Identification of a domain in Yersinia virulence factor YadA that is crucial for extracellular matrix-specific cell adhesion and uptake
Identification of a domain in Yersinia virulence factor YadA that is crucial for extracellular matrix-specific cell adhesion and uptake
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DOI：
10.1073/pnas.0507749103
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发表时间：
2006-02-28
影响因子：
11.1
通讯作者：
Dersch, P
中科院分区：
文献类型：
--
作者：
Heise, T;Dersch, P
对于许多病原体，细胞粘附因子是关键的毒力决定因子。致病性耶尔森氏菌表达无菌毛粘附素YadA，其是一类同源三聚体外膜粘附素的原型，其通过结合细胞外基质组分介导对宿主细胞的粘附。在这项研究中，我们证明了不同的致病功能是由于高度同源的YadA蛋白。假结核耶尔森氏菌（YadA（pstb））和小肠结肠炎耶尔森氏菌（YadA（ent））的YadA在其细胞外基质底物结合的特异性方面表现出根本性差异，它们引起不同的细菌聚集行为，并且YadA（pstb）而不是YadA（ent）促进有效摄取到人类细胞中。这里提出的证据表明，YadA（ent）中不存在的YadA（pstb）的独特N-末端氨基酸序列通过介导与结合在α（5）β（1）整联蛋白受体上的纤连蛋白的紧密结合而充当"摄取结构域"，这对于启动进入过程至关重要。删除YadA（pstb）中的该基序产生了YadA（ent）蛋白的所有特征，即，该分子失去了对纤连蛋白的粘附性和侵袭性，但获得了对胶原和层粘连蛋白的粘附潜力。"摄取区"的丧失也减弱了宿主组织中的Y. pseudotuberculosis在小鼠的口腔感染期间，表明该基序在定义病原体-宿主细胞相互作用和发病机制中起着至关重要的作用。我们的结论是，即使是微小的变化，粘附因子可以引起相关病原体的毒力特性的重大差异。
For many pathogens, cell adhesion factors are critical virulence determinants. Enteropathogenic Yersinia species express the afimbrial adhesin YadA, the prototype of a class of homotrimeric outer membrane adhesins, which mediates adherence to host cells by binding to extracellular matrix components. In this study, we demonstrate that different pathogenic functions are attributable to highly homologous YadA proteins. YadA of Yersinia pseudotuberculosis (YadA(pstb)) and Yersinia enterocolitical (YadA(ent)) exhibit fundamental differences in their specificity of extracellular matrix substrate binding, they cause dissimilar bacterial aggregation behaviors, and YadA(pstb), but not YadA(ent), promotes efficient uptake into human cells. Evidence is presented here that a unique N-terminal amino acid sequence of YadA(pstb), which is absent in YadA(ent), acts as an "uptake domain" by mediating tight binding to fibronectin bound on alpha(5)beta(1) integrin receptors, which are crucial for initiating the entry process. Deleting this motif in YadA(pstb) generated all features of the YadA(ent) protein, i.e., the molecule lost its adhesiveness to fibronectin and its invasiveness, but gained adhesion potential to collagen and laminin. Loss of the "uptake region" also attenuated host tissue colonization by Y. pseudotuberculosis during oral infections of mice, demonstrating that this motif plays a crucial role in defining pathogen-host cell interaction and pathogenesis. We conclude that even small variations in adhesion factors can provoke major differences in the virulence properties of related pathogens.