Section of Cell and Developmental Biology, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0349, USA.
Nature. 2010 Oct 14;467(7317):854-8. doi: 10.1038/nature09446.
Bacillus anthracis is the causative agent of anthrax in humans and other mammals. In lethal systemic anthrax, proliferating bacilli secrete large quantities of the toxins lethal factor (LF) and oedema factor (EF), leading to widespread vascular leakage and shock. Whereas host targets of LF (mitogen-activated protein-kinase kinases) and EF (cAMP-dependent processes) have been implicated in the initial phase of anthrax, less is understood about toxin action during the final stage of infection. Here we use Drosophila melanogaster to identify the Rab11/Sec15 exocyst, which acts at the last step of endocytic recycling, as a novel target of both EF and LF. EF reduces levels of apically localized Rab11 and indirectly blocks vesicle formation by its binding partner and effector Sec15 (Sec15-GFP), whereas LF acts more directly to reduce Sec15-GFP vesicles. Convergent effects of EF and LF on Rab11/Sec15 inhibit expression of and signalling by the Notch ligand Delta and reduce DE-cadherin levels at adherens junctions. In human endothelial cells, the two toxins act in a conserved fashion to block formation of Sec15 vesicles, inhibit Notch signalling, and reduce cadherin expression at adherens junctions. This coordinated disruption of the Rab11/Sec15 exocyst by anthrax toxins may contribute to toxin-dependent barrier disruption and vascular dysfunction during B. anthracis infection.
炭疽芽孢杆菌是人类和其他哺乳动物炭疽病的病原体。在致命性全身炭疽病中，增殖的芽孢杆菌会大量分泌致死因子（LF）和水肿因子（EF）两种毒素，导致广泛的血管渗漏和休克。尽管 LF（丝裂原活化蛋白激酶激酶）和 EF（cAMP 依赖性过程）的宿主靶标已被牵连到炭疽病的初始阶段，但对于毒素在感染的最后阶段的作用知之甚少。在这里，我们使用黑腹果蝇来鉴定 Rab11/Sec15 外核蛋白复合物，它在胞内体再循环的最后一步起作用，是 EF 和 LF 的一个新靶点。EF 通过其结合伴侣和效应物 Sec15（Sec15-GFP）降低顶端定位的 Rab11 水平，并间接阻断囊泡形成，而 LF 则更直接地降低 Sec15-GFP 囊泡。EF 和 LF 对 Rab11/Sec15 的趋同作用抑制了 Notch 配体 Delta 的表达和信号转导，并降低了黏着连接处的 DE-钙黏蛋白水平。在人内皮细胞中，这两种毒素以保守的方式作用，阻断 Sec15 囊泡的形成，抑制 Notch 信号转导，并降低黏着连接处的钙黏蛋白表达。炭疽毒素对 Rab11/Sec15 外核蛋白复合物的这种协调破坏可能有助于毒素依赖性屏障破坏和 B. anthracis 感染期间的血管功能障碍。
