Receptors of anthrax toxin and cell entry

Abstract

Anthrax toxin-receptor interactions are critical for toxin delivery to the host cell cytoplasm. This review summarizes what is known about the molecular details of the protective antigen (PA) toxin subunit interaction with either the ANTXR1 and ANTXR2 cellular receptors, and how receptor-type can dictate the low pH threshold of PA pore formation. The roles played by cellular factors in regulating the endocytosis of toxin-receptor complexes is also discussed.

Figure 1

ANTXR2 determinants that dictate the low pH threshold of PA-heptamer pore formation.

Figure 2. Schematic representation of anthrax toxin endocytosis and cytoplasmic delivery

PA83 binds to one of the anthrax toxin receptors and is processed to PA63 by members of the furin family. PA63 subsequently heptamerizes in to PA^7mer and concomitantly binds EF and LF. Processing and heptamerization of PA trigger a series of posttranslational modifications in the receptors tails that in turn trigger clathrin mediated endocytosis. In particular ubiquitination of the receptors is though to target the toxin receptor complex to intraluminal vesicles in early endosomes. At the acidic endosomal pH, PA^7mer inserts into the membrane of intraluminal vesicles lead to the translocation of EF and LF into the luminal of these vesicles. Carrier intermediates are subsequently form, transported to late endosomes, where back fusion of intraluminal vesicles with the limiting membrane finally lead to release of the enzymatic subunits into the cytoplasm. There LF can process its targets such as MAP kinase kinases and EF can encounter calmodulin and become an active adenylate cyclase.