Incorporation of a non-human glycan mediates human susceptibility to a bacterial toxin

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Title Incorporation of a non-human glycan mediates human susceptibility to a bacterial toxin
Author Byres, Emma; Paton, Adrienne W.; Paton, James C.; Löfling, Jonas C.; Smith, David F.; Wilce, Matthew C. J.; Talbot, Ursula M.; Chong, Damien C.; Yu, Hai; Huang, Shengshu; Chen, Xi; Varki, Nissi M.; Varki, Ajit; Rossjohn, Jamie; Beddoe, Travis
Journal Name Nature
Year Published 2008
Place of publication United Kingdom
Publisher Nature Publishing Group
Abstract AB5 toxins comprise an A subunit that corrupts essential eukaryotic cell functions, and pentameric B subunits that direct target-cell uptake after binding surface glycans. Subtilase cytotoxin (SubAB) is an AB5 toxin secreted by Shiga toxigenic Escherichia coli (STEC)1, which causes serious gastrointestinal disease in humans2. SubAB causes haemolytic uraemic syndrome-like pathology in mice3 through SubA-mediated cleavage of BiP/GRP78, an essential endoplasmic reticulum chaperone4. Here we show that SubB has a strong preference for glycans terminating in the sialic acid N-glycolylneuraminic acid (Neu5Gc), a monosaccharide not synthesized in humans. Structures of SubB-Neu5Gc complexes revealed the basis for this specificity, and mutagenesis of key SubB residues abrogated in vitro glycan recognition, cell binding and cytotoxicity. SubAB specificity for Neu5Gc was confirmed using mouse tissues with a human-like deficiency of Neu5Gc and human cell lines fed with Neu5Gc. Despite lack of Neu5Gc biosynthesis in humans, assimilation of dietary Neu5Gc creates high-affinity receptors on human gut epithelia and kidney vasculature. This, and the lack of Neu5Gc-containing body fluid competitors in humans, confers susceptibility to the gastrointestinal and systemic toxicities of SubAB. Ironically, foods rich in Neu5Gc are the most common source of STEC contamination. Thus a bacterial toxin's receptor is generated by metabolic incorporation of an exogenous factor derived from food.
Peer Reviewed Yes
Published Yes
Alternative URI http://dx.doi.org/10.1038/nature07428
Volume 456
Page from 648
Page to 652
ISSN 0028-0836
Date Accessioned 2011-03-16
Date Available 2011-05-03T04:48:46Z
Language en_AU
Faculty Faculty of Science, Environment, Engineering and Technology
Subject Organic Chemical Synthesis
URI http://hdl.handle.net/10072/38588
Publication Type Journal Articles (Refereed Article)
Publication Type Code c1x

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