Anthrax toxins cooperatively inhibit endocytic recycling by the Rab11/Sec15 exocyst

Bacillus anthracis is the causative agent of anthrax in humans and other mammals(1, 2). In lethal systemic anthrax, proliferating bacilli secrete large quantities of the toxins lethal factor (LF) and edema factor (EF), leading to widespread vascular leakage and shock. While host targets of LF (MAPKKs) and EF (cAMP-dependent processes)(3) have been implicated in the initial phase of anthrax(1, 2), less is understood about toxin action during the final stage of infection. Here, we use Drosophila 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), while LF acts more directly to reduce Sec15-GFP vesicles. Convergent effects of EF and LF on Rab11/Sec15 inhibit expression of and signaling by the Notch ligand Delta and reduce DE-cadherin levels at adherens junctions (AJ). In human endothelial cells, the two toxins act in a conserved fashion to block formation of Sec15 vesicles, inhibit Notch signaling, and reduce cadherin expression at AJ. This coordinated disruption of the Rab11/Sec-15 exocyst by anthrax toxins may contribute to toxin-dependent barrier disruption and vascular dysfunction during B. anthracis infection.