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dc.contributor.authorByres, Emmaen_US
dc.contributor.authorW. Paton, Adrienneen_US
dc.contributor.authorPaton, James C.en_US
dc.contributor.authorC. Löfling, Jonasen_US
dc.contributor.authorF. Smith, Daviden_US
dc.contributor.authorC. J. Wilce, Matthewen_US
dc.contributor.authorM. Talbot, Ursulaen_US
dc.contributor.authorC. Chong, Damienen_US
dc.contributor.authorYu, Haien_US
dc.contributor.authorHuang, Shengshuen_US
dc.contributor.authorChen, Xien_US
dc.contributor.authorM. Varki, Nissien_US
dc.contributor.authorVarki, Ajiten_US
dc.contributor.authorRossjohn, Jamieen_US
dc.contributor.authorBeddoe, Travisen_US
dc.description.abstractAB5 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.en_US
dc.publisherNature Publishing Groupen_US
dc.publisher.placeUnited Kingdomen_US
dc.subject.fieldofresearchOrganic Chemical Synthesisen_US
dc.titleIncorporation of a non-human glycan mediates human susceptibility to a bacterial toxinen_US
dc.typeJournal articleen_US
dc.type.descriptionC1 - Peer Reviewed (HERDC)en_US
dc.type.codeC - Journal Articlesen_US
gro.hasfulltextNo Full Text

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