Cell invasion by Neisseria meningitidis requires a functional interplay between the focal adhesion kinase, Src and cortactin.
Cell invasion by Neisseria meningitidis requires a functional interplay between the focal adhesion kinase, Src and cortactin.
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DOI：
10.1371/journal.pone.0039613
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Schubert-Unkmeir A
中科院分区：
文献类型：
--
作者：
Slanina H;Hebling S;Hauck CR;Schubert-Unkmeir A
脑膜炎奈瑟菌（脑膜炎球菌）进入人脑微血管内皮细胞（HBMEC）是由纤连蛋白或玻连蛋白介导的，纤连蛋白或玻连蛋白与表面蛋白 Opc 结合，形成与相应整合素的桥梁。这种相互作用导致细胞骨架重排和脑膜炎球菌的摄取。在这项研究中，我们确定与整合素直接相关的粘着斑激酶 (FAK) 参与整合素介导的 HBMEC 脑膜炎奈瑟氏菌内化。特异性 FAK 抑制剂 PF 573882 对 FAK 活性的抑制使 Opc 介导的 HBMEC 侵袭减少了 90% 以上。此外，激酶活性受损或不能自磷酸化的 FAK 突变体的过表达或 FAK (FRNK) 显性失活版本的过表达会阻断整合素介导的脑膜炎奈瑟氏球菌的内化。重要的是，FAK 缺陷的成纤维细胞受到脑膜炎奈瑟氏球菌的侵袭明显减少。此外，脑膜炎奈瑟氏球菌诱导多种宿主蛋白的酪氨酸磷酸化，包括 FAK/Src 复合体底物皮质蛋白。通过 siRNA 沉默和 Cortactin 内关键氨基酸残基的突变（包括 Arp2/3 关联和动力结合）抑制 Cortactin 表达，显着减少脑膜炎球菌对真核细胞的侵袭，表明这两个结构域对于脑膜炎奈瑟氏球菌有效摄取真核细胞至关重要。总之，这些结果表明脑膜炎奈瑟氏菌利用整合素信号通路进入，并且 FAK 介导信号从激活的整合素到细胞骨架的转移。 FAK、Src 和 cortactin 之间的协同相互作用使得脑膜炎奈瑟氏菌能够内吞到宿主细胞中。
Entry of Neisseria meningitidis (the meningococcus) into human brain microvascular endothelial cells (HBMEC) is mediated by fibronectin or vitronectin bound to the surface protein Opc forming a bridge to the respective integrins. This interaction leads to cytoskeletal rearrangement and uptake of meningococci. In this study, we determined that the focal adhesion kinase (FAK), which directly associates with integrins, is involved in integrin-mediated internalization of N. meningitidis in HBMEC. Inhibition of FAK activity by the specific FAK inhibitor PF 573882 reduced Opc-mediated invasion of HBMEC more than 90%. Moreover, overexpression of FAK mutants that were either impaired in the kinase activity or were not capable of autophosphorylation or overexpression of the dominant-negative version of FAK (FRNK) blocked integrin-mediated internalization of N. meningitidis. Importantly, FAK-deficient fibroblasts were significantly less invaded by N. meningitidis. Furthermore, N. meningitidis induced tyrosine phosphorylation of several host proteins including the FAK/Src complex substrate cortactin. Inhibition of cortactin expression by siRNA silencing and mutation of critical amino acid residues within cortactin, that encompass Arp2/3 association and dynamin binding, significantly reduced meningococcal invasion into eukaryotic cells suggesting that both domains are critical for efficient uptake of N. meningitidis into eukaryotic cells. Together, these results indicate that N. meningitidis exploits the integrin signal pathway for its entry and that FAK mediates the transfer of signals from activated integrins to the cytoskeleton. A cooperative interplay between FAK, Src and cortactin then enables endocytosis of N. meningitidis into host cells.
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影响因子：
6.7
作者：
Sa E Cunha C;Griffiths NJ;Virji M
通讯作者：
Virji M
DOI：
10.1038/nrmicro1952
发表时间：
2008-08
期刊：
Nature reviews. Microbiology
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1083/jcb.200106148
发表时间：
2001-10-01
期刊：
The Journal of cell biology
影响因子：
--
作者：
Hoffmann I;Eugène E;Nassif X;Couraud PO;Bourdoulous S
通讯作者：
Bourdoulous S
纳达（Nada），奈瑟氏菌脑膜炎的新型疫苗候选者。
影响因子：
15.3
作者：
Comanducci, Maurizio;Bambini, Stefania;Brunelli, Brunella;Adu-Bobie, Jeannette;Arico, Beatrice;Capecchi, Barbara;Giuliani, Marzia Monica;Masignani, Vega;Santini, Laura;Savino, Silvana;Granoff, Dan M;Caugant, Dominique A;Pizza, Mariagrazia;Rappuoli, Rino;Mora, Marirosa
通讯作者：
Mora, Marirosa
影响因子：
168.9
作者：
MCGUINNESS, BT;CLARKE, IN;HECKELS, JE
通讯作者：
HECKELS, JE