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Identification of Rab11 as a target of edema factor and dominant-negative mutants of anthrax lethal factor


Anthrax is a fatal disease caused by the spore-formulating bacterium, Bacillus anthracis. The potential for anthrax as a bioterrorist weapon raises concern, and is still common in the developing world. Antibiotic treatment of anthrax is often not effective, because toxins released in the host bloodstream can cause death even after clearance of the bacterium. Thus, it is important to further develop our knowledge of how anthrax causes its deadly effects as well as develop treatments targeting the toxins themselves. The anthrax toxin edema factor (EF) is a calmodulin-dependent adenylate cyclase and lethal factor (LF) is a zinc metalloprotease, which cleaves and inactivates MAPKKs. Like many other bacterial toxins, their activity targets conserved cellular components, making it possible to study their activity using an invertebrate model such as Drosophila. Using UAS-EF and UAS-LF transgenic lines, an extensive interaction screen with candidate UAS lines was used to identify novel targets for toxin activity. EF and LF showed synergistic interaction with Rab11 GTPase, a recycling endosome regulator, and its exocyst binding partner Sec15. Also, loss of other exocyst components Sec5, Sec15, and Exo70 enhanced the severity of the LF phenotype. Two other candidates, CG5745 and CG17282, disrupt the exocyst through their action on Sec15 and possibly Rab11. Increased knowledge of toxin activity in the long run may prove to be useful in rational drug design. Furthermore, as a more direct approach to treatment development, I conducted a genetic screen, which generated two dominant negative mutants of lethal factor

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