Muc5ac gastric mucin glycosylation is shaped by FUT2 activity and functionally impacts Helicobacter pylori binding.
Muc5ac gastric mucin glycosylation is shaped by FUT2 activity and functionally impacts Helicobacter pylori binding.
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DOI：
10.1038/srep25575
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发表时间：
2016-05-10
影响因子：
4.6
通讯作者：
Reis CA
中科院分区：
文献类型：
--
作者：
Magalhães A;Rossez Y;Robbe-Masselot C;Maes E;Gomes J;Shevtsova A;Bugaytsova J;Borén T;Reis CA
胃肠道由一层厚厚而复杂的粘液构成，保护粘膜上皮免受生化和机械侵袭。这种粘液屏障提供了对病原体的保护，但也是支持微生物黏附的保护性利基的结合部位。致癌细菌幽门螺杆菌通过与存在于上皮细胞和细胞外粘液的糖萼中的宿主多糖结合来定植于胃。分泌的MUC5AC粘蛋白是胃粘液层的主要成分，而BABA介导的幽门螺杆菌与MUC5AC的结合增加了临床疾病的风险。在这项研究中，我们从糖工程小鼠模型中解开了Muc5ac的O-糖基化图谱，该模型缺乏FUT2酶，因此模仿了非分泌型人类的表型。我们的结果表明，FUT2决定了Muc5ac的O-糖基化模式，Fut2基因敲除导致α1，2-岩藻糖基化结构显著减少，末端1型糖链结构Lewis-a表达增加。重要的是，我们首次从结构上验证了Lewis-a在小鼠胃粘膜中的表达。最后，我们证明了粘蛋白FUT2介导的岩藻糖基化的缺失损害了胃粘膜与幽门螺杆菌Baba粘附素的结合，这是公认的致病性特征。
The gastrointestinal tract is lined by a thick and complex layer of mucus that protects the mucosal epithelium from biochemical and mechanical aggressions. This mucus barrier confers protection against pathogens but also serves as a binding site that supports a sheltered niche of microbial adherence. The carcinogenic bacteria Helicobacter pylori colonize the stomach through binding to host glycans present in the glycocalyx of epithelial cells and extracellular mucus. The secreted MUC5AC mucin is the main component of the gastric mucus layer, and BabA-mediated binding of H. pylori to MUC5AC confers increased risk for overt disease. In this study we unraveled the O-glycosylation profile of Muc5ac from glycoengineered mice models lacking the FUT2 enzyme and therefore mimicking a non-secretor human phenotype. Our results demonstrated that the FUT2 determines the O-glycosylation pattern of Muc5ac, with Fut2 knock-out leading to a marked decrease in α1,2-fucosylated structures and increased expression of the terminal type 1 glycan structure Lewis-a. Importantly, for the first time, we structurally validated the expression of Lewis-a in murine gastric mucosa. Finally, we demonstrated that loss of mucin FUT2-mediated fucosylation impairs gastric mucosal binding of H. pylori BabA adhesin, which is a recognized feature of pathogenicity.