Anthrax lethal toxin disrupts the endothelial permeability barrier through blocking p38 signaling.
Anthrax lethal toxin disrupts the endothelial permeability barrier through blocking p38 signaling.
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炭疽致死毒素通过阻断 p38 信号传导破坏内皮细胞通透性屏障。
DOI：
10.1002/jcp.22859
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发表时间：
2012
影响因子：
5.6
通讯作者：
Kayyali,UsamahS
中科院分区：
文献类型：
--
作者：
Liu,Tiegang;Milia,Erica;Warburton,RodR;Hill,NicholasS;Gaestel,Matthias;Kayyali,UsamahS
接触炭疽会通过炭疽杆菌产生的毒素引起危及生命的疾病。致死因子（LF）是一种能特异性降解MAP激酶激酶（MKK）的蛋白酶，是一种引起严重血管渗漏和水肿的炭疽毒素成分。我们最近发现，p38 MAP激酶激活导致HSP 27磷酸化增强内皮通透性屏障。我们现在表明，治疗大鼠肺微血管内皮细胞与炭疽致死毒素（LeTx），这是由LF和保护性抗原，增加内皮屏障通透性和间隙形成内皮细胞之间通过破坏p38信号。LeTx处理增加MKK 3b降解，并进而降低基线时以及p38信号传导激活后的p38活性。因此，LeTx处理降低了p38底物激酶MK2的活化和后者底物HSP 27的磷酸化。LeTx治疗破坏了其他信号传导途径，导致Erk介导的信号传导受到抑制，但这些作用与LeTx诱导的屏障受损无关。过度表达磷酸模拟（pm）HSP 27，其保护内皮通透性屏障免受LeTx的影响，阻断P38和MK2的LeTx失活，但它不阻断MKK 3b降解或Erk失活。我们的研究结果表明，LeTx可能通过灭活p38-MK2-HSP 27信号传导导致血管渗漏，激活HSP 27磷酸化特异性恢复p38信号传导并阻断炭疽LeTx毒性。pmHSP 27过表达可以恢复屏障完整性而不影响MKK 3b的降解或Erk的失活，这一事实表明p38-MK2-HSP 27在内皮屏障通透性调节中具有特异性和中心作用。J.细胞。227：1438-1445，2012。© 2011 Wiley Periodicals，Inc.
Exposure to anthrax causes life‐threatening disease through the action of the toxin produced by theBacillus anthracisbacteria. Lethal factor (LF), an anthrax toxin component which causes severe vascular leak and edema, is a protease which specifically degrades MAP kinase kinases (MKK). We have recently shown that p38 MAP kinase activation leading to HSP27 phosphorylation augments the endothelial permeability barrier. We now show that treatment of rat pulmonary microvascular endothelial cells with anthrax lethal toxin (LeTx), which is composed of LF and the protective antigen, increases endothelial barrier permeability and gap formation between endothelial cells through disrupting p38 signaling. LeTx treatment increases MKK3b degradation and in turn decreases p38 activity at baseline as well as after activation of p38 signaling. Consequently, LeTx treatment decreases activation of the p38 substrate kinase, MK2, and the phosphorylation of the latter's substrate, HSP27. LeTx treatment disrupts other signaling pathways leading to suppression of Erk‐mediated signaling, but these effects do not correlate with LeTx‐induced barrier compromise. Overexpressing phosphomimicking (pm)HSP27, which protects the endothelial permeability barrier against LeTx, blocks LeTx inactivation of p38 and MK2, but it does not block MKK3b degradation or Erk inactivation. Our results suggest that LeTx might cause vascular leak through inactivating p38‐MK2‐HSP27 signaling and that activating HSP27 phosphorylation specifically restores p38 signaling and blocks anthrax LeTx toxicity. The fact that barrier integrity could be restored by pmHSP27 overexpression without affecting degradation of MKK3b, or inactivation of Erk, suggests a specific and central role for p38‐MK2‐HSP27 in endothelial barrier permeability regulation. J. Cell. Physiol. 227: 1438–1445, 2012. © 2011 Wiley Periodicals, Inc.