalized via retrograde transport into the Golgi and the ER

Summary

Introduction

Ricin is a naturally occurring plant toxin produced in the seeds of Ricinus communis, the castor oil plant [1]. For the first time, a detailed study of the role of the GDP-fucose transporter Slc35c1 and the α1,3-fucosyltransferase Fut9 in ricin toxicity, in diverse cellular backgrounds and human patient cells. Loss of Fut9 and Slc35c1 increases ricin resistance in different cell types

Results

Conclusion