Helicobacter pylori adhesin HopQ engages in a virulence-enhancing interaction with human CEACAMs
Helicobacter pylori adhesin HopQ engages in a virulence-enhancing interaction with human CEACAMs
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DOI：
10.1038/nmicrobiol.2016.189
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发表时间：
2017-01-01
影响因子：
28.3
通讯作者：
Gerhard, Markus
中科院分区：
文献类型：
--
作者：
Javaheri, Anahita;Kruse, Tobias;Gerhard, Markus
幽门螺杆菌特异性地定植于人类胃上皮，并且是溃疡疾病和胃癌发展的主要致病因子。在这里，我们确定了癌胚抗原相关细胞粘附分子（CEACAM）家族的成员作为H。pylori的表达，并显示HopQ是特异性结合人CEACAM 1、CEACAM 3、CEACAM 5和CEACAM 6的表面暴露粘附素。HopQ-CEACAM结合是聚糖非依赖性的，靶向N结构域。H. pylori结合诱导CEACAM 1介导的信号传导，并且HopQ-CEACAM 1相互作用使毒力因子CagA易位到宿主细胞中并增强促炎介质如白细胞介素-8的释放。基于HopQ的晶体结构，我们发现在HopQ的胞外3+4螺旋束结构域中的β-发夹插入（HopQ-ID）对于CEACAM结合是重要的。衍生自该结构域的肽竞争性抑制HopQ介导的Cag毒力途径的激活，如遗传或抗体介导的HopQ功能的废除所示。总之，我们的数据表明HopQ-CEACAM 1相互作用是一个潜在的有前途的新的治疗靶点，以打击H。幽门相关疾病
Helicobacter pylori specifically colonizes the human gastric epithelium and is the major causative agent for ulcer disease and gastric cancer development. Here, we identify members of the carcinoembryonic antigen-related cell adhesion molecule (CEACAM) family as receptors of H. pylori and show that HopQ is the surface-exposed adhesin that specifically binds human CEACAM1, CEACAM3, CEACAM5 and CEACAM6. HopQ-CEACAM binding is glycan-independent and targeted to the N-domain. H. pylori binding induces CEACAM1-mediated signalling, and the HopQ-CEACAM1 interaction enables translocation of the virulence factor CagA into host cells and enhances the release of pro-inflammatory mediators such as interleukin-8. Based on the crystal structure of HopQ, we found that a beta-hairpin insertion (HopQ-ID) in HopQ's extracellular 3+4 helix bundle domain is important for CEACAM binding. A peptide derived from this domain competitively inhibits HopQ-mediated activation of the Cag virulence pathway, as genetic or antibody-mediated abrogation of the HopQ function shows. Together, our data suggest the HopQ-CEACAM1 interaction to be a potentially promising novel therapeutic target to combat H. pylori-associated diseases.