Botulinum hemagglutinin disrupts the intercellular epithelial barrier by directly binding E-cadherin
Botulinum hemagglutinin disrupts the intercellular epithelial barrier by directly binding E-cadherin
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DOI：
10.1083/jcb.200910119
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发表时间：
2010-05-17
影响因子：
7.8
通讯作者：
Fujinaga, Yukako
中科院分区：
文献类型：
--
作者：
Sugawara, Yo;Matsumura, Takuhiro;Fujinaga, Yukako
肉毒杆菌神经毒素由肉毒杆菌产生，通过与无毒成分结合形成大的蛋白质复合体。我们最近发现，血凝素(HA)是一种无毒成分，它可以破坏细胞间上皮屏障；然而，这种现象背后的机制尚不清楚。在本研究中，我们确定上皮钙粘蛋白(E-cadherin)是HA的靶分子。HA直接结合E-钙粘蛋白，破坏E-钙粘附素介导的细胞与细胞间的黏附。尽管HA能结合人、牛和小鼠的E-钙粘蛋白，但它不能结合大鼠或鸡的E-钙粘蛋白同源物。HA不与经典钙粘附素家族的其他成员如神经和血管内皮钙粘附素相互作用。大鼠E-钙粘蛋白的表达而不是小鼠的表达使Madin-Darby犬肾细胞免于HA诱导的紧密连接(TJ)中断。这些数据表明，肉毒杆菌HA直接与E-钙粘蛋白结合，并以物种特异性的方式破坏E-钙粘附素介导的细胞与细胞的黏附，HA-E-钙粘附素的相互作用是破坏TJ功能所必需的。
Botulinum neurotoxin is produced by Clostridium botulinum and forms large protein complexes through associations with nontoxic components. We recently found that hemagglutinin (HA), one of the nontoxic components, disrupts the intercellular epithelial barrier; however, the mechanism underlying this phenomenon is not known. In this study, we identified epithelial cadherin (E-cadherin) as a target molecule for HA. HA directly binds E-cadherin and disrupts E-cadherin-mediated cell to cell adhesion. Although HA binds human, bovine, and mouse E-cadherin, it does not bind rat or chicken E-cadherin homologues. HA does not interact with other members of the classical cadherin family such as neural and vascular endothelial cadherin. Expression of rat E-cadherin but not mouse rescues Madin-Darby canine kidney cells from HA-induced tight junction (TJ) disruptions. These data demonstrate that botulinum HA directly binds E-cadherin and disrupts E-cadherin-mediated cell to cell adhesion in a species-specific manner and that the HA-E-cadherin interaction is essential for the disruption of TJ function.