Cellular invasion by Staphylococcus aureus reveals a functional link between focal adhesion kinase and cortactin in integrin-mediated internalisation
Cellular invasion by Staphylococcus aureus reveals a functional link between focal adhesion kinase and cortactin in integrin-mediated internalisation
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DOI：
10.1242/jcs.02328
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发表时间：
2005-05-15
影响因子：
4
通讯作者：
Hauck, CR
中科院分区：
文献类型：
--
作者：
Agerer, F;Lux, S;Hauck, CR
金黄色葡萄球菌（Staphylococcus aureus）是一种定植于人类皮肤和粘膜表面的革兰氏阳性病原体，其引起的医院感染是日益严重的卫生保健问题。临床分离株几乎总是表达纤连蛋白结合蛋白，通过将细菌与宿主整合素α（5）β（1）间接连接，可以促进真核细胞对微生物的摄取。致病性纤连蛋白结合S.金黄色葡萄球菌，而不是由非致病性S.肉，引发募集的焦点接触相关蛋白纽蛋白，张力蛋白，zyxin和FAK的网站的细菌附着。此外，显性阴性形式的FAK阻断的整合素介导的内化和FAK缺陷细胞在其内化S.金黄色的病原体结合诱导与细菌附着位点相关的几种宿主蛋白质的酪氨酸磷酸化，包括FAK和Src底物corpine。在FAK缺陷的细胞中，局部招募的coronin仍然发生，而整合素和Src依赖的酪氨酸磷酸化coronin被废除。由于siRNA介导的coronin基因沉默或coronin关键氨基酸残基的突变干扰了S.金黄色葡萄球菌，我们的研究结果揭示了一种新的功能之间的连接，整合素的参与，FAK激活和Src介导的coronin磷酸化。FAK，Src和corneumn在整合素介导的细菌内化之间的合作也表明了整合素的参与如何与膜内吞作用耦合的分子情景。
Nosocomial infections by Staphylococcus aureus, a Gram-positive pathogen colonising human skin and mucosal surfaces, are an increasing health care problem. Clinical isolates almost invariably express fibronectin-binding proteins that, by indirectly linking the bacteria with host integrin alpha(5)beta(1), can promote uptake of the microorganisms by eukaryotic cells. Integrin engagement by pathogenic fibronectin-binding S. aureus, but not by non-pathogenic S. carnosus, triggered the recruitment of focal contact-associated proteins vinculin, tensin, zyxin and FAK to the sites of bacterial attachment. Moreover, dominant-negative versions of FAK-blocked integrin-mediated internalisation and FAK-deficient cells were severely impaired in their ability to internalise S. aureus. Pathogen binding induced tyrosine phosphorylation of several host proteins associated with bacterial attachment sites, including FAK and the Src substrate cortactin. In FAK-deficient cells, local recruitment of cortactin still occurred, whereas the integrin- and Src-dependent tyrosine phosphorylation of cortactin was abolished. As siRNA-mediated gene silencing of cortactin or mutation of critical amino acid residues within cortactin interfered with uptake of S. aureus, our results reveal a novel functional connection between integrin engagement, FAK activation and Src-mediated cortactin phosphorylation. Cooperation between FAK, Src and cortactin in integrin-mediated internalisation of bacteria also suggests a molecular scenario of how engagement of integrins could be coupled to membrane endocytosis.