UC San Diego

Bacillus anthracis secretes a harmful exotoxin called anthrax toxin. Anthrax toxin has deleterious effects on several host cell types and is a significant contributor to anthrax pathogenesis. Toxin-deleted strains of B. anthracis are highly attenuated and many of the symptoms of anthrax can be replicated with anthrax toxin alone. Anthrax toxin is an AB-type toxin with two catalytic A moieties. PA, the B moiety, is responsible for receptor binding, pore formation and translocation of the catalytic moieties, EF and LF. PA binds one of two identified cellular receptors, ANTXR1 or ANTXR2. Previously, it was thought that pore formation and toxin translocation were both low-pH dependent processes and that the requirements for toxin entry mediated by either receptor were the same. Here, I report that while toxin entry mediated by ANTXR2 does require low-pH, when bound to ANTXR1 toxin can form pores in host membranes and translocate under near-neutral pH conditions. Additionally, I report that LRP6, a putative anthrax toxin co-receptor, is not absolutely required for toxin entry into cells. Finally, using a targeted siRNA screen, I identify other cellular factors involved in anthrax toxin entry. Studies characterizing these factors provide evidence in favor of a role for the recycling pathway in anthrax toxin receptor cell surface expression