Cytoskeleton as an emerging target of anthrax toxins

Abstract

Bacillus anthracis, the agent of anthrax, has gained virulence through its exotoxins produced by vegetative bacilli and is composed of three components forming lethal toxin (LT) and edema toxin (ET). So far, little is known about the effects of these toxins on the eukaryotic cytoskeleton. Here, we provide an overview on the general effects of toxin upon the cytoskeleton architecture. Thus, we shall discuss how anthrax toxins interact with their receptors and may disrupt the interface between extracellular matrix and the cytoskeleton. We then analyze what toxin molecular effects on cytoskeleton have been described, before discussing how the cytoskeleton may help the pathogen to corrupt general cell processes such as phagocytosis or vascular integrity.

Keywords: actin; anthrax toxins; cytoskeleton; phagocytosis; vascular integrity.

Figure 1

Interactions between anthrax toxin receptors and cytoskeleton. This figure highlights the links between cytoskeleton, anthrax toxin receptor (ANTXR) and the extracellular matrix. The physiological roles of ANTXR are not well known so far, unless they interact with extracellular matrix fibers. Their intracellular tail interacts with actin, and there is an inverse correlation between the binding of TEM8 to actin and the amount of protective antigen (PA) bound to receptors. After PA-ANTXR interaction, at least several signals can be sent to trigger PA endocytosis: (i) PA-ANTXR interactions trigger src-like kinase which in turn phosphorylates CMG-2 and TEM-8 intracellular tail favoring the toxin intracellular entry; (ii) a second target for anthrax receptor signaling may be ARAP3 (Arf GAP and Rho GAP with ankyrin repeat and pleckstrin homology domains); (iii) LRP6 coreceptor control Wnt signaling.

Figure 2

Effects of anthrax lethal and edema factors on cytoskeleton regulatory pathways.This hypothetical figure describes anthrax lethal factor (LF, red) and edema factor (EF, green) main targets along the regulatory pathways of cytoskeleton. On the one hand, LF probably activates Cdc42 and/or ROCK. ROCK activation could increase Myosin Light Chain (MLC) phosphorylation, leading to cell contractility. In parallel, LF-Mitogen-Activated Protein Kinase (MEK) cleavage blocks the Hsp27 phosphorylation cycle, impairing actin monomer transport to an area of new actin filament assembly. On the other hand, EF increases the cAMP level which signals via PKA and/or Epac/Rap1, potentially leading to the activation of Rac1 and inducing protrusions and retraction of the membrane. In parallel, EF could inhibit RhoA, leading to a reduction of F-actin via cofilin activation.