Incorporation of a non-human glycan mediates human susceptibility to a bacterial toxin.
Incorporation of a non-human glycan mediates human susceptibility to a bacterial toxin.
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DOI：
10.1038/nature07428
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发表时间：
2008-12-04
期刊：
影响因子：
64.8
通讯作者：
Beddoe, Travis
中科院分区：
文献类型：
--
作者：
Byres, Emma;Paton, Adrienne W.;Paton, James C.;Lofling, 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
AB5毒素包含一个破坏真核细胞基本功能的A亚基，以及在结合表面聚糖后引导靶细胞摄取的五聚体B亚基。枯草杆菌蛋白酶细胞毒素（SubAB）是一种由产志贺毒素大肠杆菌（STEC）分泌的AB5毒素，它会导致人类严重的胃肠道疾病。SubAB通过SubA介导的BiP/GRP78（一种内质网必需的伴侣蛋白）的切割，在小鼠中引起溶血性尿毒综合征样的病理变化。在此我们表明，SubB对以唾液酸N - 羟乙酰神经氨酸（Neu5Gc）为末端的聚糖有强烈的偏好，Neu5Gc是一种人体无法合成的单糖。SubB - Neu5Gc复合物的结构揭示了这种特异性的基础，对关键SubB残基的诱变消除了体外聚糖识别、细胞结合和细胞毒性。通过使用具有类似人类Neu5Gc缺乏情况的小鼠组织以及喂食Neu5Gc的人类细胞系，证实了SubAB对Neu5Gc的特异性。尽管人类缺乏Neu5Gc的生物合成，但饮食中Neu5Gc的吸收会在人类肠道上皮和肾血管上产生高亲和力受体。这一点，再加上人体缺乏含Neu5Gc的体液竞争物，使得人体对SubAB的胃肠道和全身性毒性易感。具有讽刺意味的是，富含Neu5Gc的食物是STEC污染的最常见来源。因此，一种细菌毒素的受体是通过代谢摄入来自食物的外源性因子而产生的。
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), which causes serious gastrointestinal disease in humans. SubAB causes haemolytic uraemic syndrome-like pathology in mice via SubA-mediated cleavage of BiP/GRP78, an essential endoplasmic reticulum chaperone. Here we show that SubB has a strong preference for glycans terminating in the sialic acid N-glycolylneuraminic acid (Neu5Gc), a monosaccharide not synthesised 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 human lack of Neu5Gc biosynthesis, assimilation of dietary Neu5Gc creates high-affinity receptors on human gut epithelia and kidney vasculature. This, together with the human lack of Neu5Gc-containing body fluid competitors, 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.
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DOI：
10.1073/pnas.2131556100
发表时间：
2003-10-14
影响因子：
11.1
作者：
Tangvoranuntakul, P;Gagneux, P;Muchmore, E
通讯作者：
Muchmore, E
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
2.8
作者：
Gagneux, P;Amess, B;Varki, A
通讯作者：
Varki, A
影响因子：
2.9
作者：
Ling, H;Boodhoo, A;Read, RJ
通讯作者：
Read, RJ
影响因子：
3.6
作者：
MERRITT, EA;SIXMA, TK;HOL, WGJ
通讯作者：
HOL, WGJ