Uptake and function of anthrax toxins

Uptake and function of anthrax toxins Bacillus anthracis bacteria target cells in an infected human through the action of three secreted bacterial proteins, lef (also known as LF, lethal factor), cya (also known as EF, edema factor), and pagA (also known as PA, protective antigen) (Turk 2007; Young and Collier 2007). lef is a protease that cleaves and inactivates many MAP2K (MAP kinase kinase, MEK) proteins (Duesbery et al. 1998; Vitale et al. 2000), disrupting MAP kinase signaling pathways. cya is an adenylate cyclase that mediates the constitutive production of cAMP (Leppla 1982), a molecule normally generated transiently in tightly regulated amounts in response to extracellular signals. Both lef and cya depend on pagA to enter their target cells, a strategy characteristic of bacterial binary toxins (Barth et al. 2004). pagA binds to the target cell receptors, is cleaved by furin or other cellular proteases, and thereupon forms an oligomer that exposes binding sites for lef and cya molecules (Young and Collier 2007). This complex is taken into the target cell by clathrin mediated endocytosis and delivered to endosomes. The low pH of the endosome causes the bacterial toxin complex to rearrange: the pagA oligomer forms a pore in the endosome membrane through which lef and cya molecules enter the target cell cytosol.